These highlights do not include all the information needed to use KEYTRUDA safely and effectively. See full prescribing information for KEYTRUDA. <br/> <br/>KEYTRUDA<sup>® </sup>(pembrolizumab) injection, for intravenous use <br/>Initial U.S. Approval: 2014
KEYTRUDA pembrolizumab pembrolizumab pembrolizumab HISTIDINE SUCROSE POLYSORBATE 80 SODIUM HYDROXIDE HYDROCHLORIC ACID KEYTRUDA pembrolizumab pembrolizumab pembrolizumab HISTIDINE SUCROSE POLYSORBATE 80 WATER
Indications and Usage (1) 02/2026
Dosage and Administration (2) 02/2026
1 INDICATIONS AND USAGE KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated: Melanoma for the treatment of patients with unresectable or metastatic melanoma. (1.1) for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. (1.1) Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. (1.2) in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. (1.2) as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. (1.2, 2.1) as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-authorized test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. (1.2, 2.1) for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.2) as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. (1.2) Malignant Pleural Mesothelioma (MPM) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with unresectable advanced or metastatic MPM. (1.3) Head and Neck Squamous Cell Cancer (HNSCC) for the treatment of adult patients with resectable locally advanced HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent. (1.4) in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. (1.4) as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test. (1.4, 2.1) as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. (1.4) Classical Hodgkin Lymphoma (cHL) for the treatment of adult patients with relapsed or refractory cHL. (1.5) for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (1.5) Primary Mediastinal Large B-Cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. (1.6) Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. (1.7) as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.7) in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy. (1.7) as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. (1.7) Microsatellite Instability-High or Mismatch Repair Deficient Cancer for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. (1.8, 2.1) Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC) for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test. (1.9, 2.1) Gastric Cancer in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. (1.10) in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. (1.10) Esophageal Cancer for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy for patients whose tumors express PD-L1 (CPS ≥1), or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. (1.11, 2.1) Cervical Cancer in combination with chemoradiotherapy, for the treatment of patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA). (1.12) in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. (1.12, 2.1) as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. (1.12, 2.1) Hepatocellular Carcinoma (HCC) for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. (1.13) Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer. (1.14) Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. (1.15) Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. (1.16) in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. (1.16) for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (1.16) Endometrial Carcinoma in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. (1.17) in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.17, 2.1) as a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.17, 2.1) Tumor Mutational Burden-High (TMB-H) Cancer for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.1 (1.18, 2.1) Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. (1.19) Triple-Negative Breast Cancer (TNBC) for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.20) in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. (1.20, 2.1) Ovarian Cancer in combination with paclitaxel, with or without bevacizumab, for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, and who have received one or two prior systemic treatment regimens. (1.21, 2.1) 1 This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
1.1 Melanoma KEYTRUDA® is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection.
1.2 Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-authorized test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-authorized test [see Dosage and Administration (2.1)], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
1.3 Malignant Pleural Mesothelioma KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM).
1.4 Head and Neck Squamous Cell Cancer KEYTRUDA is indicated for the treatment of adult patients with resectable locally advanced HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test [see Dosage and Administration (2.1)], as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent. KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
1.5 Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
1.6 Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
1.7 Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
1.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options [see Dosage and Administration (2.1)].
1.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test [see Dosage and Administration (2.1)].
1.10 Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-authorized test [see Dosage and Administration (2.1)].
1.11 Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with tumors that express PD-L1 (CPS ≥ 1) [see Dosage and Administration (2.1)], or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-authorized test [see Dosage and Administration (2.1)].
1.12 Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA). KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test [see Dosage and Administration (2.1)].
1.13 Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen.
1.14 Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).
1.15 Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).
1.16 Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC. KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [see Clinical Studies (14.16)].
1.17 Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)].
1.18 Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-authorized test [see Dosage and Administration (2.1)], that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.18)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
1.19 Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
1.20 Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test [see Dosage and Administration (2.1)].
1.21 Ovarian Cancer KEYTRUDA, in combination with paclitaxel, with or without bevacizumab, is indicated for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test [see Dosage and Administration (2.1)], and who have received one or two prior systemic treatment regimens.
2 DOSAGE AND ADMINISTRATION Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) MPM: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) Urothelial Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) HCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) BTC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting, or in the advanced setting with either: axitinib 5 mg orally twice daily or lenvatinib 20 mg orally once daily. (2.2) Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks in combination with carboplatin and paclitaxel regardless of MMR or MSI status, or in combination with lenvatinib 20 mg orally once daily for pMMR or not MSI-H tumors, or as a single agent for MSI-H or dMMR tumors. (2.2) TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Ovarian cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Administer KEYTRUDA as an intravenous infusion over 30 minutes after dilution. (2.4) See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. (2.3, 2.4)
2.1 Patient Selection Information on FDA-authorized tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics . Patient Selection for Single-Agent Treatment Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in: Stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.2)]. metastatic NSCLC [see Clinical Studies (14.2)]. first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.4)]. previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.11)]. recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.12)]. For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.8, 14.9)]. For the TMB-H indication, select patients for treatment with KEYTRUDA as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.18)]. Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas. Additional Patient Selection Information for MSI-H or dMMR in Patients with non-CRC Solid Tumors Due to discordance between local tests and FDA-authorized tests, confirmation of MSI-H or dMMR status is recommended by an FDA-authorized test in patients with MSI-H or dMMR solid tumors, if feasible. If unable to perform confirmatory MSI-H/dMMR testing, the presence of TMB ≥10 mut/Mb, as determined by an FDA-authorized test, may be used to select patients for treatment [see Clinical Studies (14.8)]. Patient Selection for Combination Therapy For use of KEYTRUDA as a single agent as neoadjuvant treatment, then in combination with radiotherapy (RT) with or without chemotherapy then continued as a single agent as adjuvant treatment, select patients based on presence of positive PD-L1 expression (CPS ≥1) in resectable locally advanced HNSCC [see Clinical Studies (14.4)]. For use of KEYTRUDA in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, and esophageal or gastroesophageal junction (GEJ) carcinoma [see Clinical Studies (14.10), (14.11)]. An FDA-authorized test for the detection of PD-L1 for the selection of patients with PD-L1 (CPS ≥ 1) expression in esophageal carcinoma in combination with platinum- and fluoropyrimidine-based chemotherapy is not available. For use of KEYTRUDA in combination with chemotherapy, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.12)]. For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with KEYTRUDA in combination with lenvatinib based on MMR or MSI status in tumor specimens [see Clinical Studies (14.17)]. For use of KEYTRUDA in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC [see Clinical Studies (14.20)]. For use of KEYTRUDA in combination with paclitaxel, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma [see Clinical Studies (14.21)].
2.2 Recommended Dosage Administer KEYTRUDA as a 30-minute intravenous infusion. The recommended dosages of KEYTRUDA are presented in Table 1.
Table 1: Recommended Dosage
Indication Recommended Dosage of
KEYTRUDA 		Duration/Timing of Treatment
  Monotherapy
  Adult patients with unresectable or
  metastatic melanoma		 200 mg every 3 weeks
or
400 mg every 6 weeks 		  Until disease progression or
  unacceptable toxicity
  Adjuvant treatment of adult patients
  with melanoma, NSCLC, or RCC		 200 mg every 3 weeks
or
400 mg every 6 weeks 		  Until disease recurrence, unacceptable
  toxicity, or up to 12 months
  Adult patients with NSCLC, HNSCC,
  cHL, PMBCL, locally advanced or
  metastatic Urothelial Carcinoma, MSI-H
  or dMMR Cancer, MSI-H or dMMR
  CRC, MSI-H or dMMR Endometrial
  Carcinoma, Esophageal Cancer,
  Cervical Cancer, HCC, MCC, TMB-H
  Cancer, or cSCC		 200 mg every 3 weeks
or
400 mg every 6 weeks 		  Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with high-risk BCG-
  unresponsive NMIBC		 200 mg every 3 weeks
or
400 mg every 6 weeks 		  Until persistent or recurrent high-risk
  NMIBC, disease progression,
  unacceptable toxicity, or up to
  24 months
  Pediatric patients with cHL, PMBCL,
  MSI-H or dMMR Cancer, MCC, or TMB-
  H Cancer		 2 mg/kg every 3 weeks (up to a
maximum of 200 mg) 		  Until disease progression, unacceptable
  toxicity, or up to 24 months
  Pediatric patients (12 years and older)
  for adjuvant treatment of melanoma
 2 mg/kg every 3 weeks (up to a
maximum of 200 mg) 		  Until disease recurrence, unacceptable
  toxicity, or up to 12 months
  Combination Therapy Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.
  Adult patients with resectable NSCLC 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to chemotherapy when given on the same day.		   Neoadjuvant treatment in combination with
  chemotherapy for 12 weeks or until
  disease progression that precludes
  definitive surgery or unacceptable toxicity,
  followed by adjuvant treatment with
  KEYTRUDA as a single agent after
  surgery for 39 weeks or until disease
  recurrence or unacceptable toxicity
  Adult patients with NSCLC, MPM,
  HNSCC, HER2-negative Gastric
  Cancer, Esophageal Cancer, or BTC		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to
chemotherapy when given on
the same day.		   Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with locally advanced or
  metastatic urothelial cancer		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA after
enfortumab vedotin when given
on the same day.		   Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with MIBC 200 mg every 3 weeks
(neoadjuvant)

200mg every 3 weeks
or
400 mg every 6 weeks
(adjuvant)

Administer KEYTRUDA after
enfortumab vedotin when given
on the same day.		   Neoadjuvant:
Administer KEYTRUDA 200 mg every 3 weeks for 3 doses in combination with enfortumab vedotin or until disease progression that precludes curative-intent cystectomy or unacceptable toxicity.   Adjuvant:
Administer KEYTRUDA 200 mg every 3 weeks for 14 doses or 400 mg every 6 weeks for 7 doses in combination with enfortumab vedotin or until disease recurrence or unacceptable toxicity
  Adult patients with locally advanced
  HNSCC		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to
cisplatin when given on the
same day.		   Neoadjuvant:
Administer KEYTRUDA for 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity.   Adjuvant:
Administer KEYTRUDA in combination with RT with or without cisplatin. Continue KEYTRUDA as a single agent. Continue KEYTRUDA until disease recurrence or unacceptable toxicity or up to one year
  Adult patients with HER2-positive
  Gastric Cancer		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to
trastuzumab and chemotherapy
when given on the same day.		   Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with Cervical Cancer 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to
chemoradiotherapy or prior to
chemotherapy with or without
bevacizumab when given on the
same day.		   Until disease progression, unacceptable
  toxicity, or for KEYTRUDA, up to
  24 months
  Adult patients with RCC 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA in
combination with axitinib 5 mg
orally twice dailyWhen axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer.
or
Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily.		   Until disease progression, unacceptable
  toxicity, or for KEYTRUDA, up to
  24 months
  Adult patients with Endometrial
  Carcinoma		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to
carboplatin and paclitaxel when
given on the same day.
or
Administer KEYTRUDA in
combination with lenvatinib
20 mg orally once daily.		   Until disease progression, unacceptable
  toxicity, or for KEYTRUDA, up to
  24 months
  Adult patients with high-risk early-stage
  TNBC		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to chemotherapy when given on the same day.		   Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent for up to 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicityPatients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA.
  Adult patients with locally recurrent
  unresectable or metastatic TNBC		 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to
chemotherapy when given on
the same day.		   Until disease progression, unacceptable
  toxicity, or up to 24 months
  Adult patients with Ovarian Cancer 200 mg every 3 weeks
or
400 mg every 6 weeks
Administer KEYTRUDA prior to paclitaxel with or without bevacizumab when given on the same day.		   Until disease progression, unacceptable
  toxicity, or up to 24 months
2.3 Dose Modifications No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table 2.
Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction SeverityBased on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Pneumonitis Grade 2 WithholdResume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
Grade 3 or 4 Permanently discontinue
Colitis Grade 2 or 3 Withhold
Grade 4 Permanently discontinue


Hepatitis with no tumor involvement
of the liver		 AST or ALT increases to more than 3
and up to 8 times ULN
or
Total bilirubin increases to more than
1.5 and up to 3 times ULN		 Withhold
For liver enzyme elevations in
patients treated with combination
therapy with axitinib, see Table 3.		 AST or ALT increases to more than
8 times ULN
or
Total bilirubin increases to more than
3 times ULN		 Permanently discontinue
Hepatitis with tumor involvement of
the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement. 		Baseline AST or ALT is more than 1
and up to 3 times ULN and increases to
more than 5 and up to 10 times ULN
or
Baseline AST or ALT is more than 3
and up to 5 times ULN and increases to
more than 8 and up to 10 times ULN		 Withhold
ALT or AST increases to more than
10 times ULN
or
Total bilirubin increases to more than
3 times ULN		 Permanently discontinue
Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently
discontinue depending on severity
Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold
Grade 4 increased blood creatinine Permanently discontinue
Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold
Confirmed SJS, TEN, or DRESS Permanently discontinue
Myocarditis Grade 2, 3, or 4 Permanently discontinue
Neurological Toxicities Grade 2 Withhold
Grade 3 or 4 Permanently discontinue
Hematologic toxicity in patients with
cHL or PMBCL 		Grade 4 Withhold until resolution to Grades 0 or 1
Other Adverse Reactions
Infusion-related reactions
[see Warnings and Precautions (5.2)] 		Grade 1 or 2 Interrupt or slow the rate of infusion
Grade 3 or 4 Permanently discontinue
The following table represents dosage modifications that are different from those described above for KEYTRUDA or in the Full Prescribing Information for the drug administered in combination.
Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib
Treatment Adverse Reaction Severity Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal
KEYTRUDA in
combination with
axitinib		 Liver enzyme elevationsConsider corticosteroid therapy ALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both KEYTRUDA
and axitinib until resolution to
Grades 0 or 1Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.
ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN
or ALT or AST ≥10 times ULN		 Permanently discontinue both
KEYTRUDA and axitinib
Recommended Dose Modifications for Adverse Reactions for KEYTRUDA in Combination with Lenvatinib When administering KEYTRUDA in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information.
2.4 Preparation and Administration
<text> <paragraph> <content styleCode="underline">Preparation for Intravenous Infusion</content> </paragraph> <list listType="unordered" styleCode="Disc"> <item>Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.</item> <item>Dilute KEYTRUDA injection (solution) prior to intravenous administration.</item> <item>Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. <content styleCode="bold">Mix diluted solution by gentle inversion.</content> Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.</item> <item>Discard any unused portion left in the vial.</item> </list> </text> <effectiveTime value="20260210"/> </section> </component> <component> <section> <id root="bb10256a-bc0b-431c-bbc4-0bf45f8b79fc"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title/> <text> <paragraph> <content styleCode="underline">Storage of Diluted Solution</content> </paragraph> <paragraph>The product does not contain a preservative.</paragraph> <paragraph>Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:</paragraph> <list listType="unordered" styleCode="Disc"> <item>At room temperature (temperatures at or below 25°C) for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion.</item> <item>Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake.</item> </list> <paragraph>Discard after 6 hours at room temperature or after 96 hours under refrigeration.</paragraph> <paragraph>Do not freeze.</paragraph> </text> <effectiveTime value="20260210"/> </section> </component> <component> <section> <id root="e8b9d615-befc-44c5-a1f2-784eb47c8d82"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <text> <paragraph> <content styleCode="underline">Administration</content> </paragraph> <list listType="unordered" styleCode="Disc"> <item>Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.</item> <item>Do not co-administer other drugs through the same infusion line.</item> </list> </text> <effectiveTime value="20260210"/> </section> </component> </section> </component> </section> </component> <component> <section ID="S3"> <id root="cd47d872-cee1-4a68-95bd-20ae0f079338"/> <code code="43678-2" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE FORMS & STRENGTHS SECTION"/> <title>3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial (3)
4 CONTRAINDICATIONS None. None. (4)
5 WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions (5.1) Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue based on severity and type of reaction. Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue KEYTRUDA based on the severity of reaction. (5.2) Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3) Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception. (5.5, 8.1, 8.3)
5.1 Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients. In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received KEYTRUDA as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients. KEYTRUDA with Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.3)]. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both KEYTRUDA and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). No patients discontinued KEYTRUDA due to thyroiditis. KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (2) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy. Immune-Mediated Nephritis with Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica Endocrine: Hypoparathyroidism Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection
5.2 Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].
5.3 Complications of Allogeneic HSCT
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.
5.5 Embryo-Fetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)]. Infusion-related reactions [see Warnings and Precautions (5.2)]. Most common adverse reactions (reported in ≥20% of patients) were: KEYTRUDA as a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. (6.1) KEYTRUDA in combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain. (6.1) KEYTRUDA in combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, decreased appetite, pyrexia, epistaxis, decreased white blood cell count, and stomatitis. (6.1) KEYTRUDA in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. (6.1) KEYTRUDA in combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury. (6.1) KEYTRUDA in combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.
Melanoma
Ipilimumab-Naive Melanoma The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year. The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%). In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.
Table 4: SelectedAdverse reactions occurring at same or higher incidence than in the ipilimumab arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006
  Adverse Reaction KEYTRUDA
10 mg/kg every 2 or 3 weeks		 Ipilimumab
n=555 n=256
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
General
  Fatigue 28 0.9 28 3.1
Skin and Subcutaneous Tissue
  RashIncludes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. 24 0.2 23 1.2
  VitiligoIncludes skin hypopigmentation 13 0 2 0
Musculoskeletal and Connective Tissue
  Arthralgia 18 0.4 10 1.2
  Back pain 12 0.9 7 0.8
Respiratory, Thoracic and Mediastinal
  Cough 17 0 7 0.4
  Dyspnea 11 0.9 7 0.8
Metabolism and Nutrition
  Decreased appetite 16 0.5 14 0.8
Nervous System
  Headache 14 0.2 14 0.8
Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).
Table 5: SelectedLaboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205. KEYTRUDA
10 mg/kg every 2 or 3 weeks		 Ipilimumab
All GradesGraded per NCI CTCAE v4.0
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 45 4.2 45 3.8
  Hypertriglyceridemia 43 2.6 31 1.1
  Hyponatremia 28 4.6 26 7
  Increased AST 27 2.6 25 2.5
  Hypercholesterolemia 20 1.2 13 0
Hematology
  Anemia 35 3.8 33 4.0
  Lymphopenia 33 7 25 6
Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4).
Ipilimumab-Refractory Melanoma The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months. The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis. In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.
Table 6: SelectedAdverse reactions occurring at same or higher incidence than in chemotherapy arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002
  Adverse Reaction KEYTRUDA
2 mg/kg or 10 mg/kg every 3 weeks		 ChemotherapyChemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin
n=357 n=171
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Skin and Subcutaneous Tissue
  Pruritus 28 0 8 0
  RashIncludes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic 24 0.6 8 0
Gastrointestinal
  Constipation 22 0.3 20 2.3
  Diarrhea 20 0.8 20 2.3
  Abdominal pain 13 1.7 8 1.2
Respiratory, Thoracic and Mediastinal
  Cough 18 0 16 0
General
  Pyrexia 14 0.3 9 0.6
  Asthenia 10 2.0 9 1.8
Musculoskeletal and Connective Tissue
  Arthralgia 14 0.6 10 1.2
Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).
Table 7: SelectedLaboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123. KEYTRUDA
2 mg/kg or 10 mg/kg every 3 weeks		 Chemotherapy
All GradesGraded per NCI CTCAE v4.0
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 49 6 44 6
  Hypoalbuminemia 37 1.9 33 0.6
  Hyponatremia 37 7 24 3.8
  Hypertriglyceridemia 33 0 32 0.9
  Increased alkaline phosphatase 26 3.1 18 1.9
  Increased AST 24 2.2 16 0.6
  Decreased bicarbonate 22 0.4 13 0
  Hypocalcemia 21 0.3 18 1.9
  Increased ALT 21 1.8 16 0.6
Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).
Adjuvant Treatment of Resected Stage IIB or IIC Melanoma Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Adjuvant Treatment of Stage III Resected Melanoma The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes). Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.
Table 8: SelectedAdverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
n=509		 Placebo

n=502
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Gastrointestinal
  Diarrhea 28 1.2 26 1.2
  Nausea 17 0.2 15 0
Skin and Subcutaneous Tissue
  Pruritus 19 0 12 0
  Rash 13 0.2 9 0
Musculoskeletal and Connective Tissue
  Arthralgia 16 1.2 14 0
Endocrine
  Hypothyroidism 15 0 2.8 0
  Hyperthyroidism 10 0.2 1.2 0
Respiratory, Thoracic and Mediastinal
  Cough 14 0 11 0
General
  Asthenia 11 0.2 8 0
  Influenza like illness 11 0 8 0
Investigations
  Weight loss 11 0 8 0
Table 9: SelectedLaboratory abnormalities occurring at same or higher incidence than placebo. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 502 to 505 patients) and placebo (range: 491 to 497 patients). KEYTRUDA
200 mg every 3 weeks		 Placebo
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Increased ALT 25 2.4 15 0.2
  Increased AST 22 1.8 14 0.4
Hematology
  Lymphopenia 22 1 15 1.2
NSCLC
First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and investigator's choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189.
Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy
n=405		 Placebo

Pemetrexed
Platinum Chemotherapy
n=202
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Gastrointestinal
  Nausea 56 3.5 52 3.5
  Constipation 35 1.0 32 0.5
  Diarrhea 31 5 21 3.0
  Vomiting 24 3.7 23 3.0
General
  FatigueIncludes asthenia and fatigue 56 12 58 6
  Pyrexia 20 0.2 15 0
Metabolism and Nutrition
  Decreased appetite 28 1.5 30 0.5
Skin and Subcutaneous Tissue
  RashIncludes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 25 2.0 17 2.5
Respiratory, Thoracic and Mediastinal
  Cough 21 0 28 0
  Dyspnea 21 3.7 26 5
Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). KEYTRUDA
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy		 Placebo

Pemetrexed
Platinum Chemotherapy
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Hematology
  Anemia 85 17 81 18
  Lymphopenia 65 22 64 25
  Neutropenia 50 21 41 19
  Thrombocytopenia 30 12 29 8
Chemistry
  Hyperglycemia 63 9 60 7
  Increased ALT 47 3.8 42 2.6
  Increased AST 47 2.8 40 1.0
  Hypoalbuminemia 39 2.8 39 1.1
  Increased creatinine 37 4.2 25 1.0
  Hyponatremia 32 7 23 6
  Hypophosphatemia 30 10 28 14
  Increased alkaline phosphatase 26 1.8 29 2.1
  Hypocalcemia 24 2.8 17 0.5
  Hyperkalemia 24 2.8 19 3.1
  Hypokalemia 21 5 20 5
First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin. The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases. KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%). The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.
Previously Untreated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had treated brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042.
Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
n=636		 Chemotherapy

n=615
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-5
(%)		 All Grades
(%)		 Grades 3-5
(%)
General
  FatigueIncludes fatigue and asthenia 25 3.1 33 3.9
  Pyrexia 10 0.3 8 0
Metabolism and Nutrition
  Decreased appetite 17 1.7 21 1.5
Respiratory, Thoracic and Mediastinal
  Dyspnea 17 2.0 11 0.8
  Cough 16 0.2 11 0.3
Skin and Subcutaneous Tissue
  RashIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 15 1.3 8 0.2
Gastrointestinal
  Constipation 12 0 21 0.2
  Diarrhea 12 0.8 12 0.5
  Nausea 12 0.5 32 1.1
Endocrine
  Hypothyroidism 12 0.2 1.5 0
Infections
  Pneumonia 12 7 9 6
Investigations
  Weight loss 10 0.9 7 0.2
Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 585 to 598 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173. KEYTRUDA
200 mg every 3 weeks		 Chemotherapy
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 52 4.7 51 5
  Increased ALT 33 4.8 34 2.9
  Hypoalbuminemia 33 2.2 29 1.0
  Increased AST 31 3.6 32 1.7
  Hyponatremia 31 9 32 8
  Increased alkaline phosphatase 29 2.3 29 0.3
  Hypocalcemia 25 2.5 19 0.7
  Hyperkalemia 23 3.0 20 2.2
  Increased prothrombin INR 21 2.0 15 2.9
  Hypophosphatemia 20 4.7 17 4.3
Hematology
  Anemia 43 4.4 79 19
  Lymphopenia 30 7 42 13
Previously Treated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease. In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010.
Table 14: SelectedAdverse reactions occurring at same or higher incidence than in docetaxel arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010
  Adverse Reaction KEYTRUDA
2 or 10 mg/kg every 3 weeks
n=682		 Docetaxel
75 mg/m2 every 3 weeks
n=309
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Metabolism and Nutrition
  Decreased appetite 25 1.5 23 2.6
Respiratory, Thoracic and Mediastinal
  Dyspnea 23 3.7 20 2.6
  Cough 19 0.6 14 0
Gastrointestinal
  Nausea 20 1.3 18 0.6
  Constipation 15 0.6 12 0.6
  Vomiting 13 0.9 10 0.6
Skin and Subcutaneous Tissue
  RashIncludes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic 17 0.4 8 0
  Pruritus 11 0 3 0.3
Musculoskeletal and Connective Tissue
  Arthralgia 11 1.0 9 0.3
  Back pain 11 1.5 8 0.3
Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).
Table 15: SelectedLaboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 271 to 277 patients). KEYTRUDA
2 or 10 mg/kg every 3 weeks		 Docetaxel
75 mg/m2 every 3 weeks
All GradesGraded per NCI CTCAE v4.0
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyponatremia 32 8 27 2.9
  Increased alkaline phosphatase 28 3.0 16 0.7
  Increased AST 26 1.6 12 0.7
  Increased ALT 22 2.7 9 0.4
  Hypocalcemia 20 0.9 20 1.8
Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (32% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4). Neoadjuvant and Adjuvant Treatment of Resectable NSCLC The safety of KEYTRUDA in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.2)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino. Adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. Neoadjuvant Phase of KEYNOTE-671 A total of 396 patients received at least 1 dose of KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 34% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the 396 KEYTRUDA-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reactions that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). Of the 325 KEYTRUDA-treated patients who received surgery, 3.1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions. Of the 325 KEYTRUDA-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of KEYNOTE-671 A total of 290 patients in the KEYTRUDA arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent KEYTRUDA as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%). Adjuvant Treatment of Resected NSCLC The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.2)]. A total of 1161 patients received KEYTRUDA 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. The median duration of exposure to KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. Malignant Pleural Mesothelioma (MPM) First-line treatment of unresectable advanced or metastatic MPM with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and platinum chemotherapy (either carboplatin or cisplatin) was investigated in KEYNOTE-483, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with previously untreated, unresectable advanced or metastatic MPM [see Clinical Studies (14.3)]. A total of 473 patients received KEYTRUDA 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by KEYTRUDA (n=241), or pemetrexed and platinum chemotherapy every 3 weeks for up to 6 cycles (n=232). Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 6.9 months (range: 1 day to 25.2 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy.
HNSCC
Neoadjuvant and Adjuvant Treatment of Locally Advanced HNSCC The safety of KEYTRUDA as neoadjuvant and adjuvant treatment added to standard of care (SOC) therapy was evaluated in KEYNOTE-689, a multicenter, randomized (1:1), open-label, active-controlled trial in patients with resectable locally advanced (Stage III-IVA by AJCC 8th edition) head and neck squamous cell carcinoma (HNSCC) [see Clinical Studies (14.4)]. KEYTRUDA was administered as single-agent neoadjuvant therapy before definitive surgery, during adjuvant radiotherapy (RT) with or without concurrent cisplatin, and then as single agent adjuvant therapy. Concurrent cisplatin was added to KEYTRUDA and adjuvant RT for high-risk disease pathology. A total of 361 patients received treatment on the KEYTRUDA arm and 315 patients received treatment on the SOC therapy arm. The median duration of exposure to KEYTRUDA in the neoadjuvant phase was 3.1 weeks (range: 1 day to 4.9 weeks). The median duration of exposure to KEYTRUDA in the adjuvant phase was 42 weeks (range: 1 day to 82 weeks). The median age of patients who received KEYTRUDA was 60 years (range: 29 to 82), 32% age 65 or older, 6% age 75 or older; 79% male; 78% White, 14% Asian, 2.2% Black or African American, 2% Other races, 2.7% unknown race; and 15% Hispanic or Latino. The most common adverse reactions (≥ 20%) on the KEYTRUDA arm were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%). Table 16 and Table 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-689.
Table 16: Adverse Reactions in ≥20% of Patients with HNSCC Who Received KEYTRUDA in KEYNOTE-689
Adverse Reaction KEYTRUDA
Neoadjuvant then adjuvant
beginning with RT with or without
cisplatin
n=361		 Standard of Care
Adjuvant RT with or without
cisplatin
n=315
All GradesGraded per NCI CTCAE v4.03
(%)		 Grade 3or 4
(%)		 All Grades
(%)		 Grade 3 or 4
(%)
Gastrointestinal
  StomatitisIncludes pharyngeal inflammation, cheilitis, oral mucosal erythema, mucosal inflammation, glossitis, mouth ulceration, tongue ulceration 48 14 60 13
  Dysphagia 29 12 32 11
  Constipation 27 0.3 22 0.3
  Nausea 24 1.9 28 2.9
  Dry mouth 22 1.4 26 1.6
  DiarrheaIncludes colitis, enteritis, hemorrhagic diarrhea 22 4.2 11 0.6
Injury, poisoning and procedural complications
  Radiation skin injury 40 4.2 48 5.7
Investigations
  Weight loss 36 14 27 10
Endocrine disorders
  HypothyroidismIncludes blood thyroid stimulating hormone increased 26 0 6 0
General
  FatigueIncludes asthenia 33 2.2 27 1.6
Skin and subcutaneous tissue disorders
  RashIncludes dermatitis, skin exfoliation, dermatitis acneiform, eczema, rash macular, rash maculo-papular, erythema multiforme, dermatitis exfoliative, urticarial dermatitis, eczema asteatotic, exfoliative rash, rash pruritic, rash pustular 22 1.9 10 1.9
Musculoskeletal and connective tissue disorders
  Musculoskeletal pain Includes neck pain, arthralgia, pain in extremity, back pain, myalgia, bone pain, arthritis, non-cardiac chest pain, musculoskeletal chest pain, musculoskeletal stiffness, spinal pain 22 1.9 16 0.6
Table 17: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with HNSCC Who Received KEYTRUDA in KEYNOTE-689
 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + CRT/RT (range: 342 to 357 patients) and CRT/RT (range: 300 to 309 patients) KEYTRUDA
Neoadjuvant then adjuvant
beginning
with radiation with or without
cisplatin		 Radiation with or without
cisplatin
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Hematology
  Lymphopenia 76 50 86 55
  Anemia 75 12 74 12
  Neutropenia 32 13 35 19
  Thrombocytopenia 22 1.7 29 1.9
Chemistry
  Hyperglycemia 57 5.7 47 2.7
  Hyponatremia 47 16 36 11
  Increased ALT 42 6.2 37 2.0
  Hypoalbuminemia 40 1.4 38 1.0
  Increased AST 38 4.8 23 2.0
  Hypomagnesemia 34 1.2 22 1.3
  Hypokalemia 29 6.8 20 7.4
  Hyperkalemia 29 3.4 24 2.3
  Increased alkaline phosphatase 27 2.5 19 0.0
  Hypocalcemia 27 2.6 26 3.3
  Hypophosphatemia 23 6.1 15 7.0
  Increased creatinine 22 2.0 27 2.9
  Hypercalcemia 21 2.0 14 1.3
Neoadjuvant Phase of KEYNOTE 689 Of the 361 patients who received at least one dose of single agent KEYTRUDA as neoadjuvant treatment, 11% of patients experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). Fatal adverse reactions occurred in 1.1% of patients who received neoadjuvant KEYTRUDA including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 2.8% of patients who received KEYTRUDA as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant KEYTRUDA in more than one patient was arthralgia (0.6%). Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% (n=38) did not receive surgery. Surgical cancellation on the KEYTRUDA arm was due to disease progression in 4% (n=15), patient decision in 3% (n=10), adverse reactions in 1.4% (n=5), physician’s decision in 1.1% (n=4), unresectable tumor in 0.6% (n=2), loss of follow-up in 0.3% (n=1), and use of non-study anti-cancer therapy in 0.3% (n=1). Of the 351 patients randomized to SOC, 12% (n=43) did not receive surgery. Surgical cancellation on the SOC arm was due to patient decision in 7% (n=24), physician’s decision in 2.3% (n=8), disease progression in 1.7% (n=6), and adverse reactions in 1.4% (n=5). Of the 323 KEYTRUDA-treated patients who received surgery, 1.2% (n=4) experienced delay of surgery (defined as on-study surgery occurring ≥ 9 weeks after initiation of neoadjuvant KEYTRUDA) due to adverse reactions. Of the 307 patients randomized to SOC who received surgery on study, 0.3% (n=1) experienced delay of surgery (defined as surgery occurring ≥ 6 weeks after randomization) due to adverse reactions Among the KEYTRUDA-treated patients who received surgery, 2.8% (n=9) did not receive adjuvant treatment due to adverse reactions. Among the SOC-treated patients who received surgery, 3.6% (n=11) did not receive adjuvant RT or chemoradiation due to adverse reactions. Adjuvant Phase of KEYNOTE 689 A total of 275 patients in the KEYTRUDA arm and 275 patients in the SOC arm started the adjuvant phase of treatment. On the KEYTRUDA arm, 100 patients received KEYTRUDA and cisplatin with concurrent RT, 154 patients received KEYTRUDA alone with concurrent RT, 7 patients received cisplatin alone with concurrent RT, and 13 patients received RT alone. One patient received KEYTRUDA alone. On the SOC arm, 139 patients received cisplatin with concurrent RT while 136 patients received RT alone. For the KEYTRUDA arm, a total of 222 patients received single-agent KEYTRUDA following RT. Of the 255 patients who received at least one dose of KEYTRUDA in the adjuvant phase, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA-treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%). Fatal adverse reactions occurred in 5% including death not otherwise specified (1.2%), acute renal failure (0.4%), hypercalcemia (0.4%), pulmonary hemorrhage (0.4%), dysphagia/malnutrition (0.4%), mesenteric thrombosis (0.4%), sepsis (0.4%), pneumonia (0.4%), COVID-19 (0.4%), respiratory failure (0.4%), cardiovascular disorder (0.4%) and gastrointestinal hemorrhage (0.4%). Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were pneumonitis, colitis, immune-mediated hepatitis and death not otherwise specified. Of the 275 patients who received SOC in the adjuvant phase, 23% experienced serious adverse reactions. The most frequent serious adverse reactions reported in >1% of SOC-treated patients were pneumonia (3.6%) and acute kidney injury (3.3%). Fatal adverse reactions occurred in 4.7% including pneumonia (0.7%), septic shock (0.4%), death not otherwise specified (0.4%), sudden death (0.4%), myocardial infarction (0.4%), pancreatic neoplasm (0.4%) and other infections (2.9%). First-line treatment of metastatic or unresectable, recurrent HNSCC The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.4)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab. The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin. KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%). Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048.
Table 18: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048
  KEYTRUDA
200 mg every 3 weeks		 KEYTRUDA
200 mg every 3 weeks
Platinum
FU		 Cetuximab
Platinum
FU
Adverse Reaction n=300 n=276 n=287
  All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
General
  FatigueIncludes fatigue, asthenia 33 4 49 11 48 8
  Pyrexia 13 0.7 16 0.7 12 0
  Mucosal inflammation 4.3 1.3 31 10 28 5
Gastrointestinal
  Constipation 20 0.3 37 0 33 1.4
  Nausea 17 0 51 6 51 6
  DiarrheaIncludes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis 16 0.7 29 3.3 35 3.1
  Vomiting 11 0.3 32 3.6 28 2.8
  Dysphagia 8 2.3 12 2.9 10 2.1
  Stomatitis 3 0 26 8 28 3.5
Skin
  RashIncludes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis 20 2.3 17 0.7 70 8
  Pruritus 11 0 8 0 10 0.3
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 18 0.3 22 0 15 0
  DyspneaIncludes dyspnea, exertional dyspnea 14 2.0 10 1.8 8 1.0
Endocrine
  Hypothyroidism 18 0 15 0 6 0
Metabolism and Nutrition
  Decreased appetite 15 1.0 29 4.7 30 3.5
  Weight loss 15 2 16 2.9 21 1.4
Infections
  PneumoniaIncludes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal 12 7 19 11 13 6
Nervous System
  Headache 12 0.3 11 0.7 8 0.3
  Dizziness 5 0.3 10 0.4 13 0.3
  Peripheral sensory neuropathyIncludes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia 1 0 14 1.1 7 1
Musculoskeletal
  MyalgiaIncludes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia 12 1.0 13 0.4 11 0.3
  Neck pain 6 0.7 10 1.1 7 0.7
Psychiatric
  Insomnia 7 0.7 10 0 8 0
Table 19: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048
  KEYTRUDA
200 mg every 3 weeks		 KEYTRUDA
200 mg every 3 weeks
Platinum
FU		 Cetuximab
Platinum
FU
Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 240 to 267 patients), KEYTRUDA (range: 245 to 292 patients), cetuximab/chemotherapy (range: 249 to 282 patients). All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Hematology
  Lymphopenia 54 25 70 35 75 46
  Anemia 52 7 89 29 79 20
  Thrombocytopenia 12 3.8 73 18 76 18
  Neutropenia 8 1.4 68 37 73 43
Chemistry
  Hyperglycemia 47 3.8 54 6 65 4.7
  Hyponatremia 46 18 55 20 59 20
  Hypoalbuminemia 44 3.5 46 3.9 49 1.1
  Increased AST 28 3.1 25 1.9 37 3.6
  Increased ALT 25 2.1 22 1.5 38 1.8
  Increased alkaline phosphatase 25 2.1 26 1.1 33 1.1
  Hypercalcemia 22 4.5 16 4.2 13 2.5
  Hypocalcemia 22 1.0 32 3.8 58 6
  Hyperkalemia 21 2.8 28 4.2 29 4.6
  Hypophosphatemia 20 5 34 12 49 20
  Hypokalemia 19 5 33 12 47 15
  Increased creatinine 17 1.0 36 2.3 27 2.1
  Hypomagnesemia 15 0.4 40 1.7 76 9
Previously treated recurrent or metastatic HNSCC Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012. The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease. KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.1)].
Relapsed or Refractory cHL KEYNOTE-204 The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.5)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/µL, platelet count ≥75,000/µL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment. Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia. Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Table 20 summarizes adverse reactions in KEYNOTE-204.
Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204
      Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=148		 Brentuximab Vedotin
1.8 mg/kg every 3 weeks
N=152
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3- 4
(%)		 All Grades
(%)		 Grades 3- 4Adverse reactions in BV arm were Grade 3 only.
(%)
Infections
  Upper respiratory tract infectionIncludes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection 41 1.4 24 0
  Urinary tract infection 11 0 3 0.7
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity 32 0 29 1.3
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 22 2.7 17 1.3
  Nausea 14 0 24 0.7
  Vomiting 14 1.4 20 0
  Abdominal painIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper 11 0.7 13 1.3
General
  Pyrexia 20 0.7 13 0.7
  FatigueIncludes fatigue, asthenia 20 0 22 0.7
Skin and Subcutaneous Tissue
  RashIncludes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular‚ rash maculo-papular, rash papular, rash pruritic, toxic skin eruption 20 0 19 0.7
  Pruritus 18 0 12 0
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 20 0.7 14 0.7
  PneumonitisIncludes pneumonitis, interstitial lung disease 11 5 3 1.3
  DyspneaIncludes dyspnea, dyspnea exertional, wheezing 11 0.7 7 0.7
Endocrine
  Hypothyroidism 19 0 3 0
Nervous System
  Peripheral neuropathyIncludes dysesthesia, hypoesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy 11 0.7 43 7
  HeadacheIncludes headache, migraine, tension headache 11 0 11 0
Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare. Table 21 summarizes laboratory abnormalities in KEYNOTE-204.
Table 21: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204
  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148 patients) and BV (range: 145 to 152 patients); hypomagnesemia: KEYTRUDA n=52 and BV n=47. KEYTRUDA
200 mg every 3 weeks		 Brentuximab Vedotin
1.8 mg/kg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Chemistry
  Hyperglycemia 45 4.1 36 2.0
  Increased AST 38 4.7 38 2.0
  Increased ALT 31 5 43 2.6
  Hypophosphatemia 31 4.9 17 2.8
  Increased creatinine 26 3.4 13 2.6
  Hypomagnesemia 23 0 13 0
  Hyponatremia 24 4.1 20 3.3
  Hypocalcemia 21 2.0 15 0
  Increased alkaline phosphatase 19 2.1 21 2.0
  Hypoalbuminemia 16 0.7 18 0.7
  Hyperbilirubinemia 15 1.4 8 0.7
Hematology
  Lymphopenia 34 8 32 13
  Thrombocytopenia 32 9 24 4.0
  Neutropenia 27 8 42 16
  Anemia 22 4.1 32 7
KEYNOTE-087 Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.
Table 22: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=210
All GradesGraded per NCI CTCAE v4.0
(%)		 Grade 3
(%)
General
  FatigueIncludes fatigue, asthenia 26 1.0
  Pyrexia 24 1.0
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 24 0.5
  DyspneaIncludes dyspnea, dyspnea exertional, wheezing 11 1.0
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 21 1.0
  Arthralgia 10 0.5
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 20 1.4
  Vomiting 15 0
  Nausea 13 0
Skin and Subcutaneous Tissue
  Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrheic dermatitis, dermatitis psoriasiform 20 0.5
  Pruritus 11 0
Endocrine
  Hypothyroidism 14 0.5
Infections
  Upper respiratory tract infection 13 0
Nervous System
  Headache 11 0.5
  Peripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 10 0
Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).
Table 23: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087
  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients) KEYTRUDA
200 mg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)
Chemistry
  HypertransaminasemiaIncludes elevation of AST or ALT 35 2.4
  Increased alkaline phosphatase 17 0
  Increased creatinine 15 0.5
Hematology
  Anemia 30 6
  Thrombocytopenia 27 4.3
  Neutropenia 25 7
Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).
PMBCL Among the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.6)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.
Table 24: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=53
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain 30 0
Infections
  Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection 28 0
General
  Pyrexia 28 0
  FatigueIncludes fatigue, asthenia 23 2
Respiratory, Thoracic and Mediastinal
  CoughIncludes allergic cough, cough, productive cough 26 2
  Dyspnea 21 11
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis 13 2
  Abdominal pain Includes abdominal pain, abdominal pain upper 13 0
  Nausea 11 0
Cardiac
  Arrhythmia Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia 11 4
Nervous System
  Headache 11 0
Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).
Table 25: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170
  Laboratory AbnormalityEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 41 to 45 patients) KEYTRUDA
200 mg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)
Hematology
  Anemia 23 0
  Leukopenia 47 12
  Lymphopenia 27 10
  Neutropenia 39 15
Chemistry
  Hyperglycemia 33 2.2
  Hypophosphatemia 24 11
  HypertransaminasemiaIncludes elevation of AST or ALT 24 4.4
  Hypoglycemia 20 0
  Increased creatinine 16 0
Urothelial Cancer Patients with urothelial cancer in combination with enfortumab vedotin The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.7)]. A total of 440 patients received KEYTRUDA 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received KEYTRUDA and enfortumab vedotin, the median duration of exposure to KEYTRUDA was 8.5 months (range: 9 days to 28.5 months). Fatal adverse reactions occurred in 3.9% of patients treated with KEYTRUDA in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). Dose interruptions of KEYTRUDA occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%). Tables 26 and 27 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-A39.
Table 26: Adverse Reactions ≥20% (All Grades) in Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-A39
Adverse Reaction KEYTRUDA in combination with
Enfortumab Vedotin
n=440		 Chemotherapy

n=433
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Skin and subcutaneous tissue disorders
  RashIncludes multiple terms 68 15 15 0
  Pruritus 41 1.1 7 0
  Alopecia 35 0.5 8 0.2
General disorders and administration site conditions
  Fatigue 51 6 57 7
Nervous system disorders
  Peripheral neuropathy 67 8 14 0
  Dysgeusia 21 0 9 0
Metabolism and nutrition disorders
  Decreased appetite 33 1.8 26 1.8
Gastrointestinal disorders
  Diarrhea 38 4.5 16 1.4
  Nausea 26 1.6 41 2.8
  Constipation 26 0 34 0.7
Investigations
  Weight loss 33 3.6 9 0.2
Eye disorders
  Dry eye 24 0 2.1 0
Infections and infestations
  Urinary tract infection 21 5 19 8
Clinically relevant adverse reactions (<20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%).
Table 27: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-A39
Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 407 to 439 patients) KEYTRUDA
200 mg every 3 weeks and
Enfortumab Vedotin		 Chemotherapy
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Increased aspartate aminotransferase 75 4.6 39 3.3
  Increased creatinine 71 3.2 68 2.6
  Hyperglycemia 66 14 54 4.7
  Increased alanine aminotransferase 59 5 49 3.3
  Hyponatremia 46 13 47 13
  Hypophosphatemia 44 9 36 9
  Hypoalbuminemia 39 1.8 35 0.5
  Hypokalemia 26 5 16 3.1
  Hyperkalemia 24 1.4 36 4.0
  Hypercalcemia 21 1.2 14 0.2
Hematology
  Lymphopenia 58 15 59 17
  Anemia 53 7 89 33
  Neutropenia 30 9 80 50
Cisplatin-ineligible patients with urothelial cancer in combination with enfortumab vedotin The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer and who are not eligible for cisplatin-based chemotherapy [see Clinical Studies (14.7)]. A total of 121 patients received KEYTRUDA 200 mg on Day 1, and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle. The median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 29.6 months). Fatal adverse reactions occurred in 5% of patients treated with KEYTRUDA in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA and enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%). Permanent discontinuation of KEYTRUDA occurred in 32% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%). Dose interruptions of KEYTRUDA occurred in 69% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), lipase increased (5%), acute kidney injury (3.3%), ALT increased (2.5%), and COVID-19 (2.5%). Tables 28 and 29 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-869.
Table 28: Adverse Reactions Occurring in ≥20% of Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-869
Adverse Reaction KEYTRUDA in combination with Enfortumab
Vedotin
n=121
All GradesGraded per NCI CTCAE v4.03
%		 Grade 3-4
%
Skin and subcutaneous tissue disorders
  RashIncludes: blister, conjunctivitis, dermatitis, dermatitis bullous, dermatitis exfoliative generalized, erythema, erythema multiforme, exfoliative rash, palmar-plantar erythrodysesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, skin exfoliation, and stomatitis 71 21
  Alopecia 52 0
  Pruritus 40 3.3
  Dry skin 21 0.8
Nervous system disorders
  Peripheral neuropathyIncludes: dysesthesia, hypoesthesia, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and gait disturbance 65 3.3
  Dysgeusia 35 0
  Dizziness 23 0
General disorders and administration site conditions
  Fatigue 60 11
  Peripheral edema 26 0
Investigations
  Weight loss 48 5
Gastrointestinal disorders
  Diarrhea 45 7
  Nausea 36 0.8
  Constipation 27 0
Metabolism and nutrition disorders
  Decreased appetite 38 0.8
Infections and infestations
  Urinary tract infection 30 12
Eye disorders
  Dry eye 25 0
Musculoskeletal and connective tissue disorders
  Arthralgia 23 1.7
Clinically relevant adverse reactions (<20%) include vomiting (19.8%), fever (18%), hypothyroidism (11%), pneumonitis/ILD (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%).
Table 29: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-869
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 114 to 121 patients) KEYTRUDA
200 mg every 3 weeks and
Enfortumab Vedotin
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 74 13
  Increased aspartate aminotransferase 73 9
  Increased creatinine 69 3.3
  Hyponatremia 60 19
  Increased alanine aminotransferase 60 7
  Increased lipase 59 32
  Hypoalbuminemia 59 4.2
  Hypophosphatemia 51 15
  Hypokalemia 35 8
  Increased potassium 27 1.7
  Increased calcium 27 4.2
Hematology
  Anemia 69 15
  Lymphopenia 64 17
  Neutropenia 32 12
Platinum-Ineligible Patients with Urothelial Carcinoma The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.7)]. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent. Table 30 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.
Table 30: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-052
Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=370
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3–4
(%)
General
FatigueIncludes fatigue, asthenia 38 6
Pyrexia 11 0.5
Weight loss 10 0
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain 24 4.9
  Arthralgia 10 1.1
Metabolism and Nutrition
Decreased appetite 22 1.6
Hyponatremia 10 4.1
Gastrointestinal
  Constipation 21 1.1
  DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements 20 2.4
  Nausea 18 1.1
  Abdominal painIncludes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper 18 2.7
  Elevated LFTsIncludes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases, hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests 13 3.5
  Vomiting 12 0
Skin and Subcutaneous Tissue
  RashIncludes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized 21 0.5
  Pruritus 19 0.3
  Edema peripheralIncludes edema peripheral, peripheral swelling 14 1.1
Infections
  Urinary tract infection 19 9
Blood and Lymphatic System
  Anemia 17 7
Respiratory, Thoracic, and Mediastinal
  Cough 14 0
  Dyspnea 11 0.5
Renal and Urinary
Increased blood creatinine 11 1.1
Hematuria 13 3.0
Previously Treated Urothelial Carcinoma The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator's choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.7)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.
Table 31: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-045
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks		 ChemotherapyChemotherapy: paclitaxel, docetaxel, or vinflunine
n=266 n=255
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
General
  FatigueIncludes asthenia, fatigue, malaise, lethargy 38 4.5 56 11
  Pyrexia 14 0.8 13 1.2
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 32 3.0 27 2.0
Skin and Subcutaneous Tissue
  Pruritus 23 0 6 0.4
  RashIncludes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis 20 0.4 13 0.4
Gastrointestinal
  Nausea 21 1.1 29 1.6
  Constipation 19 1.1 32 3.1
  DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 18 2.3 19 1.6
  Vomiting 15 0.4 13 0.4
  Abdominal pain 13 1.1 13 2.7
Infections
  Urinary tract infection 15 4.9 14 4.3
Metabolism and Nutrition
  Decreased appetite 21 3.8 21 1.2
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough 15 0.4 9 0
  DyspneaIncludes dyspnea, dyspnea exertional, wheezing 14 1.9 12 1.2
Renal and Urinary
  Hematuria Includes blood urine present, hematuria, chromaturia 12 2.3 8 1.6
Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: KEYTRUDA n=232 and chemotherapy n=222. KEYTRUDA
200 mg every 3 weeks		 Chemotherapy
All GradesGraded per NCI CTCAE v4.0
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 52 8 60 7
  Anemia 52 13 68 18
  Lymphopenia 45 15 55 26
  Hypoalbuminemia 43 1.7 50 3.8
  Hyponatremia 37 9 47 13
  Increased alkaline phosphatase 37 7 33 4.9
  Increased creatinine 35 4.4 28 2.9
  Hypophosphatemia 29 8 34 14
  Increased AST 28 4.1 20 2.5
  Hyperkalemia 28 0.8 27 6
  Hypocalcemia 26 1.6 34 2.1
Neoadjuvant and Adjuvant Treatment of Cisplatin-Ineligible Patients with MIBC in Combination with Enfortumab Vedotin The safety of KEYTRUDA in combination with enfortumab vedotin as neoadjuvant treatment and continued after radical cystectomy (RC) as adjuvant treatment was investigated in KEYNOTE-905, an open-label, multicenter, randomized, active-controlled trial in patients with previously untreated MIBC who were ineligible for or declined cisplatin-based chemotherapy. Patients received KEYTRUDA in combination with enfortumab vedotin (n=167) before and after RC with pelvic lymph node dissection (PLND) or RC with PLND alone (n=159) [see Clinical Studies (14.7)]. For the 167 patients who received KEYTRUDA in the neoadjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 1.4 months (range: 1 day to 2.7 months) and the median number of cycles of KEYTRUDA was 3 (range: 1 to 3) out of the planned 3 cycles in the neoadjuvant phase. For the 96 patients who received KEYTRUDA in the adjuvant phase, the median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 8.5 months (range: 1 day to 12.9 months) and the median number of cycles of KEYTRUDA was 12 (range: 1 to 14) out of the planned 14 cycles in the adjuvant phase. Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of KEYTRUDA was 5 (range: 1 to 17) out of the planned 17 cycles. Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-905.
Table 33: Adverse Reactions ≥20% (All Grades) in Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-905
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks in combination with
enfortumab vedotin before and after RC with
PLND
n=167
RC with PLND alone
n=159
All Grades
%		 Grade 3-4
%		 All Grades
%		 Grade 3-4
%
Skin and subcutaneous tissue disorders
RashIncludes multiple terms. , Includes rash, rash maculo-papular, conjunctivitis, erythema, eczema, skin exfoliation, palmar-plantar erythrodysesthesia syndrome, blister, dermatitis, dermatitis exfoliative generalized, exfoliative rash, rash papular, rash pruritic, dermatitis bullous, drug eruption, pemphigoid, rash vesicular, and dermatitis contact. 54 7 1.3 0
Pruritus 47 3 0 0
Alopecia 35 0.6 0 0
General disorders and administration site conditions
Fatigue 47 4.2 6 0.6
Nervous system disorders
Peripheral neuropathy 39 3 1.9 0
Dysgeusia 35 0 0 0
Gastrointestinal disorders
Diarrhea 34 5 3.1 1.3
Constipation 28 1.8 8 0
Nausea 26 1.2 8 0.6
Metabolism and nutrition disorders
Decreased appetite 28 0.6 1.9 0
Infections and infestations
Urinary tract infection 24 12 13 11
Eye disorders
Dry eye 21 0 0 0
Investigations
Weight loss 20 0 3.1 0
Clinically relevant adverse reactions (<20%) include dry skin (15%), hypothyroidism (14%), vomiting (9%), pneumonitis/ILD (4.2%), skin hyperpigmentation (3.0%), infusion site extravasation (1.2%), and myasthenia gravis and myositis (0.6% each).
Table 34: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-905
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA in combination with enfortumab vedotin (167 patients), and RC and PLND alone (range: 110 to 121 patients). KEYTRUDA
200 mg every 3 weeks in
combination with enfortumab
vedotin before and after RC with
PLND
n=167		 RC with PLND alone
n=159
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Chemistry
  Increased glucose 72 12 24 1.7
  Increased AST 55 6 11 1.8
  Increased ALT 53 4.8 13 0.9
  Increased creatinine 47 8 31 2.5
  Decreased sodium 44 13 18 7
  Increased potassium 39 7 20 6
  Decreased phosphate 26 6 1.8 0
Hematology
  Decreased hemoglobin 60 13 48 8
  Decreased lymphocytes 40 8 17 1.7
Neoadjuvant Phase of KEYNOTE-905 A total of 167 patients received at least 1 dose of KEYTRUDA in combination with enfortumab vedotin as neoadjuvant treatment before receiving RC. In the neoadjuvant phase, serious adverse reactions occurred in 27% of patients receiving KEYTRUDA in combination with enfortumab vedotin. The most frequent (≥2%) serious adverse reactions were urinary tract infection (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.4%, including generalized exfoliative dermatitis), increased alanine aminotransferase, increased aspartate aminotransferase, diarrhea, dysgeusia, and toxic epidermal necrolysis (1.2% each). Adverse reactions leading to dose interruption of KEYTRUDA in the neoadjuvant phase occurred in 20% of patients. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (4.8%) and neutropenia (2.4%). Of the 167 patients in the KEYTRUDA in combination with enfortumab vedotin arm who received neoadjuvant treatment, 7 (4.2%) patients did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, urinary tract infection, and the two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each). Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin and underwent radical cystectomy, 6 (4.1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions. Adjuvant Phase of KEYNOTE-905 Patients who did not proceed to surgery were ineligible for adjuvant therapy. Of the 149 patients who underwent surgery, 100 patients received adjuvant treatment with KEYTRUDA in combination with enfortumab vedotin. Of the 49 patients who did not receive adjuvant treatment, discontinuation of treatment prior to the adjuvant phase was due to an adverse event in 21 patients. In the adjuvant phase, serious adverse reactions occurred in 43% of patients; the most frequent (≥2%) serious adverse reactions were urinary tract infection (8%), acute kidney injury and pyelonephritis (5% each), urosepsis (4%), and hypokalemia, intestinal obstruction, and sepsis (2% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 28% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were diarrhea (5%), and peripheral neuropathy, acute kidney injury, and pneumonitis (2% each). Adverse reactions leading to dose interruption of KEYTRUDA in the adjuvant phase occurred in 38% of patients. The most common adverse reactions (≥2%) leading to dose interruption of KEYTRUDA were rash (7%), urinary tract infection (6%), diarrhea (4%), and abdominal pain, COVID-19, fatigue, pruritus, and pyelonephritis (2% each).
BCG-unresponsive High-risk NMIBC The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.
Table 35: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-057
    Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=148
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3–4
(%)
General
  FatigueIncludes asthenia, fatigue, malaise 29 0.7
  Peripheral edemaIncludes edema peripheral, peripheral swelling 11 0
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis, colitis 24 2.0
  Nausea 13 0
  Constipation 12 0
Skin and Subcutaneous Tissue
  RashIncludes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis 24 0.7
  Pruritus 19 0.7
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain 19 0
  Arthralgia 14 1.4
Renal and Urinary
  Hematuria 19 1.4
Respiratory, Thoracic, and Mediastinal
  CoughIncludes cough, productive cough 19 0
Infections
  Urinary tract infection 12 2.0
  Nasopharyngitis 10 0
Endocrine
  Hypothyroidism 11 0
Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 124 to 147 patients) KEYTRUDA
200 mg every 3 weeks
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)
Chemistry
  Hyperglycemia 59 7
  Increased ALT 25 2.7
  Hyponatremia 24 7
  Hypophosphatemia 24 6
  Hypoalbuminemia 24 1.4
  Hyperkalemia 23 1.4
  Hypocalcemia 22 0.7
  Increased AST 20 2.7
  Increased creatinine 20 0.7
Hematology
  Anemia 35 1.4
  Lymphopenia 29 1.6
Microsatellite Instability-High or Mismatch Repair Deficient Cancer The safety of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.8)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer Among the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.9)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.
Gastric Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma The safety of KEYTRUDA was evaluated in 696 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 350 patients treated with KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=297) or FP (n=53) every 3 weeks, compared to 346 patients treated with placebo, trastuzumab, and CAPOX (n=298) or FP (n=48) every 3 weeks [see Clinical Studies (14.10)]. The median duration of exposure to KEYTRUDA was 9.2 months (range: 1 day to 33.6 months). Fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX or FP and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of patients. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 71% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (7%), pneumonia (5%), anemia (4.9%), COVID-19 (3.1%), hypokalemia (3.1%), fatigue/asthenia (4.9%), decreased appetite (4%), increased AST (3.7%), increased blood bilirubin (4.6%), increased ALT (2.9%), vomiting (2.6%), pneumonitis (2.3%), pyrexia (2.3%), increased blood creatinine (2%), and colitis (2%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs. 47%), rash (35% vs. 28%), hypothyroidism (11% vs. 5%), and pneumonia (11% vs. 5%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for decreased leukocytes (60% vs. 54%), decreased calcium (56% vs. 46%), decreased lymphocytes (59% vs. 51%), decreased potassium (41% vs. 36%), increased bilirubin (33% vs. 25%), increased creatinine (28% vs. 18%), and decreased glucose (17% vs. 11%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma The safety of KEYTRUDA was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with KEYTRUDA 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.10)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 33.7 months). Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). Permanent discontinuation of KEYTRUDA due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of KEYTRUDA in ≥1% were infections (1.8%) and diarrhea (1.0%). Dosage interruptions of KEYTRUDA due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%). Tables 37 and 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-859.
Table 37: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-859
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
and FP or CAPOX
n=785		 Placebo

and FP or CAPOX
n=787
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Nervous System
  Peripheral neuropathyIncludes dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy 47 5 48 6
Gastrointestinal
  Nausea 46 3.7 46 4.4
  Diarrhea 36 6 32 5
  Vomiting 34 5 27 5
  Abdominal PainIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal tenderness, abdominal pain upper, epigastric discomfort, gastrointestinal pain 26 2.8 24 2.9
  Constipation 22 0.5 21 0.8
General
  FatigueIncludes asthenia, fatigue 40 8 39 9
Metabolism and Nutrition
  Decreased appetite 29 3.3 29 2.5
Skin and Subcutaneous Tissue
  Palmar-plantar erythrodysesthesia syndrome 25 3.1 22 1.8
Investigations
  Weight loss 20 2.8 19 2.7
Table 38: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-859
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/FP or CAPOX (range: 210 to 766 patients) and placebo/FP or CAPOX (range: 190 to 762 patients) KEYTRUDA
200 mg every 3 weeks
and FP or CAPOX 		Placebo

and FP or CAPOX
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Hematology
  Anemia 65 15 69 13
  Thrombocytopenia 64 12 62 10
  Neutropenia 63 25 58 20
  Leukopenia 59 7 56 6
  Lymphopenia 57 20 51 16
Chemistry
  Increased AST 57 4.7 48 3.6
  Hypoalbuminemia 55 4.1 52 2.9
  Hyperglycemia 53 6 52 4.6
  Hypocalcemia 49 3.6 45 3.3
  Increased alkaline phosphatase 48 6 41 5
  Hyponatremia 40 13 40 12
  Increased ALT 40 4.2 29 2.9
  Hypokalemia 35 10 27 9
  Bilirubin increased 32 5 30 5
  Hypophosphatemia 30 10 27 8
  Hypomagnesemia 29 0.3 22 0.7
  Increased creatinine 21 3.5 18 1.7
  Hyperkalemia 20 3.7 18 2.9
  Increased INR 20 1.4 22 0
Esophageal Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.11)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU. The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%). Tables 39 and 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590.
Table 39: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-590
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
Cisplatin
FU
n=370		 Placebo

Cisplatin
FU
n=370
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4One fatal event of diarrhea was reported in each arm.
(%)		 All Grades
(%)		 Grades 3-4
(%)
Gastrointestinal
  Nausea 67 7 63 7
  Constipation 40 0 40 0
  Diarrhea 36 4.1 33 3
  Vomiting 34 7 32 5
  Stomatitis 27 6 26 3.8
General
  FatigueIncludes asthenia, fatigue 57 12 46 9
Metabolism and Nutrition
  Decreased appetite 44 4.1 38 5
Investigations
  Weight loss 24 3.0 24 5
Table 40: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving KEYTRUDA in KEYNOTE-590
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 353 to 365 patients) and placebo/cisplatin/FU (range: 347 to 359 patients) KEYTRUDA
200 mg every 3 weeks
Cisplatin
FU 		Chemotherapy
(Cisplatin and FU)
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Hematology
  Anemia 84 21 87 25
  Neutropenia 77 44 73 41
  Leukopenia 73 21 73 17
  Lymphopenia 57 23 53 18
  Thrombocytopenia 43 5 46 8
Chemistry
  Hyperglycemia 56 7 55 6
  Hyponatremia 53 19 53 19
  Hypoalbuminemia 53 2.8 52 2.3
  Increased creatinine 45 2.5 42 2.5
  Hypocalcemia 44 3.9 37 2
  Hypophosphatemia 37 9 31 10
  Hypokalemia 30 12 34 15
  Increased alkaline phosphatase 29 1.9 29 1.7
  Hyperkalemia 28 3.6 28 2.5
  Increased AST 25 4.4 22 2.8
  Increased ALT 23 3.6 18 1.7
Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.11)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.
Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy The safety of KEYTRUDA in combination with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18, a placebo-controlled, randomized (1:1), multicenter, double-blind trial including 597 patients with FIGO 2014 Stage III-IVA cervical cancer [see Clinical Studies (14.12)]. Two hundred ninety-four patients received KEYTRUDA in combination with chemoradiotherapy and 303 patients received placebo in combination with chemoradiotherapy. The median duration of exposure to KEYTRUDA was 20 months (range: 1 day to 32 months). Fatal adverse reactions occurred in 1.4% of patients receiving KEYTRUDA in combination with chemoradiotherapy, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 34% of patients receiving KEYTRUDA in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of patients included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 9% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 47% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were anemia (7%), COVID-19 (7%), SARS-CoV-2 test positive (4.8%), diarrhea (4.1%), increased ALT (4.1%), increased AST (3.4%) decreased neutrophil count (3.1%), and urinary tract infection (2.7%). Table 41 and Table 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-A18.
Table 41: Adverse Reactions Occurring in ≥10% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving KEYTRUDA in KEYNOTE-A18
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks and 400 mg
every 6 weeks
with chemoradiotherapy
n=294		 Placebo
with chemoradiotherapy


n=303
All GradesGraded per NCI CTCAE v5.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Gastrointestinal
    Nausea 56 0 62 2.3
    Diarrhea 51 4.4 50 4.3
    Vomiting 34 1.0 35 1.7
    Constipation 20 0 19 0.7
    Abdominal pain 13 1.0 14 1.7
Infections
    Urinary tract infectionIncludes urinary tract infection, urinary tract infection pseudomonal, pyelonephritis acute, cystitis, Escherichia urinary tract infection 35 4.8 34 5
    COVID-19 10 0 7 1.0
General
    FatigueIncludes fatigue, asthenia 28 1.0 28 1.3
    Pyrexia 14 0.7 15 0
Endocrine
    HypothyroidismIncludes hypothyroidism, autoimmune hypothyroidism 23 0.7 8 0
    Hyperthyroidism 13 0.3 3.3 0
Investigations
    Weight loss 19 2.4 19 1.0
Metabolism and Nutrition
    Decreased appetite 18 0.7 17 0.3
Renal and Urinary
    Dysuria 12 0.3 12 0
Skin and Subcutaneous Tissue Disorders
    RashIncludes erythema multiforme, dermatitis, drug eruption, eczema, rash, skin exfoliation, dermatitis bullous, rash maculo-papular, lichen planus, dyshidrotic eczema, dermatitis acneiform 12 1.0 8 0.3
Musculoskeletal and Connective Tissues Disorders
    Back pain 11 0.7 11 0.7
Reproductive System
    Pelvic pain 11 1.0 14 1.7
Table 42: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving KEYTRUDA in KEYNOTE-A18
  Laboratory TestLaboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA + chemoradiotherapy (range: 288 to 293 patients) and placebo + chemoradiotherapy (range: 299 to 301 patients) KEYTRUDA
200 mg every 3 weeks and
400 mg every 6 weeks
with chemoradiotherapy		 Placebo


with chemoradiotherapy
All GradesGraded per NCI CTCAE v5.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Hematology
    Lymphopenia 99 96 99 92
    Leukopenia 96 48 94 49
    Anemia 87 33 82 27
    Neutropenia 76 33 76 33
    Thrombocytopenia 64 9 62 7
Chemistry
    Hypomagnesemia 61 4.2 63 3.7
    Hyponatremia 56 4.8 50 4.7
    Increased AST 50 1.7 44 2.3
    Increased ALT 49 3.1 46 1
    Hypocalcemia 45 5 43 5
    Hypokalemia 44 15 41 11
    Increased creatinine 44 7 46 6
    Hypoalbuminemia 38 2.4 37 2.3
    Increased alkaline phosphatase 38 0.3 35 0.3
    Hyperkalemia 21 2.0 16 1
Persistent, Recurrent, or Metastatic Cervical Cancer The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.12)]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks. The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months). Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). Table 43 and Table 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826.
Table 43: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
and chemotherapyChemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab
n=307		 Placebo

and chemotherapy with or without bevacizumab
n=309
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Nervous System
    Peripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia 58 4.2 57 6
Skin and Subcutaneous Tissue
    Alopecia 56 0 58 0
    RashIncludes rash, rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular 22 3.6 15 0.3
General
    FatigueIncludes fatigue, asthenia 47 7 46 6
Gastrointestinal
    Nausea 40 2 44 1.6
    Diarrhea 36 2 30 2.6
    Constipation 28 0.3 33 1
    Vomiting 26 2.6 27 1.9
Musculoskeletal and Connective Tissue
    Arthralgia 27 0.7 26 1.3
Vascular
    Hypertension 24 9 23 11
Infections
    Urinary tract infection 24 9 26 8
Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA plus chemotherapy (range: 296 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients) KEYTRUDA
200 mg every 3 weeks
and chemotherapyChemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab
n=307		 Placebo

and chemotherapy with or without bevacizumab
n=309
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Hematology
    Anemia 80 35 77 33
    Leukopenia 76 27 69 19
    Neutropenia 73 43 62 32
    Lymphopenia 64 35 59 35
    Thrombocytopenia 57 19 53 15
Chemistry
    Hyperglycemia 51 4.7 46 2.3
    Hypoalbuminemia 46 1.4 37 5
    Hyponatremia 39 14 38 11
    Increased ALT 40 7 38 6
    Increased AST 40 6 36 3.0
    Increased alkaline phosphatase 38 3.4 40 2.3
    Hypocalcemia 37 4.1 31 5
    Increased creatinine 34 5 32 6
    Hypokalemia 29 7 26 7
    Hyperkalemia 23 3.7 27 4.7
    Hypercalcemia 21 1.0 20 1.3
Previously Treated Recurrent or Metastatic Cervical Cancer Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.12)], the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 45 and 46 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.
Table 45: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
N=98
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3–4
(%)
General
  FatigueIncludes asthenia, fatigue, lethargy, malaise 43 5
  PainIncludes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache 22 2.0
  Pyrexia 19 1.0
  Edema peripheralIncludes edema peripheral, peripheral swelling 15 2.0
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity 27 5
Gastrointestinal
  DiarrheaIncludes colitis, diarrhea, gastroenteritis 23 2.0
  Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper 22 3.1
  Nausea 19 0
  Vomiting 19 1.0
  Constipation 14 0
Metabolism and Nutrition
  Decreased appetite 21 0
Vascular
  HemorrhageIncludes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage 19 5
Infections
  UTIIncludes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis 18 6
  Infection (except UTI)Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis 16 4.1
Skin and Subcutaneous Tissue
  RashIncludes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular 17 2.0
Endocrine
  Hypothyroidism 11 0
Nervous System
  Headache 11 2.0
Respiratory, Thoracic and Mediastinal
  Dyspnea 10 1.0
Table 46: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 76 to 79 patients) KEYTRUDA
200 mg every 3 weeks
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)
Hematology
  Anemia 54 24
  Lymphopenia 45 9
Chemistry
  Hypoalbuminemia 44 5
  Increased alkaline phosphatase 40 1.3
  Hyponatremia 38 13
  Hyperglycemia 38 1.3
  Increased AST 34 3.9
  Increased creatinine 32 5
  Hypocalcemia 27 0
  Increased ALT 21 3.9
  Hypokalemia 20 6
Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (17% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (10% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4).
HCC Previously Treated HCC The safety of KEYTRUDA was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC. Patients were randomized (2:1) and received KEYTRUDA 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.13)]. The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the KEYTRUDA arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. KEYTRUDA was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). Adverse reactions leading to interruption of KEYTRUDA occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%). Tables 47 and 48 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-394.
Table 47: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving KEYTRUDA in KEYNOTE-394
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
n=299		 Placebo

n=153
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-5
(%)		 All Grades
(%)		 Grades 3-5
(%)
General
  Pyrexia 18 0.7 14 0
Skin and Subcutaneous Tissue
  RashIncludes dermatitis, dermatitis allergic, dermatitis bullous, rash, rash erythematous, rash maculo-papular, rash pustular, and blister. 18 0.7 7 0
  Pruritus 12 0 4 0
Gastrointestinal
  Diarrhea 16 1.7 9 0
Metabolism and Nutrition
  Decreased appetite 15 0.3 9 0
Infections
  Upper respiratory tract infection 11 1.0 7 0.7
Respiratory, Thoracic, and Mediastinal
  Cough 11 0 9 0
Endocrine
  Hypothyroidism 10 0 7 0
Table 48: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with HCC Receiving KEYTRUDA in KEYNOTE-394
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 223 to 297 patients) and placebo (range: 144 to 151 patients). KEYTRUDA Placebo
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Increased AST 54 14 44 12
  Increased bilirubin 47 11 36 7
  Increased ALT 47 7 32 4.6
  Increased gamma-glutamyl transferase (GGT) 40 20 39 15
  Hypoalbuminemia 40 0.7 20 0.7
  Increased alkaline phosphatase 39 4.1 34 4
  Hyperglycemia 36 3.3 26 1.4
  Hyponatremia 36 11 28 5
  Hypophosphatemia 30 6 17 4
  Hypocalcemia 24 1.4 15 0.7
Hematology
  Lymphopenia 44 11 34 4.6
  Anemia 36 7 30 3.3
  Decreased platelets 32 4.7 29 2
  Leukopenia 30 1.3 21 0.7
  Neutropenia 25 4.4 21 2
BTC The safety of KEYTRUDA in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.14)]. A total of 1063 patients received either KEYTRUDA 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks. The median duration of exposure to KEYTRUDA was 6 months (range: 1 day to 28 months). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In the KEYTRUDA plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with KEYTRUDA versus placebo for pyrexia (26% vs. 20%), rash (21% vs. 13%), pruritus (15% vs. 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence in laboratory abnormalities between patients treated with KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs. 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.
MCC Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.15)], the median duration of exposure to KEYTRUDA was 6.3 months (range 1 day to 28 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).
RCC In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426) The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.16)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months). The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80. Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure. Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 49 and 50 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.
Table 49: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
and Axitinib
n=429		 Sunitinib
n=425
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Gastrointestinal
  DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic 56 11 45 5
  Nausea 28 0.9 32 0.9
  Constipation 21 0 15 0.2
General
  Fatigue/Asthenia 52 5 51 10
Vascular
  HypertensionIncludes hypertension, blood pressure increased, hypertensive crisis, labile hypertension 48 24 48 20
Hepatobiliary
  HepatotoxicityIncludes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased 39 20 25 4.9
Endocrine
  Hypothyroidism 35 0.2 32 0.2
Metabolism and Nutrition
  Decreased appetite 30 2.8 29 0.7
Skin and Subcutaneous Tissue
  Palmar-plantar erythrodysesthesia syndrome 28 5 40 3.8
  Stomatitis/Mucosal inflammation 27 1.6 41 4
  RashIncludes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash 25 1.4 21 0.7
Respiratory, Thoracic and Mediastinal
  Dysphonia 25 0.2 3.3 0
  Cough 21 0.2 14 0.5
Table 50: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 421 patients). KEYTRUDA
200 mg every 3 weeks
and Axitinib		 Sunitinib
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 62 9 54 3.2
  Increased ALT 60 20 44 5
  Increased AST 57 13 56 5
  Increased creatinine 43 4.3 40 2.4
  Hyponatremia 35 8 29 8
  Hyperkalemia 34 6 22 1.7
  Hypoalbuminemia 32 0.5 34 1.7
  Hypercalcemia 27 0.7 15 1.9
  Hypophosphatemia 26 6 49 17
  Increased alkaline phosphatase 26 1.7 30 2.7
  HypocalcemiaCorrected for albumin 22 0.2 29 0.7
  Blood bilirubin increased 22 2.1 21 1.9
  Activated partial thromboplastin time prolongedTwo patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity. 22 1.2 14 0
Hematology
  Lymphopenia 33 11 47 9
  Anemia 29 2.1 65 8
  Thrombocytopenia 27 1.4 78 14
In combination with lenvatinib in the first-line treatment of advanced RCC (KEYNOTE-581) The safety of KEYTRUDA was evaluated in KEYNOTE-581 [see Clinical Studies (14.16)]. Patients received KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of KEYTRUDA and lenvatinib was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients treated with KEYTRUDA in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of either of KEYTRUDA, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving KEYTRUDA in combination with lenvatinib; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with lenvatinib. KEYTRUDA was interrupted in 55% of patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of KEYTRUDA were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%). Fifteen percent (15%) of patients treated with KEYTRUDA in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 51 and 52 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581.
Table 51: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
with Lenvatinib
N=352		 Sunitinib 50 mg
N=340
All Grades
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
General
  FatigueIncludes asthenia, fatigue, lethargy, malaise 63 9 56 8
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis 62 10 50 6
  StomatitisIncludes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, stomatitis 43 2 43 2
  Nausea 36 3 33 1
  Abdominal painIncludes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain 27 2 18 1
  Vomiting 26 3 20 1
  Constipation 25 1 19 0
Musculoskeletal and Connective Tissue
  Musculoskeletal disordersIncludes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw 58 4 41 3
Endocrine
  HypothyroidismIncludes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism 57 1 32 0
Vascular
  HypertensionIncludes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure 56 29 43 20
  Hemorrhagic eventsIncludes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage 27 5 26 4
Metabolism
  Decreased appetiteIncludes decreased appetite, early satiety 41 4 31 1
Skin and Subcutaneous Tissue
  RashIncludes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular 37 5 17 1
  Palmar-plantar erythrodysesthesia syndromeIncludes palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema 29 4 38 4
Investigations
  Weight loss 30 8 9 0.3
Respiratory, Thoracic and Mediastinal
  Dysphonia 30 0 4 0
Renal and Urinary
  ProteinuriaIncludes hemoglobinuria, nephrotic syndrome, proteinuria 30 8 13 3
  Acute kidney injuryIncludes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic 21 5 16 2
Hepatobiliary
  HepatotoxicityIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gamma-glutamyltransferase increased 25 9 21 5
Nervous System
  Headache 23 1 16 1
Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDA with lenvatinib were myocardial infarction (3%) and angina pectoris (1%).
Table 52: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581
  Laboratory TestWith at least one Grade increase from baseline KEYTRUDA
200 mg every 3 weeks
with Lenvatinib		 Sunitinib 50 mg
All Grades
%Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients). 		Grade 3-4
% 		All Grades
% 		Grade 3-4
%
Chemistry
  Hypertriglyceridemia 80 15 71 15
  Hypercholesterolemia 64 5 43 1
  Increased lipase 61 34 59 28
  Increased creatinine 61 5 61 2
  Increased amylase 59 17 41 9
  Increased AST 58 7 57 3
  Hyperglycemia 55 7 48 3
  Increased ALT 52 7 49 4
  Hyperkalemia 44 9 28 6
  Hypoglycemia 44 2 27 1
  Hyponatremia 41 12 28 9
  Decreased albumin 34 0.3 22 0
  Increased alkaline phosphatase 32 4 32 1
  Hypocalcemia 30 2 22 1
  Hypophosphatemia 29 7 50 8
  Hypomagnesemia 25 2 15 3
  Increased creatine phosphokinase 24 6 36 5
  Hypermagnesemia 23 2 22 3
  Hypercalcemia 21 1 11 1
Hematology
  Lymphopenia 54 9 66 15
  Thrombocytopenia 39 2 73 13
  Anemia 38 3 66 8
  Leukopenia 34 1 77 8
  Neutropenia 31 4 72 16
Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3). Adjuvant treatment of RCC The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.16)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia. Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 53 and 54 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564.
Table 53: SelectedAdverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-564
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
n=488		 Placebo

n=496
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Musculoskeletal and Connective Tissue
  Musculoskeletal painIncludes arthralgia, back pain, myalgia, arthritis, pain in extremity, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort 41 1.2 36 0.6
General
  FatigueIncludes asthenia, fatigue 40 1.2 31 0.2
Skin and Subcutaneous Tissue
  RashIncludes rash, rash maculo-papular, rash papular, skin exfoliation, lichen planus, rash erythematous, eczema, rash macular, dermatitis acneiform, dermatitis, rash pruritic, Stevens-Johnson Syndrome, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome 30 1.4 15 0.4
  Pruritus 23 0.2 13 0
Gastrointestinal
  DiarrheaIncludes diarrhea, colitis, enterocolitis, frequent bowel movements, enteritis 27 2.7 23 0.2
  Nausea 16 0.4 10 0
  Abdominal painIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort, gastrointestinal pain 11 0.4 13 0.2
Endocrine
  Hypothyroidism 21 0.2 3.6 0
  Hyperthyroidism 12 0.2 0.2 0
Respiratory, Thoracic and Mediastinal
  Cough Includes upper-airway cough syndrome, productive cough, cough 17 0 12 0
Nervous System
  HeadacheIncludes tension headache, headache, sinus headache, migraine with aura 15 0.2 13 0
Hepatobiliary
  HepatotoxicityIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, transaminases increased, gamma-glutamyltransferase increased, bilirubin conjugated increased 14 3.7 7 0.6
Renal and Urinary
  Acute kidney injuryIncludes acute kidney injury, blood creatinine increased, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic 13 1.2 10 0.2
Table 54: SelectedLaboratory abnormalities occurring at same or higher incidence than placebo Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-564
  Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: KEYTRUDA n=199 and placebo n=224. KEYTRUDA
200 mg every 3 weeks		 Placebo
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hyperglycemia 48 8 45 4.5
  Increased creatinine 39 1.1 28 0.2
  Increased INR 29 1.0 20 0.9
  Hyponatremia 21 3.3 13 1.9
  Increased ALT 20 3.6 11 0.2
Hematology
  Anemia 28 0.5 20 0.4
Endometrial Carcinoma Primary Advanced or Recurrent Endometrial Carcinoma The safety of KEYTRUDA in combination with chemotherapy (paclitaxel and carboplatin) was investigated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial that enrolled patients with advanced or recurrent endometrial carcinoma [see Clinical Studies (14.17)]. A total of 759 patients received KEYTRUDA 200 mg every 3 weeks and chemotherapy for 6 cycles followed by KEYTRUDA 400 mg every 6 weeks for up to 14 cycles (n=382) or placebo and chemotherapy for 6 cycles followed by placebo for up to 14 cycles (n=377). The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 24.0 months). Serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy. Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%), and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Chemotherapy dose reduction was required in 29% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 23% of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone with the exception of rash (33% all Grades; 2.9% Grades 3-4). In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H. The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.17)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325). For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months). Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%). Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%). Tables 55 and 56 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775.
Table 55: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-775
Endometrial Carcinoma (pMMR or not MSI-H)
  Adverse Reaction KEYTRUDA
200 mg every 3 weeks
and Lenvatinib
n=342		 Doxorubicin or
Paclitaxel

n=325
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
Endocrine
  HypothyroidismIncludes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, secondary hypothyroidism 67 0.9 0.9 0
Vascular
  HypertensionIncludes hypertension, blood pressure increased, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, blood pressure fluctuation 67 39 6 2.5
  Hemorrhagic eventsIncludes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, melena, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, vessel puncture site bruise 25 2.6 15 0.9
General
  FatigueIncludes fatigue, asthenia, malaise, lethargy 58 11 54 6
Gastrointestinal
  DiarrheaIncludes diarrhea, gastroenteritis 55 8 20 2.8
  Nausea 49 2.9 47 1.5
  Vomiting 37 2.3 21 2.2
  StomatitisIncludes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration 35 2.6 26 1.2
  Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, epigastric discomfort 34 2.6 21 1.2
  Constipation 27 0 25 0.6
Musculoskeletal and Connective Tissue
  Musculoskeletal disordersIncludes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw 53 5 27 0.6
Metabolism
  Decreased appetiteIncludes decreased appetite, early satiety 44 7 21 0
Investigations
  Weight loss 34 10 6 0.3
Renal and Urinary
  ProteinuriaIncludes proteinuria, protein urine present, hemoglobinuria 29 6 3.4 0.3
Infections
  Urinary tract infectionIncludes urinary tract infection, cystitis, pyelonephritis 31 5 13 1.2
Nervous System
  Headache 26 0.6 9 0.3
Respiratory, Thoracic and Mediastinal
  Dysphonia 22 0 0.6 0
Skin and Subcutaneous Tissue
  Palmar-plantar erythrodysesthesiaIncludes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema 23 2.9 0.9 0
  RashIncludes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, application site rash 20 2.3 4.9 0
Table 56: Laboratory Abnormalities Worsened from BaselineWith at least one grade increase from baseline Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775
Endometrial Carcinoma (pMMR or not MSI-H)
  Laboratory TestLaboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). KEYTRUDA
200 mg every 3 weeks
and Lenvatinib		 Doxorubicin or
Paclitaxel
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Chemistry
  Hypertriglyceridemia 70 6 45 1.7
  Hypoalbuminemia 60 2.7 42 1.6
  Increased aspartate aminotransferase 58 9 23 1.6
  Hyperglycemia 58 8 45 4.4
  Hypomagnesemia 46 0 27 1.3
  Increased alanine aminotransferase 55 9 21 1.2
  Hypercholesterolemia 53 3.2 23 0.7
  Hyponatremia 46 15 28 7
  Increased alkaline phosphatase 43 4.7 18 0.9
  Hypocalcemia 40 4.7 21 1.9
  Increased lipase 36 14 13 3.9
  Increased creatinine 35 4.7 18 1.9
  Hypokalemia 34 10 24 5
  Hypophosphatemia 26 8 17 3.2
  Increased amylase 25 7 8 1
  Hyperkalemia 23 2.4 12 1.2
  Increased creatine kinase 19 3.7 7 0
  Increased bilirubin 18 3.6 6 1.6
Hematology
  Lymphopenia 51 18 66 23
  Thrombocytopenia 50 8 30 4.7
  Anemia 49 8 84 14
  Leukopenia 43 3.5 83 43
  Neutropenia 34 8 80 60
As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.17)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. TMB-H Cancer The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.18)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. cSCC Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.19)], the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%). TNBC Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The safety of KEYTRUDA in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC. A total of 778 patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.20)]. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months). Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%). Tables 57 and 58 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522.
Table 57: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522
      Adverse Reaction KEYTRUDA
200 mg every 3 weeks
with chemotherapyChemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide/KEYTRUDA
n=778		 Placebo
with chemotherapy/Placebo

n=389
All GradesGraded per NCI CTCAE v4.0
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
General
  FatigueIncludes asthenia, fatigue 70 8 66 3.9
  Pyrexia 28 1.3 19 0.3
Gastrointestinal
  Nausea 67 3.7 66 1.8
  Constipation 42 0 39 0.3
  Diarrhea 41 3.2 34 1.8
  StomatitisIncludes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oral mucosal eruption, oral pain, stomatitis, tongue blistering, tongue ulceration 34 2.7 29 1
  Vomiting 31 2.7 28 1.5
  Abdominal painIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness 24 0.5 23 0.8
Skin and Subcutaneous Tissue
  Alopecia 61 0 58 0
  RashIncludes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, incision site rash, injection site rash, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash rubelliform, skin exfoliation, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash 52 5 41 0.5
Nervous System
  Peripheral neuropathyIncludes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy 41 3.3 42 2.3
  Headache 30 0.5 29 1
Musculoskeletal and Connective Tissue
  Arthralgia 29 0.5 31 0.3
  Myalgia 20 0.5 19 0
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough, upper-airway cough syndrome 26 0.1 24 0
Metabolism and Nutrition
  Decreased appetite 23 0.9 17 0.3
Psychiatric
  Insomnia 21 0.5 19 0
Table 58: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522
      Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA in combination with chemotherapy followed by KEYTRUDA as a single agent (range: 762 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 381 to 389 patients). KEYTRUDA
200 mg every 3 weeks
with chemotherapyChemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide/KEYTRUDA		 Placebo
with chemotherapy/Placebo
All GradesGraded per NCI CTCAE v4.0
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Hematology
  Anemia 97 22 96 19
  Leukopenia 93 41 91 32
  Neutropenia 88 62 89 62
  Lymphopenia 79 28 74 22
  Thrombocytopenia 57 10 56 8
Chemistry
  Increased ALT 70 9 67 3.9
  Increased AST 65 6 56 1.5
  Hyperglycemia 63 4.3 61 2.8
  Increased alkaline phosphatase 37 1 35 0.5
  Hyponatremia 35 9 25 4.6
  Hypoalbuminemia 34 1.0 30 1.3
  Hypocalcemia 31 2.2 28 3.1
  Hypokalemia 31 6 22 2.8
  Hypophosphatemia 20 6 15 4.2
Locally Recurrent Unresectable or Metastatic TNBC The safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.20)]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. The median duration of exposure to KEYTRUDA was 5.7 months (range: 1 day to 33.0 months). Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. Serious adverse reactions in ≥2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%). Tables 59 and 60 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.
Table 59: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355
      Adverse Reaction KEYTRUDA
200 mg every 3 weeks
with chemotherapy
n=596		 Placebo
every 3 weeks
with chemotherapy
n=281
All GradesGraded per NCI CTCAE v4.03
(%)		 Grades 3-4
(%)		 All Grades
(%)		 Grades 3-4
(%)
General
  FatigueIncludes fatigue and asthenia 48 5 49 4.3
Gastrointestinal
  Nausea 44 1.7 47 1.8
  Diarrhea 28 1.8 23 1.8
  Constipation 28 0.5 27 0.4
  Vomiting 26 2.7 22 3.2
Skin and Subcutaneous Tissue
  Alopecia 34 0.8 35 1.1
  RashIncludes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash, rash erythematous, eyelid rash 26 2 16 0
Respiratory, Thoracic and Mediastinal
  CoughIncludes cough, productive cough, upper-airway cough syndrome 23 0 20 0.4
Metabolism and Nutrition
  Decreased appetite 21 0.8 14 0.4
Nervous System
  HeadacheIncludes headache, migraine, tension headache 20 0.7 23 0.7
Table 60: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355
      Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients). KEYTRUDA
200 mg every 3 weeks
with chemotherapy		 Placebo
every 3 weeks
with chemotherapy
All GradesGraded per NCI CTCAE v4.03
%		 Grades 3-4
%		 All Grades
%		 Grades 3-4
%
Hematology
  Anemia 90 20 85 19
  Leukopenia 85 39 86 39
  Neutropenia 78 50 79 53
  Lymphopenia 73 28 71 19
  Thrombocytopenia 54 19 53 21
Chemistry
  Increased ALT 60 11 58 8
  Increased AST 57 9 55 6
  Hyperglycemia 52 4.4 51 2.2
  Hypoalbuminemia 36 2.0 32 2.2
  Increased alkaline phosphatase 35 3.9 39 2.2
  Hypocalcemia 29 3.3 27 1.8
  Hyponatremia 28 5 26 6
  Hypophosphatemia 21 7 18 4.8
  Hypokalemia 20 4.4 18 4.0
Ovarian Cancer The safety of KEYTRUDA in combination with paclitaxel with or without bevacizumab was evaluated in 463 patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) enrolled in KEYNOTE-B96 [see Clinical Studies (14.21)]. Among patients who received KEYTRUDA, the median duration of exposure was 7.4 months (range: 1 day to 35.9 months). Serious adverse reactions occurred in 54% of patients receiving KEYTRUDA and paclitaxel with or without bevacizumab. Serious adverse reactions in ≥2% of patients were pneumonia (4.3%), urinary tract infection (3.9%), adrenal insufficiency (3%), hyponatremia (3%), COVID-19 (2.6%), decreased neutrophil count (2.6%), pulmonary embolism (2.6%), abdominal pain (2.1%), anemia (2.1%), colitis (2.1%), diarrhea (2.1%), febrile neutropenia (2.1%), pyrexia (2.1%) and vomiting (2.1%). Fatal adverse reactions occurred in 3.9% of patients receiving KEYTRUDA and paclitaxel with or without bevacizumab, including assisted suicide (0.9%), death (0.4%), intestinal perforation (0.4%), sepsis (0.4%), COVID-19 (0.4%), cardio-respiratory arrest (0.4%), colitis (0.4%), and embolic stroke (0.4%). KEYTRUDA was permanently discontinued for adverse reactions in 16% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were colitis (1.3%), and increased alanine aminotransferase (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 44% of patients. The most common adverse reactions leading to interruption of KEYTRUDA in ≥2% were urinary tract infection (3.9%), adrenal insufficiency (2.6%), pyrexia (2.6%), pneumonitis (2.6%), upper respiratory tract infection (2.6%), neutropenia (2.1%), diarrhea (2.1%) and COVID-19 (2.1%). The most common (≥20%) adverse reactions for patients treated with KEYTRUDA in combination with paclitaxel with or without bevacizumab were: diarrhea (45%), fatigue (43%), nausea (41%), alopecia (38%), peripheral neuropathy (38%), epistaxis (31%), urinary tract infection (27%), constipation (25%), abdominal pain (24%), decreased appetite (24%), vomiting (24%), hypothyroidism (21%), cough (20%), hypertension (20%), and rash (20%). The most common (≥20%) laboratory abnormalities worsening from baseline were: anemia (85%), leukopenia (82%), decreased neutrophil count (71%), lymphopenia (60%), hypoalbuminemia (50%), hyponatremia (53%), hypomagnesemia (45%), increased aspartate aminotransferase (43%), increased alanine aminotransferase (40%), hypocalcemia (40%), increased alkaline phosphatase (31%), increased creatinine (29%), hypokalemia (27%) and neutropenia (21%). For patients treated with KEYTRUDA in combination with paclitaxel and bevacizumab (N=169), decreased white blood cell count (27%), stomatitis (22%) and pyrexia (21%) were also reported as adverse reactions.
6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of KEYTRUDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: Exocrine pancreatic insufficiency Hepatobiliary: sclerosing cholangitis
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2)
8.1 Pregnancy
Risk Summary Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.
8.2 Lactation
Risk Summary There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to KEYTRUDA are unknown. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the last dose.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)].
Contraception KEYTRUDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose.
8.4 Pediatric Use The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, cHL, PMBCL, MCC, MSI-H or dMMR cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1, 14.5, 14.6, 14.8, 14.15, 14.18)]. In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive or MSI-H solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Laboratory abnormalities that occurred at a ≥10% higher rate in pediatric patients when compared to adults were leukopenia (30%), neutropenia (28%), thrombocytopenia (22%), and Grade 3 anemia (17%). The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)].
8.5 Geriatric Use Of 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 48% were 65 years and over and 17% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 years and over had a higher incidence of serious adverse reactions (50%) than patients aged younger than 65 years (24%). Clinical studies of KEYTRUDA in cHL did not include sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from that in younger patients. Of 506 adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 596 adult patients with TNBC who were treated with KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 406 adult patients with endometrial carcinoma who were treated with KEYTRUDA in combination with lenvatinib in KEYNOTE-775, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Of the 167 patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin, 37% (n=61) were 65-74 years and 46% (n=77) were 75 years or older. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 12% in patients 75 years or older. Of the 432 patients randomized to KEYTRUDA in combination with axitinib in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger. Of 294 adult patients with FIGO 2014 Stage III-IVA cervical cancer who were treated with KEYTRUDA in combination with CRT in KEYNOTE-A18, 42 (14%) were 65 years and over. No overall difference in safety was observed between patients ≥65 years of age and younger patients. Of 643 adult patients with ovarian cancer who were treated with KEYTRUDA in combination with paclitaxel with or without bevacizumab in KEYNOTE-B96, 236 (37%) were 65 years and over and 58 (9%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients ≥65 years of age and younger patients.
11 DESCRIPTION Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. In syngeneic mouse tumor models, combination treatment of a PD-1 blocking antibody and kinase inhibitor lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth compared to either treatment alone.
12.2 Pharmacodynamics There are no clinically significant exposure-response relationships for efficacy or safety at pembrolizumab dosages of 200 mg or 2 mg/kg every 3 weeks and 400 mg every 6 weeks regardless of cancer type based on observed data in adult patients with melanoma, cHL, and PMBCL.
12.3 Pharmacokinetics The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.
Distribution The geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%).
Elimination Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t1/2) is 22 days (32%).
Specific Populations The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥15 mL/min/1.73 m2), mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST), or tumor burden. The impact of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on the pharmacokinetics of pembrolizumab is unknown.
Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (10 months to 17 years) are comparable to those of adults at the same dose.
12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described in this section with the incidence of ADA in other studies, including those of KEYTRUDA or of other pembrolizumab products. Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the KEYTRUDA-treated patients with a pembrolizumab concentration below the drug tolerance level of the ADA assay. In clinical studies in patients treated with KEYTRUDA at a dosage of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 27 (2.1%) of 1,289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom 6 (0.5%) patients had neutralizing antibodies against pembrolizumab. There were no identified clinically significant effects of ADA on pembrolizumab pharmacokinetics or on the risk of infusion reactions. Because of the low occurrence of ADA, the effect of these ADA on the effectiveness of KEYTRUDA is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity. Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.
13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1/PD-L1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 and PD-L1 knockout mice and mice receiving PD-L1-blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.
14 CLINICAL STUDIES
14.1 Melanoma
Ipilimumab-Naive Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DoR). The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 66% had no prior systemic therapy for metastatic disease; 69% ECOG PS of 0; 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay; 65% had M1c stage disease; 68% with normal LDH; 36% with reported BRAF mutation-positive melanoma; and 9% with a history of brain metastases. Among patients with BRAF mutation-positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor. The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 61 and Figure 1.
Table 61: Efficacy Results in KEYNOTE-006
Endpoint KEYTRUDA
10 mg/kg every 3 weeks
n=277		 KEYTRUDA
10 mg/kg every 2 weeks
n=279		 Ipilimumab
3 mg/kg every 3 weeks
n=278
OS
  Deaths (%) 92 (33%) 85 (30%) 112 (40%)
  Hazard ratioHazard ratio (KEYTRUDA compared to ipilimumab) based on the stratified Cox proportional hazard model (95% CI) 0.69 (0.52, 0.90) 0.63 (0.47, 0.83) ---
  p-Value (stratified log-rank) 0.004 <0.001 ---
PFS by BICR
  Events (%) 157 (57%) 157 (56%) 188 (68%)
  Median in months (95% CI) 4.1 (2.9, 6.9) 5.5 (3.4, 6.9) 2.8 (2.8, 2.9)
  Hazard ratio (95% CI) 0.58 (0.47, 0.72) 0.58 (0.46, 0.72) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
Best objective response by BICR
  ORR (95% CI) 33% (27, 39) 34% (28, 40) 12% (8, 16)
    Complete response rate 6% 5% 1%
    Partial response rate 27% 29% 10%
Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006 Based on the final analysis with an additional follow-up of 9 months (total of 383 deaths as pre-specified in the protocol)
Figure 1
Ipilimumab-Refractory Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-002 (NCT01704287), a multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of KEYTRUDA in a blinded fashion or investigator's choice chemotherapy. The treatment arms consisted of KEYTRUDA 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator's choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every 3 weeks (26%), temozolomide 200 mg/m2 orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 mg/mL/min intravenously plus paclitaxel 225 mg/m2 intravenously every 3 weeks for four cycles then carboplatin AUC of 5 mg/mL/min plus paclitaxel 175 mg/m2 every 3 weeks (25%), paclitaxel 175 mg/m2 intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 mg/mL/min intravenously every 3 weeks (8%). Randomization was stratified by ECOG PS (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received KEYTRUDA until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician's decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. The major efficacy outcomes were PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Additional efficacy outcome measures were confirmed ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. The study population characteristics were: median age of 62 years (range: 15 to 89), 43% age 65 or older; 61% male; 98% White; and 55% ECOG PS of 0 and 45% ECOG PS of 1. Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease. The study demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared to control arm. There was no statistically significant difference between KEYTRUDA 2 mg/kg and chemotherapy or between KEYTRUDA 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive KEYTRUDA. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 62 and Figure 2.
Table 62: Efficacy Results in KEYNOTE-002
Endpoint KEYTRUDA
2 mg/kg every 3 weeks		 KEYTRUDA
10 mg/kg every 3 weeks		 Chemotherapy
n=180 n=181 n=179
PFS
  Number of Events, n (%) 129 (72%) 126 (70%) 155 (87%)
  Progression, n (%) 105 (58%) 107 (59%) 134 (75%)
  Death, n (%) 24 (13%) 19 (10%) 21 (12%)
  Median in months (95% CI) 2.9 (2.8, 3.8) 2.9 (2.8, 4.7) 2.7 (2.5, 2.8)
  p-Value (stratified log-rank) <0.001 <0.001 ---
  Hazard ratioHazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI) 0.57 (0.45, 0.73) 0.50 (0.39, 0.64) ---
OS With additional follow-up of 18 months after the PFS analysis
  Deaths (%) 123 (68%) 117 (65%) 128 (72%)
  Hazard ratio (95% CI) 0.86 (0.67, 1.10) 0.74 (0.57, 0.96) ---
  p-Value (stratified log-rank) 0.117 0.011Not statistically significant compared to multiplicity adjusted significance level of 0.01 ---
  Median in months (95% CI) 13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8)
Objective Response Rate
  ORR (95% CI) 21% (15, 28) 25% (19, 32) 4% (2, 9)
    Complete response rate 2% 3% 0%
    Partial response rate 19% 23% 4%
Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002
Figure 2
Adjuvant Treatment of Resected Stage IIB or IIC Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-716 (NCT03553836), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIB or IIC melanoma. Patients were randomized to KEYTRUDA 200 mg or the pediatric (≥12 years old) dose of KEYTRUDA 2 mg/kg intravenously (up to a maximum of 200 mg) every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by AJCC 8th edition T Stage (>2.0-4.0 mm with ulceration vs. >4.0 mm without ulceration vs. >4.0 mm with ulceration). Patients must not have been previously treated for melanoma beyond complete surgical resection for their melanoma prior to study entry. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) (defined as the time between the date of randomization and the date of first recurrence [local, in-transit or regional lymph nodes or distant recurrence] or death, whichever occurred first). New primary melanomas were excluded from the definition of RFS. Distant metastasis-free survival (DMFS), defined as a spread of tumor to distant organs or distant lymph nodes, was an additional efficacy outcome measure. Patients underwent imaging every six months for one year from randomization, every 6 months from years 2 to 4, and then once in year 5 from randomization or until recurrence, whichever came first. The study population characteristics were: median age of 61 years (range: 16 to 87), 39% age 65 or older; 60% male; 98% White; and 93% ECOG PS of 0 and 7% ECOG PS of 1. Sixty-four percent had Stage IIB and 35% had Stage IIC. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 63 and Figure 3.
Table 63: Efficacy Results in KEYNOTE-716
Endpoint KEYTRUDA
200 mg every 3 weeks
n=487		 Placebo
n=489
NR = not reached
RFS
  Number (%) of patients with event 54 (11%) 82 (17%)
  Median in months (95% CI) NR (22.6, NR) NR (NR, NR)
  Hazard ratioBased on the stratified Cox proportional hazard model , Based on a log-rank test stratified by American Joint Committee on Cancer 8th edition (AJCC) stage (95% CI) 0.65 (0.46, 0.92)
  p-Value 0.0132p-Value is compared with 0.0202 of the allocated alpha for this interim analysis.
DMFS
  Number (%) of patients with event 63 (13%) 95 (19%)
  Median in months (95% CI) NR (NR, NR) NR (NR, NR)
  Hazard ratio , (95% CI) 0.64 (0.47, 0.88)
  p-Value 0.0058p-Value is compared with 0.0256 of the allocated alpha for this interim analysis.
Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-716
Adjuvant Treatment of Stage III Resected Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. New primary melanomas were excluded from the definition of RFS. DMFS in the whole population and in the population with PD-L1 positive tumors were additional efficacy outcome measures. DMFS was defined as a spread of tumor to distant organs or distant lymph nodes. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD-L1 positive melanoma with TPS ≥1% according to an IUO assay. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 64 and Figure 4.
Table 64: Efficacy Results in KEYNOTE-054
Endpoint KEYTRUDA
200 mg every 3 weeks
n=514		 Placebo
n=505
NR = not reached
RFS
  Number (%) of patients with event 135 (26%) 216 (43%)
  Median in months (95% CI) NR 20.4 (16.2, NR)
  Hazard ratioBased on the stratified Cox proportional hazard model , Stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (95% CI) 0.57 (0.46, 0.70)
  p-Value (log-rank) <0.001p-Value is compared with 0.016 of the allocated alpha for this interim analysis.
DMFS
  Number (%) of patients with event 173 (34%) 245 (49%)
  Median in months (95% CI) NR (49.6, NR) 40.0 (27.7, NR)
  Hazard ratio , (95% CI) 0.60 (0.49, 0.73)
  p-Value (log-rank) <0.0001p-Value is compared with 0.028 of the allocated alpha for this analysis.
For patients with PD-L1 positive tumors, the RFS HR was 0.54 (95% CI: 0.42, 0.69); p<0.0001. For patients with PD-L1 positive tumors, the DMFS HR was 0.61 (95% CI: 0.49, 0.76); p<0.0001. The RFS and DMFS benefit for KEYTRUDA compared to placebo was observed regardless of tumor PD-L1 expression.
Figure 4: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054
Figure 3 Figure 4
14.2 Non-Small Cell Lung Cancer
First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms: KEYTRUDA 200 mg, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. Placebo, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks. Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 65 and Figure 5 summarize the efficacy results for KEYNOTE-189.
Table 65: Efficacy Results in KEYNOTE-189
Endpoint KEYTRUDA
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy
n=410		 Placebo
Pemetrexed
Platinum Chemotherapy

n=206
NR = not reached
OS
  Number (%) of patients with event 127 (31%) 108 (52%)
  Median in months (95% CI) NR
(NR, NR)		 11.3
(8.7, 15.1)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.49 (0.38, 0.64)
  p-ValueBased on a stratified log-rank test <0.0001
PFS
  Number of patients with event (%) 245 (60%) 166 (81%)
  Median in months (95% CI) 8.8 (7.6, 9.2) 4.9 (4.7, 5.5)
  Hazard ratio (95% CI) 0.52 (0.43, 0.64)
  p-Value <0.0001
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 48% (43, 53) 19% (14, 25)
    Complete response 0.5% 0.5%
    Partial response 47% 18%
  p-ValueBased on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status <0.0001
Duration of Response
  Median in months (range) 11.2 (1.1+, 18.0+) 7.8 (2.1+, 16.4+)
At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with pemetrexed and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).
Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189Based on the protocol-specified final OS analysis
Figure 5
First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The efficacy of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi-center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks. Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. An additional efficacy outcome measure was DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel. The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 66 and Figure 6 summarize the efficacy results for KEYNOTE-407.
Table 66: Efficacy Results in KEYNOTE-407
Endpoint KEYTRUDA
200 mg every 3 weeks
Carboplatin
Paclitaxel/Paclitaxel protein-bound
n=278		 Placebo
Carboplatin
Paclitaxel/Paclitaxel protein-bound

n=281
NE = not estimable
OS
  Number of events (%) 85 (31%) 120 (43%)
  Median in months (95% CI) 15.9 (13.2, NE) 11.3 (9.5, 14.8)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.64 (0.49, 0.85)
  p-ValueBased on a stratified log-rank test 0.0017
PFS
  Number of events (%) 152 (55%) 197 (70%)
  Median in months (95% CI) 6.4 (6.2, 8.3) 4.8 (4.2, 5.7)
  Hazard ratio (95% CI) 0.56 (0.45, 0.70)
  p-Value <0.0001
n=101 n=103
Objective Response Rate ORR primary analysis and DoR analysis were conducted with the first 204 patients enrolled.
  ORR (95% CI) 58% (48, 68) 35% (26, 45)
  Difference (95% CI) 23.6% (9.9, 36.4)
  p-ValueBased on a stratified Miettinen-Nurminen test 0.0008
Duration of Response
  Median duration of response in months (range) 7.2 (2.4, 12.4+) 4.9 (2.0, 12.4+)
At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm was 17.1 months (95% CI: 14.4, 19.9) compared to 11.6 months (95% CI: 10.1, 13.7) in the placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm, with an HR of 0.71 (95% CI: 0.58, 0.88).
Figure 6: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407Based on the protocol-specified final OS analysis
Figure 6
First-line treatment of metastatic NSCLC with PD-L1 expression (TPS≥ 1%) as a single agent
KEYNOTE-042 The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx assay and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator's choice of either of the following platinum-containing chemotherapy regimens: Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies. Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC. The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to KEYTRUDA as compared with chemotherapy. Table 67 and Figure 7 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%.
Table 67: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042
TPS ≥1% TPS ≥50%
Endpoint KEYTRUDA
200 mg every 3 weeks		 Chemotherapy KEYTRUDA
200 mg every 3 weeks		 Chemotherapy
n=637 n=637 n=299 n=300
OS
  Number of events (%) 371 (58%) 438 (69%) 157 (53%) 199 (66%)
  Median in months (95% CI) 16.7 (13.9, 19.7) 12.1 (11.3, 13.3) 20.0 (15.4, 24.9) 12.2 (10.4, 14.2)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.81 (0.71, 0.93) 0.69 (0.56, 0.85)
  p-ValueBased on a stratified log-rank test; compared to a p-Value boundary of 0.0291 0.0036 0.0006
PFS
  Number of events (%) 507 (80%) 506 (79%) 221 (74%) 233 (78%)
  Median in months (95% CI) 5.4 (4.3, 6.2) 6.5 (6.3, 7.0) 6.9 (5.9, 9.0) 6.4 (6.1, 6.9)
  Hazard ratio , Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints (95% CI) 1.07
(0.94, 1.21)		 0.82
(0.68, 0.99)
  p-Value - NSNot significant compared to a p-Value boundary of 0.0291
Objective Response Rate
  ORR (95% CI) 27% (24, 31) 27% (23, 30) 39% (33.9, 45.3) 32% (26.8, 37.6)
    Complete response rate 0.5% 0.5% 0.7% 0.3%
    Partial response rate 27% 26% 39% 32%
Duration of Response
  % with duration ≥12 monthsBased on observed duration of response 47% 16% 42% 17%
  % with duration ≥18 months 26% 6% 25% 5%
The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11).
Figure 7: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%)
Figure 7
KEYNOTE-024 The efficacy of KEYTRUDA was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx assay were eligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator's choice of any of the following platinum-containing chemotherapy regimens: Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles; Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles; Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies). Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG PS of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression. The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 68 and Figure 8 summarize the efficacy results for KEYNOTE-024.
Table 68: Efficacy Results in KEYNOTE-024
Endpoint KEYTRUDA
200 mg every 3 weeks		 Chemotherapy
n=154 n=151
NR = not reached
PFS
  Number (%) of patients with event 73 (47%) 116 (77%)
  Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2)
  Hazard ratioBased on the stratified Cox proportional hazard model for the interim analysis (95% CI) 0.50 (0.37, 0.68)
  p-Value (stratified log-rank) <0.001
OS
  Number (%) of patients with event 44 (29%) 64 (42%)
  Median in months (95% CI)Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. 30.0
(18.3, NR)		 14.2
(9.8, 19.0)
  Hazard ratio (95% CI) 0.60 (0.41, 0.89)
  p-Value (stratified log-rank) 0.005p-Value is compared with 0.0118 of the allocated alpha for the interim analysis
Objective Response Rate
  ORR (95% CI) 45% (37, 53) 28% (21, 36)
    Complete response rate 4% 1%
    Partial response rate 41% 27%
  p-Value (Miettinen-Nurminen) 0.001
  Median duration of response in months (range) NR
(1.9+, 14.5+)		 6.3
(2.1+, 12.6+)
Figure 8: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.
Figure 8
Previously treated NSCLC with PD-L1 expression (TPS≥ 1%) The efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx assay. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG PS (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA 2 mg/kg intravenously every 3 weeks, KEYTRUDA 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and DoR in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG PS of 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease. Tables 69 and 70 and Figure 9 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively.
Table 69: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010
Endpoint KEYTRUDA
2 mg/kg every 3 weeks
n=139		 KEYTRUDA
10 mg/kg every 3 weeks
n=151		 Docetaxel
75 mg/m2 every 3 weeks
n=152
NR = not reached
OS
  Deaths (%) 58 (42%) 60 (40%) 86 (57%)
  Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7)
  Hazard ratioHazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
PFS
  Events (%) 89 (64%) 97 (64%) 118 (78%)
  Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3)
  Hazard ratio (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
Objective Response Rate
  ORRAll responses were partial responses (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13)
  p-Value (Miettinen-Nurminen) <0.001 <0.001 ---
  Median duration of response in months (range) NR
(0.7+, 16.8+)		 NR
(2.1+, 17.8+)		 8.1
(2.1+, 8.8+)
Table 70: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010
Endpoint KEYTRUDA
2 mg/kg every 3 weeks
n=344		 KEYTRUDA
10 mg/kg every 3 weeks
n=346		 Docetaxel
75 mg/m2 every 3 weeks
n=343
NR = not reached
OS
  Deaths (%) 172 (50%) 156 (45%) 193 (56%)
  Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8)
  Hazard ratioHazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
PFS
  Events (%) 266 (77%) 255 (74%) 257 (75%)
  Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2)
  Hazard ratio (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94) ---
  p-Value (stratified log-rank) 0.068 0.005 ---
Objective Response Rate
  ORRAll responses were partial responses (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13)
  p-Value (Miettinen-Nurminen) <0.001 <0.001 ---
  Median duration of response in months (range) NR
(0.7+, 20.1+)		 NR
(2.1+, 17.8+)		 6.2
(1.4+, 8.8+)
Figure 9: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%)
Neoadjuvant and adjuvant treatment of resectable NSCLC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial conducted in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or a history of interstitial lung disease or pneumonitis that required steroids were ineligible. Randomization was stratified by stage (II vs. III), tumor PD-L1 expression (TPS ≥50% or <50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms: Treatment Arm A: neoadjuvant KEYTRUDA 200 mg on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, KEYTRUDA 200 mg was administered every 3 weeks for up to 13 cycles. Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, placebo was administered every 3 weeks for up to 13 cycles. All study medications were administered via intravenous infusion. Treatment with KEYTRUDA or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumor status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measures were OS and investigator-assessed event-free survival (EFS). Additional efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review. The study population characteristics were: median age of 64 years (range: 26 to 83); 45% age 65 or older and 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino; 63% ECOG PS of 0 and 37% ECOG PS of 1. Thirty percent had Stage II and 70% had Stage III disease; 33% had TPS ≥50% and 67% had TPS <50%; 43% had tumors with squamous histology and 57% had tumors with non-squamous histology; 31% were from the East Asian region. Eighty-one percent of patients in the KEYTRUDA in combination with platinum-containing chemotherapy arm received definitive surgery compared to 76% of patients in the placebo in combination with platinum-containing chemotherapy arm. The trial demonstrated statistically significant improvements in OS and EFS for patients randomized to KEYTRUDA in combination with platinum-containing chemotherapy followed by KEYTRUDA as a single agent compared with patients randomized to placebo in combination with platinum-containing chemotherapy followed by placebo alone. Table 71 and Figure 10 summarize the efficacy results for KEYNOTE-671.
Table 71: Efficacy Results in KEYNOTE-671
Endpoint KEYTRUDA
200 mg every 3 weeks
with
chemotherapy/KEYTRUDA
n=397		 Placebo with
chemotherapy/Placebo


n=400
NR = not reached
OS
  Number of patients with event (%) 110 (28%) 144 (36%)
  Median in monthsBased on Kaplan-Meier estimates (95% CI) NR (NR, NR) 52.4 (45.7, NR)
  Hazard ratioBased on Cox regression model with treatment as a covariate stratified by stage, tumor PD-L1 expression, histology, and geographic region (95% CI) 0.72 (0.56, 0.93)
  p-ValueBased on stratified log-rank test , Compared to a two-sided p-Value boundary of 0.0109 0.0103
EFS
  Number of patients with event (%) 139 (35%) 205 (51%)
  Median in months (95% CI) NR (34.1, NR) 17.0 (14.3, 22.0)
  Hazard ratio (95% CI) 0.58 (0.46, 0.72)
  p-Value , Compared to a two-sided p-Value boundary of 0.0092 <0.0001
Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-671
The trial demonstrated a statistically significant difference in pCR rate (18.1% vs. 4.0%; p<0.0001) and mPR rate (30.2% vs. 11.0%; p<0.0001). Adjuvant treatment of resected NSCLC The efficacy of KEYTRUDA was investigated in KEYNOTE-091 (NCT02504372), a multicenter, randomized, triple-blind, placebo-controlled trial conducted in 1177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC by AJCC 7th edition. Patients had not received neoadjuvant radiotherapy or chemotherapy. Adjuvant chemotherapy up to 4 cycles was optional. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. Randomization was stratified by stage (IB vs. II vs. IIIA), receipt of adjuvant chemotherapy (yes vs. no), PD-L1 status (TPS <1% [negative] vs. TPS 1-49% vs. TPS ≥50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomized (1:1) to receive KEYTRUDA 200 mg or placebo intravenously every 3 weeks. Treatment continued until RECIST v1.1-defined disease recurrence as determined by the investigator, unacceptable toxicity or up to one year. Tumor assessments were conducted every 12 weeks for the first year, then every 6 months for years 2 to 3, and then annually through year 5. After year 5, imaging was performed as per local standard of care. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). An additional efficacy outcome measure was OS. Of 1177 patients randomized, 1010 (86%) received adjuvant platinum-based chemotherapy following resection. Among these 1010 patients, the median age was 64 years (range: 35 to 84), 49% age 65 or older; 68% male; 77% White, 18% Asian; 86% current or former smokers; and 39% with ECOG PS of 1. Eleven percent had Stage IB, 57% had Stage II, and 31% had Stage IIIA disease. Thirty-nine percent had PD-L1 TPS <1% [negative], 33% had TPS 1-49%, and 28% had TPS ≥50%. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World. The trial met its primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population for patients randomized to the KEYTRUDA arm compared to patients randomized to the placebo arm. In an exploratory subgroup analysis of the 167 patients (14%) who did not receive adjuvant chemotherapy, the DFS HR was 1.25 (95% CI: 0.76, 2.05). OS results were not mature with only 42% of pre-specified OS events in the overall population. Table 72 and Figure 11 summarize the efficacy results for KEYNOTE-091 in patients who received adjuvant chemotherapy.
Table 72: Efficacy Results in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy
Endpoint KEYTRUDA
200 mg every 3 weeks
n=506		 Placebo

n=504
NR = not reached
DFS
  Number (%) of patients with event 177 (35%) 231 (46%)
  Median in months (95% CI) 58.7
(39.2, NR)		 34.9
(28.6, NR)
  Hazard ratioBased on the unstratified univariate Cox regression model (95% CI) 0.73 (0.60, 0.89)
Figure 11: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy
Figure 9 Figure 10 Figure 11
14.3 Malignant Pleural Mesothelioma First-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma (MPM) with pemetrexed and platinum chemotherapy The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-483 (NCT02784171), a multicenter, randomized, open-label, active-controlled trial that enrolled 440 patients with unresectable advanced or metastatic MPM and no prior systemic therapy for advanced/metastatic disease. Patients were enrolled regardless of tumor PD-L1 expression. Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by histological subtype (epithelioid vs. non-epithelioid). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: KEYTRUDA 200 mg with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles. Treatment with KEYTRUDA continued until disease progression as determined by the investigator according to modified RECIST 1.1 for mesothelioma (mRECIST), unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks for 18 weeks, followed by every 12 weeks thereafter. The main efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR, and DoR, as assessed by BICR according to mRECIST. The study population characteristics were: median age of 70 years (77% age 65 or older); 76% male; 79% White, 21% race not reported or unknown; 2% Hispanic or Latino; and 53% ECOG performance status of 1. Seventy-eight percent had epithelioid and 22% had non-epithelioid histology; 60% had tumors with PD-L1 CPS ≥1 and 30% had tumors with PD-L1 CPS <1. The trial demonstrated a statistically significant improvement in OS, PFS, and ORR in patients randomized to KEYTRUDA in combination with chemotherapy compared with patients randomized to chemotherapy alone. Table 73 and Figure 12 summarize the efficacy results for KEYNOTE-483.
Table 73: Efficacy Results in KEYNOTE-483
Endpoint KEYTRUDA
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy		 Pemetrexed
Platinum Chemotherapy
(n=222) (n=218)
OS
  Number (%) of patients with event 167 (75%) 175 (80%)
  Median in months (95% CI) 17.3 (14.4, 21.3) 16.1 (13.1, 18.2)
  Hazard ratioBased on stratified Cox proportional hazard model (95% CI) 0.79 (0.64, 0.98)
  p-ValueBased on stratified log-rank test 0.0162
PFS
  Number (%) of patients with event 190 (86%) 166 (76%)
  Median in months (95% CI) 7.1 (6.9, 8.1) 7.1 (6.8, 7.7)
  Hazard ratio (95% CI) 0.80 (0.65, 0.99)
  p-Value 0.0194
Objective Response Rate
  ORR % (95% CI) 52% (45.5, 59.0) 29% (23.0, 35.4)
    Complete responses 1 (0.5%) 0 (0%)
    Partial responses 115 (52%) 63 (29%)
  p-ValueBased on Miettinen and Nurminen method stratified by histological subtype at randomization (epithelioid vs. non-epithelioid) <0.00001
Duration of Response Based on patients with a best overall response as confirmed complete or partial response; n=116 for patients in the KEYTRUDA combination arm; n=63 for patients in the chemotherapy arm
  Median in months (95% CI) 6.9 (5.8, 8.3) 6.8 (5.5, 8.5)
Figure 12: Kaplan-Meier Curve for Overall Survival in KEYNOTE-483
In a pre-specified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology (n=345), the hazard ratio (HR) for OS was 0.89 (95% CI: 0.70, 1.13), with median OS of 19.8 months in KEYTRUDA in combination with chemotherapy and 18.2 months in chemotherapy alone. In the subgroup of patients with non-epithelioid histology (n=95), the HR for OS was 0.57 (95% CI: 0.36, 0.89), with median OS of 12.3 months in KEYTRUDA in combination with chemotherapy and 8.2 months in chemotherapy alone. Figure 12
14.4 Head and Neck Squamous Cell Cancer
Neoadjuvant and Adjuvant Treatment of Locally Advanced HNSCC for Tumors Expressing PD-L1 (CPS≥ 1) The efficacy of KEYTRUDA was investigated in KEYNOTE-689 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 714 patients with resectable locally advanced (Stage III-IVA) HNSCC [AJCC, 8th edition]. Patients with active autoimmune disease requiring systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by primary tumor site (oropharynx/oral cavity vs. larynx vs. hypopharynx), tumor stage (III vs. IVA) and PD-L1 status (TPS ≥ 50% vs. TPS<50%) according to the PD-L1 IHC 22C3 pharmDx assay. Patients were randomized (1:1) to one of the following treatment arms: neoadjuvant KEYTRUDA 200 mg for 2 cycles prior to surgical resection. Within 6 weeks following surgery, 3 cycles of adjuvant KEYTRUDA 200 mg every 3 weeks in combination with radiotherapy (RT) with or without 3 cycles of cisplatin 100 mg/m2 every 3 weeks. This was followed by KEYTRUDA 200 mg every 3 weeks for up to 12 cycles. no neoadjuvant treatment prior to surgery. Within 6 weeks following surgery, adjuvant RT with or without 3 cycles of concurrent cisplatin 100 mg/m2 every 3 weeks.

On both treatment arms, patients received cisplatin with adjuvant RT if high-risk pathological features (i.e., positive margins <1 mm or extranodal extension) were present at surgery. Treatment with KEYTRUDA continued until disease progression by RECIST v1.1 per BICR during the neoadjuvant phase that precluded surgery, local or metastatic recurrence during the adjuvant phase, completion of treatment, or unacceptable toxicity. Assessment of tumor status was performed prior to surgery at Week 6 in the neoadjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed 12 weeks after end of RT with or without cisplatin treatment and then every 3 months until the end of year 3; then every 6 months thereafter up to the end of year 5. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measure was event-free survival (EFS) by BICR defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant disease progression or recurrence, or death due to any cause. Additional efficacy outcome measures were major pathological response (mPR) as assessed by BIPR, and overall survival (OS). The demographic and baseline characteristics in the 682 patients with PD-L1 expression of CPS ≥1 were: median age of 60 years (range: 22 to 87), 33% age 65 or older; 79% male; 78% White, 13% Asian and 2.5% Black or African American, 14% were Hispanic or Latino; 43% had ECOG PS of 1, and 79% were former/current smokers. Four percent of patients’ tumors were HPV-positive, and 26% had Stage III disease, 74% had Stage IVA disease. Sixty-eight percent of patients’ tumors had PD-L1 expression of CPS ≥10. Eighty-eight percent of patients received definitive surgery in both the KEYTRUDA and the SOC arm. Seventy-six percent of patients in the KEYTRUDA arm and 78% of patients in the SOC arm started the radiation phase of treatment. In the KEYTRUDA arm, 35% of patients received KEYTRUDA and cisplatin with concurrent RT, 57% of patients received KEYTRUDA alone with concurrent RT, 3% of patients received cisplatin alone with concurrent RT, 5% of patients received RT alone and one patient (0.4%) received KEYTRUDA alone without concurrent RT. On the SoC arm, 52% of patients received cisplatin with concurrent RT while 48% patients received RT alone. The trial demonstrated a statistically significant improvement in EFS for patients randomized to the KEYTRUDA arm compared to those randomized to the standard of care (SOC) arm at the first pre-specified interim analysis. Table 74 and Figure 13 summarize efficacy results in KEYNOTE-689 for patients with HNSCC CPS ≥1.
Table 74: Efficacy Results for Perioperative KEYTRUDA with adjuvant RT with or without cisplatin in Patients with HNSCC CPS ≥1 in KEYNOTE-689
Endpoint KEYTRUDA
200 mg every 3 weeks
with
RT with or without cisplatin
n=347		 RT with or without cisplatin
n=335
NR = not reached
  EFS
  Number of events, n (%) 128 (37%) 156 (47%)
  Median in monthsFrom product-limit (Kaplan-Meier) method for censored data. (95% CI) 59.7 (37.9, NR) 29.6 (19.5, 41.9)
  Hazard ratioBased on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by primary tumor site and tumor stage. (95% CI) 0.70 (0.55, 0.89)
  p-ValueOne-sided p-value based on log-rank test stratified by primary tumor site and tumor stage. Compared to a one-sided p-value boundary of 0.0124 , 0.00140
Figure 13: Kaplan-Meier Curve for Event-free Survival for KEYTRUDA in Patients with HNSCC CPS ≥1 in KEYNOTE-689
While OS results were not mature at this interim analysis, with 76% of pre-specified OS events in the CPS≥1 population, no trend towards a detriment was observed. Hypopharyngeal Tumors In an exploratory subgroup analysis of patients with PD-L1-positive (CPS ≥1) hypopharyngeal tumors who were randomized (n=51), the EFS HR was 2.28 (95% CI: 0.79, 6.56). Among these patients, 23 patients in the KEYTRUDA arm received surgery, of which 17 patients (74%) had R0 resections. On the SOC arm, 23 patients received surgery, of which 20 (87%) had R0 resections. Oral Cavity, Oropharyngeal and Laryngeal Tumors In an exploratory subgroup analysis of patients with PD-L1 positive (CPS ≥1) oral cavity, oropharyngeal and laryngeal tumors who received surgery (n=555), 91% of patients on the KEYTRUDA arm had R0 resections while 85% of patients on the SOC arm had R0 resections. First-line treatment of metastatic or unresectable, recurrent HNSCC The efficacy of KEYTRUDA was investigated in KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (TPS ≥50% or <50%) according to the PD-L1 IHC 22C3 pharmDx assay, HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms: KEYTRUDA 200 mg intravenously every 3 weeks KEYTRUDA 200 mg intravenously every 3 weeks, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients' tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx assay was conducted using the tumor specimens used for randomization. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population. The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% had ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients' tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients' tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20. The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population. Table 75 and Figure 14 summarize efficacy results for KEYTRUDA in combination with chemotherapy.
Table 75: Efficacy ResultsResults at a pre-specified interim analysis for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048
Endpoint KEYTRUDA
200 mg every 3 weeks
Platinum
FU		 Cetuximab
Platinum
FU
n=281 n=278
OS
  Number (%) of patients with event 197 (70%) 223 (80%)
  Median in months (95% CI) 13.0 (10.9, 14.7) 10.7 (9.3, 11.7)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.77 (0.63, 0.93)
  p-ValueBased on stratified log-rank test 0.0067
PFS
  Number of patients with event (%) 244 (87%) 253 (91%)
  Median in months (95% CI) 4.9 (4.7, 6.0) 5.1 (4.9, 6.0)
  Hazard ratio (95% CI) 0.92 (0.77, 1.10)
  p-Value 0.3394
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 36% (30.0, 41.5) 36% (30.7, 42.3)
    Complete response rate 6% 3%
    Partial response rate 30% 33%
Duration of Response
  Median in months (range) 6.7 (1.6+, 30.4+) 4.3 (1.2+, 27.9+)
At the pre-specified final OS analysis for the ITT population, the hazard ratio was 0.72 (95% CI: 0.60, 0.87). In addition, KEYNOTE-048 demonstrated a statistically significant improvement in OS for the subgroups of patients with PD-L1 CPS ≥1 (HR=0.65, 95% CI: 0.53, 0.80) and CPS ≥20 (HR=0.60, 95% CI: 0.45, 0.82).
Figure 14: Kaplan-Meier Curve for Overall Survival for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048At the time of the protocol-specified final analysis.
First-line treatment of metastatic or unresectable, recurrent HNSCC for Tumors Expressing PD-L1 (CPS≥ 1) as a single agent The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to KEYTRUDA as a single agent compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis. At the time of the interim and final analyses, there was no significant difference in OS between the KEYTRUDA single agent arm and the control arm for the overall population. Table 76 summarizes efficacy results for KEYTRUDA as a single agent in the subgroups of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC. Figure 15 summarizes the OS results in the subgroup of patients with CPS ≥1 HNSCC.
Table 76: Efficacy ResultsResults at a pre-specified interim analysis for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20)
Endpoint CPS ≥1 CPS ≥20
KEYTRUDA
200 mg every 3 weeks		 Cetuximab
Platinum
FU		 KEYTRUDA
200 mg every 3 weeks		 Cetuximab
Platinum
FU
n=257 n=255 n=133 n=122
OS
  Number of events (%) 177 (69%) 206 (81%) 82 (62%) 95 (78%)
  Median in months (95% CI) 12.3 (10.8, 14.9) 10.3 (9.0, 11.5) 14.9 (11.6, 21.5) 10.7 (8.8, 12.8)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.78 (0.64, 0.96) 0.61 (0.45, 0.83)
  p-ValueBased on a stratified log-rank test 0.0171 0.0015
PFS
  Number of events (%) 225 (88%) 231 (91%) 113 (85%) 111 (91%)
  Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 5.8) 3.4 (3.2, 3.8) 5.0 (4.8, 6.2)
  Hazard ratio (95% CI) 1.15 (0.95, 1.38) 0.97 (0.74, 1.27)
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 19% (14.5, 24.4) 35% (29.1, 41.1) 23% (16.4, 31.4) 36% (27.6, 45.3)
    Complete response rate 5% 3% 8% 3%
    Partial response rate 14% 32% 16% 33%
Duration of Response
  Median in months (range) 20.9 (1.5+, 34.8+) 4.5 (1.2+, 28.6+) 20.9 (2.7, 34.8+) 4.2 (1.2+, 22.3+)
At the pre-specified final OS analysis comparing KEYTRUDA as a single agent to cetuximab in combination with chemotherapy, the hazard ratio for the subgroup of patients with CPS ≥1 was 0.74 (95% CI: 0.61, 0.90) and the hazard ratio for the subgroup of patients with CPS ≥20 was 0.58 (95% CI: 0.44, 0.78). In an exploratory subgroup analysis for patients with CPS 1-19 HNSCC at the time of the pre-specified final OS analysis, the median OS was 10.8 months (95% CI: 9.0, 12.6) for KEYTRUDA as a single agent and 10.1 months (95% CI: 8.7, 12.1) for cetuximab in combination with chemotherapy, with an HR of 0.86 (95% CI: 0.66, 1.12).
Figure 15: Kaplan-Meier Curve for Overall Survival for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1)At the time of the protocol-specified final analysis.
Figure 13 Figure 14 Figure 15
Previously treated recurrent or metastatic HNSCC The efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), a multicenter, non-randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible. Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. The study population characteristics were median age of 60 years, 32% age 65 or older; 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2. The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median DoR had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and DoR were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.
14.5 Classical Hodgkin Lymphoma KEYNOTE-204 The efficacy of KEYTRUDA was investigated in KEYNOTE-204 (NCT02684292), a randomized, open-label, active controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized (1:1) to receive: KEYTRUDA 200 mg intravenously every 3 weeks or Brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks Treatment was continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (up to approximately 2 years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse <12 months after completion vs. relapse ≥12 months after completion). The main efficacy measure was PFS as assessed by BICR using 2007 revised International Working Group criteria. The study population characteristics were: median age of 35 years (range: 18 to 84); 57% male; 77% White, 9% Asian, 3.9% Black. The median number of prior therapies was 2 (range: 1 to 10) in the KEYTRUDA arm and 3 (range: 1 to 11) in the BV arm, with 18% in both arms having 1 prior line. Forty-two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy. Efficacy is summarized in Table 77 and Figure 16.
Table 77: Efficacy Results in Patients with cHL in KEYNOTE-204
Endpoint KEYTRUDA
200 mg every 3 weeks
n=151		 Brentuximab Vedotin
1.8 mg/kg every 3 weeks
n=153
+ Denotes a censored value.
PFS
  Number of patients with event (%) 81 (54%) 88 (58%)
  Median in months (95% CI)Based on Kaplan-Meier estimates. 13.2 (10.9, 19.4) 8.3 (5.7, 8.8)
  Hazard ratioBased on the stratified Cox proportional hazard model. (95% CI) 0.65 (0.48, 0.88)
  p-ValueBased on a stratified log-rank test. One-sided p-Value, with a prespecified boundary of 0.0043. 0.0027
Objective Response Rate
  ORRDifference in ORR is not statistically significant. (95% CI) 66% (57, 73) 54% (46, 62)
    Complete response 25% 24%
    Partial response 41% 30%
Duration of Response
  Median in months (range) 20.7 (0.0+, 33.2+) 13.8 (0.0+, 33.9+)
Figure 16: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-204
KEYNOTE-087 The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), a multicenter, non-randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria. The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior autologous HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy. Efficacy results for KEYNOTE-087 are summarized in Table 78.
Table 78: Efficacy Results in Patients with cHL in KEYNOTE-087
Endpoint KEYTRUDA
200 mg every 3 weeks
n=210Median follow-up time of 9.4 months
Objective Response Rate
  ORR (95% CI) 69% (62, 75)
    Complete response rate 22%
    Partial response rate 47%
Duration of Response
  Median in months (range) 11.1 (0.0+, 11.1)Based on patients (n=145) with a response by independent review
Figure 16
14.6 Primary Mediastinal Large B-Cell Lymphoma The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open-label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR. The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy. For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 79.
Table 79: Efficacy Results in Patients with PMBCL in KEYNOTE-170
Endpoint KEYTRUDA
200 mg every 3 weeks
n=53Median follow-up time of 9.7 months
NR = not reached
Objective Response Rate
  ORR (95% CI) 45% (32, 60)
    Complete response rate 11%
    Partial response rate 34%
Duration of Response
  Median in months (range) NR (1.1+, 19.2+)Based on patients (n=24) with a response by independent review
14.7 Urothelial Cancer
In Combination with Enfortumab Vedotin for the Treatment of Patients with Urothelial Cancer The efficacy of KEYTRUDA in combination with enfortumab vedotin was evaluated in KEYNOTE-A39 (NCT04223856), an open-label, randomized, multicenter trial that enrolled 886 patients with locally advanced or metastatic urothelial cancer who received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded. Patients were randomized 1:1 to receive either: KEYTRUDA 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. KEYTRUDA was given approximately 30 minutes after enfortumab vedotin. Treatment was continued until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, KEYTRUDA was continued for up to 2 years. Gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m2 or carboplatin (AUC = 4.5 or 5) on Day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity for up to 6 cycles. Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases. The median age was 69 years (range: 22 to 91); 77% were male; 67% were White, 22% were Asian, 1% were Black or African American, and 10% were unknown or other; 12% were Hispanic or Latino. Patients had a baseline ECOG performance status of 0 (49%), 1 (47%), or 2 (3%). Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% of patients had metastatic urothelial cancer, including 72% with visceral and 22% with liver metastases, and 5% had locally advanced urothelial cancer. Eighty-five percent of patients had urothelial carcinoma (UC) histology including 6% with UC mixed squamous differentiation and 2% with UC mixed other histologic variants. Forty-six percent of patients were considered cisplatin-ineligible and 54% were considered cisplatin-eligible at time of randomization. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR. The trial demonstrated statistically significant improvements in OS, PFS, and ORR for patients randomized to KEYTRUDA in combination with enfortumab vedotin as compared to platinum-based chemotherapy. Efficacy results were consistent across all stratified patient subgroups. Table 80 and Figures 17 and 18 summarize the efficacy results for KEYNOTE-A39.
Table 80: Efficacy Results in KEYNOTE-A39
Endpoint KEYTRUDA
200 mg every 3 weeks
in combination with
Enfortumab Vedotin
n=442		 Cisplatin or carboplatin
with gemcitabine
n=444
NR = not reached
OS
  Number (%) of patients with event 133 (30%) 226 (51%)
  Median in months (95% CI) 31.5 (25.4, NR) 16.1 (13.9, 18.3)
  Hazard ratioBased on the stratified Cox proportional hazard regression model (95% CI) 0.47 (0.38, 0.58)
  p-ValueTwo-sided p-Value based on stratified log-rank test <0.0001
PFS
  Number (%) of patients with event 223 (50%) 307 (69%)
  Median in months (95% CI) 12.5 (10.4, 16.6) 6.3 (6.2, 6.5)
  Hazard ratio (95% CI) 0.45 (0.38, 0.54)
  p-Value <0.0001
Confirmed Objective Response Rate Includes only patients with measurable disease at baseline (n=437 for KEYTRUDA in combination with enfortumab vedotin, n=441 for chemotherapy).
  ORRBased on patients with a best overall response as confirmed complete or partial response % (95% CI) 68% (63, 72) 44% (40, 49)
  p-ValueTwo-sided p-Value based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility and liver metastases <0.0001
    Complete response 29% 12%
    Partial response 39% 32%
Figure 17: Kaplan-Meier Curve for Overall Survival in KEYNOTE-A39
Figure 18: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A39
In Combination with Enfortumab Vedotin for the Treatment of Cisplatin-Ineligible Patients with Urothelial Cancer The efficacy of KEYTRUDA in combination with enfortumab vedotin was evaluated in KEYNOTE-869 (NCT03288545), an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded from participating in the study. Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received enfortumab vedotin 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by KEYTRUDA 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients were treated until disease progression or unacceptable toxicity. A total of 121 patients received KEYTRUDA in combination with enfortumab vedotin. The median age was 71 years (range: 51 to 91); 74% were male; 85% were White, 5% were Black, 4% were Asian and 6% were other, unknown or not reported. Ten percent of patients were Hispanic or Latino. Forty-five percent of patients had an ECOG performance status of 1 and 15% had an ECOG performance status of 2. Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. Reasons for cisplatin-ineligibility included: 60% with baseline creatinine clearance of 30-59 mL/min, 10% with ECOG PS of 2, 13% with Grade 2 or greater hearing loss, and 16% with more than one cisplatin-ineligibility criteria. At baseline, 97.5% of patients had metastatic urothelial cancer and 2.5% of patients had locally advanced urothelial cancer. Thirty-seven percent of patients had upper tract disease. Eighty-four percent of patients had visceral metastasis at baseline, including 22% with liver metastases. Thirty-nine percent of patients had TCC histology; 13% had TCC with squamous differentiation, and 48% had TCC with other histologic variants. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1. The median follow-up time for the dose escalation cohort + Cohort A was 44.7 months (range 0.7 to 52.4) and for Cohort K was 14.8 months (range: 0.6 to 26.2). Efficacy results are presented in Table 81 below.
Table 81: Efficacy Results in KEYNOTE-869, Combined Dose Escalation Cohort, Cohort A, and Cohort K
Endpoint KEYTRUDA in combination
with Enfortumab Vedotin
n=121
  Confirmed ORR (95% CI) 68% (58.7, 76.0)
    Complete response rate 12%
    Partial response rate 55%
The median duration of response for the dose escalation cohort + Cohort A was 22.1 months (range: 1.0+ to 46.3+) and for Cohort K was not reached (range: 1.2 to 24.1+). Platinum-Ineligible Patients with Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open-label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities, including patients who were not eligible for any platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 74 years; 77% male; and 89% White. Eighty-seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Fifty percent of patients had baseline creatinine clearance of <60 mL/min, 32% had ECOG PS of 2, 9% had ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% had one or more of Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss. Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. The median follow-up time for 370 patients treated with KEYTRUDA was 11.4 months (range 0.1 to 63.8 months). Efficacy results are summarized in Table 82.
Table 82: Efficacy Results in KEYNOTE-052
Endpoint KEYTRUDA
200 mg every 3 weeks
All Subjects
n=370
+ Denotes ongoing response
Objective Response Rate
  ORR (95% CI) 29% (24, 34)
    Complete response rate 10%
    Partial response rate 20%
Duration of Response
  Median in months (range) 33.4
(1.4+, 60.7+)
Figure 17 Figure 18
Platinum-Eligible Patients with Previously Untreated Urothelial Carcinoma The efficacy of KEYTRUDA for the first-line treatment of platinum-eligible patients with locally advanced or metastatic urothelial carcinoma was investigated in KEYNOTE-361 (NCT02853305), a multicenter, randomized, open-label, active-controlled study in 1010 previously untreated patients. The safety and efficacy of KEYTRUDA in combination with platinum-based chemotherapy for previously untreated patients with locally advanced or metastatic urothelial carcinoma has not been established. The study compared KEYTRUDA with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. Among the patients receiving KEYTRUDA plus platinum-based chemotherapy, 44% received cisplatin and 56% received carboplatin. The study did not meet its major efficacy outcome measures of improved PFS or OS in the KEYTRUDA plus chemotherapy arm compared to the chemotherapy-alone arm. Additional efficacy endpoints, including improvement of OS in the KEYTRUDA monotherapy arm, could not be formally tested.
Previously Treated Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients were randomized to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=90), docetaxel 75 mg/m2 (n=92), or vinflunine 320 mg/m2 (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. The study population characteristics were: median age of 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0 and 56% ECOG PS of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens. The study demonstrated statistically significant improvements in OS and ORR for patients randomized to KEYTRUDA as compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 83 and Figure 19 summarize the efficacy results for KEYNOTE-045.
Table 83: Efficacy Results in KEYNOTE-045
KEYTRUDA
200 mg every 3 weeks		 Chemotherapy
n=270 n=272
+ Denotes ongoing response
NR = not reached
OS
  Deaths (%) 155 (57%) 179 (66%)
  Median in months (95% CI) 10.3 (8.0, 11.8) 7.4 (6.1, 8.3)
  Hazard ratioHazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI) 0.73 (0.59, 0.91)
  p-Value (stratified log-rank) 0.004
PFS by BICR
  Events (%) 218 (81%) 219 (81%)
  Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.3, 3.5)
  Hazard ratio (95% CI) 0.98 (0.81, 1.19)
  p-Value (stratified log-rank) 0.833
Objective Response Rate
  ORR (95% CI) 21% (16, 27) 11% (8, 16)
    Complete response rate 7% 3%
    Partial response rate 14% 8%
    p-Value (Miettinen-Nurminen) 0.002
    Median duration of response in months (range) NR
(1.6+, 15.6+)		 4.3
(1.4+, 15.4+)
Figure 19: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045
Neoadjuvant and Adjuvant Treatment of Cisplatin-Ineligible Patients with MIBC in Combination with Enfortumab Vedotin The efficacy of KEYTRUDA in combination with enfortumab vedotin as neoadjuvant treatment and continued after radical cystectomy as adjuvant treatment was investigated in KEYNOTE-905 (NCT03924895), an open-label, randomized, multicenter, active-controlled trial in patients with previously untreated MIBC with predominant urothelial carcinoma histology and who were candidates for radical cystectomy (RC) with pelvic lymph node dissection (PLND) but were ineligible for or declined cisplatin-based chemotherapy. The study excluded patients with primary non-bladder urothelial cancer (i.e., cancer of the ureter, urethra, or renal pelvis) and those with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression. Randomization was stratified by tumor stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), cisplatin-eligibility (cisplatin-ineligible vs cisplatin-eligible but declined), and geographic region (United States vs European Union vs Rest of World). Patients were randomized 1:1 to receive: Neoadjuvant KEYTRUDA 200 mg over 30 minutes as an intravenous infusion on Day 1 and enfortumab vedotin 1.25 mg/kg as an intravenous infusion on Days 1 and 8 of each 21-day cycle for 3 cycles prior to surgery, followed by adjuvant KEYTRUDA 200 mg over 30 minutes on Day 1 of each 21-day cycle for 14 cycles and adjuvant enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle for 6 cycles (n=170). Immediate RC and PLND alone (n=174). Treatment continued until completion of study medications, disease progression, not undergoing or refusal of RC and PLND, disease recurrence in the adjuvant phase, or unacceptable toxicity. Assessment of tumor status, including CT/MRI, was performed at baseline, within 5 weeks prior to RC and PLND, and at 6 weeks post-radical cystectomy. Following RC and PLND, assessment of tumor status, including cystoscopy and urine cytology for patients who did not undergo surgery, was performed every 12 weeks up to 2 years, and every 24 weeks thereafter. The study population characteristics were: median age of 73 years (range: 46 to 87 years); 78% male; 78% White, 16% Asian, 3.2% Multiple, 1.2% Black or African American, 0.3% American Indian or Alaska Native, and 1.2% missing; 6% Hispanic or Latino, 91% not Hispanic or Latino, and 2.9% not reported; 57% had ECOG PS of 0, 29% had ECOG PS of 1, and 14% had ECOG PS of 2; 18% were T2N0, 77% T3/T4aN0, and 4.9% T1-T4aN1. Ninety-one percent of patients had pure urothelial carcinoma histology; 4.4% had urothelial carcinoma with squamous differentiation, 2.6% had urothelial carcinoma with glandular differentiation, and 2% had urothelial carcinoma with other variant histology. Among the 281 patients who were ineligible for cisplatin, 72% had baseline creatinine clearance of 30-59 mL/min, 17% had ECOG PS of 2, 21% had Grade 2 or greater hearing loss, 3.9% had New York Heart Association Class III heart failure, and 13% met more than one cisplatin-ineligibility criterion. A total of 149 (88%) patients in the KEYTRUDA in combination with enfortumab vedotin arm and 156 (90%) patients in the RC and PLND alone arm underwent RC and PLND. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measure was EFS as assessed by BICR. Overall survival (OS) and pathological complete response (pCR) rate as assessed by blinded independent pathology review were additional efficacy outcome measures. The trial demonstrated a statistically significant improvement in EFS and OS in patients treated with neoadjuvant and adjuvant KEYTRUDA in combination with enfortumab vedotin compared with RC and PLND alone. Table 84 and Figures 20 and 21 summarize key efficacy measures.
Table 84: Efficacy Results for Perioperative KEYTRUDA with Enfortumab Vedotin in KEYNOTE-905
Endpoint KEYTRUDA
200 mg every 3 weeks
in combination with
enfortumab vedotin before
and after RC with PLND
n=170		 RC with PLND alone
n=174
NR = not reached
EFS is defined as time from randomization to the first of: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery, or death.
EFS
  Number of patients with event (%) 48 (28%) 95 (55%)
  Median in monthsBased on Kaplan-Meier estimates (95% CI) NR (37.3, NR) 15.7 (10.3, 20.5)
  Hazard ratioBased on stratified Cox regression model with Efron’s method of tie handling with treatment as a covariate (95% CI) 0.40 (0.28, 0.57)
  p-ValueBased on stratified log-rank test <0.0001
OS
  Number of patients with event (%) 38 (22%) 68 (39%)
  Median in months (95% CI) NR (NR, NR) 41.7 (31.8, NR)
  Hazard ratio (95% CI) 0.50 (0.33, 0.74)
  p-Value 0.0002
Figure 20: Kaplan-Meier Curve for Event-Free Survival by Treatment Arm in KEYNOTE-905
Figure 21: Kaplan-Meier Curve for Overall Survival by Treatment Arm in KEYNOTE-905
The trial demonstrated a statistically significant difference in pCR rate (57.1% [95% CI: 49.3, 64.6] vs. 8.6% [95% CI: 4.9, 13.8]; p<0.0001). Figure 19 Figure 20 Figure 21
BCG-unresponsive High-Risk Non-Muscle Invasive Bladder Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-057 (NCT02625961), a multicenter, open-label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The study population characteristics were: median age of 73 years (range: 44 to 92); 44% age ≥75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12. The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarized in Table 85.
Table 85: Efficacy Results in KEYNOTE-057
Endpoint KEYTRUDA
200 mg every 3 weeks
n=96
Complete Response Rate (95% CI) 41% (31, 51)
Duration of Response Based on patients (n=39) that achieved a complete response; reflects period from the time complete response was achieved
  Median in months (range) 16.2 (0.0+, 30.4Denotes ongoing response)
  % (n) with duration ≥12 months 46% (18)
14.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer The efficacy of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancers enrolled in three multicenter, non-randomized, open-label, multi-cohort trials: KEYNOTE-164 (NCT02460198), KEYNOTE-158 (NCT02628067), and KEYNOTE-051 (NCT02332668). All trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumor status was determined using polymerase chain reaction (PCR; local or central) or immunohistochemistry (IHC; local or central), respectively. KEYNOTE-164 enrolled 124 patients with advanced MSI-H or dMMR colorectal cancer (CRC) that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan +/- anti-VEGF/EGFR mAb-based therapy. KEYNOTE-158 enrolled 373 patients with advanced MSI-H or dMMR non-colorectal cancers (non-CRC) who had disease progression following prior therapy. Patients were either prospectively enrolled with MSI-H/dMMR tumors (Cohort K) or retrospectively identified in one of 10 solid tumor cohorts (Cohorts A-J). KEYNOTE-051 enrolled 7 pediatric patients with MSI-H or dMMR cancers. Adult patients received KEYTRUDA 200 mg every 3 weeks (pediatric patients received 2 mg/kg every 3 weeks) until unacceptable toxicity, disease progression, or a maximum of 24 months. In KEYNOTE-164 and KEYNOTE-158, assessment of tumor status was performed every 9 weeks through the first year, then every 12 weeks thereafter. In KEYNOTE-051, assessment of tumor status was performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST v1.1 in KEYNOTE-051. In KEYNOTE-164 and KEYNOTE-158, the study population characteristics were median age of 60 years, 36% age 65 or older; 44% male; 78% White, 14% Asian, 4% American Indian or Alaska Native, and 3% Black; and 45% ECOG PS of 0 and 55% ECOG PS of 1. Ninety-two percent of patients had metastatic disease and 4% had locally advanced, unresectable disease. Thirty-seven percent of patients received one prior line of therapy and 61% received two or more prior lines of therapy. In KEYNOTE-051, the study population characteristics were median age of 11 years (range: 3 to 16); 71% female; 86% White and 14% Asian; and 57% had a Lansky/Karnofsky Score of 100. Seventy-one percent of patients had Stage IV and 14% had Stage III disease. Fifty-seven percent of patients received one prior line of therapy and 29% received two prior lines of therapy. Discordant results were observed between local MSI-H or dMMR tests and central testing among patients enrolled in Cohort K of KEYNOTE-158. Among 104 tumor samples that were MSI-H or dMMR by local testing and also tested using the FoundationOne®CDx (F1CDx) test, 59 (56.7%) were MSI-H and 45 (43.3%) were not MSI-H. Among 169 tumor samples that were MSI-H or dMMR by local testing and also tested using the VENTANA MMR RxDx Panel, 105 (62.1%) were dMMR and 64 (37.9%) were pMMR. Efficacy results are summarized in Tables 86 and 87.
Table 86: Efficacy Results for Patients with MSI-H/dMMR Cancer
Endpoint KEYTRUDA
n=504Median follow-up time of 20.1 months (range 0.1 to 71.4 months)
+ Denotes ongoing response
Objective Response Rate
  ORR (95% CI)Of the 7 pediatric patients from KEYNOTE-051, 1 patient had a radiographic complete response after initial growth of their tumor but is not reflected in the results. 33.3% (29.2, 37.6)
    Complete response rate 10.3%
    Partial response rate 23.0%
Duration of Response n=168
    Median in months (range) 63.2 (1.9+, 63.9+)
    % with duration ≥12 months 77%
    % with duration ≥36 months 39%
Table 87: Response by Tumor Type
Objective Response Rate Duration of
Response range
N n (%) 95% CI (months)
+ Denotes ongoing response
CRC 124 42 (34%) (26%, 43%) (4.4, 58.5+)
Non-CRCResults include patients in Cohort K of KEYNOTE-158 that were later determined to be pMMR or not MSI-H by central testing 380 126 (33%) (28%, 38%) (1.9+, 63.9+)
  Endometrial cancer 94 47 (50%) (40%, 61%) (2.9, 63.2)
  Gastric or GE junction cancer 51 20 (39%) (26%, 54%) (1.9+, 63.0+)
  Small intestinal cancer 27 16 (59%) (39%, 78%) (3.7+, 57.3+)
  Brain cancer 27Includes 6 pediatric patients with brain cancer 1 (4%)In addition to the 1 adult responder, 1 pediatric patient had a radiographic complete response after initial growth of their tumor. (0%, 19%) 18.9
  Ovarian cancer 25 8 (32%) (15%, 54%) (4.2, 56.6+)
  Biliary cancer 22 9 (41%) (21%, 64%) (6.2, 49.0+)
  Pancreatic cancer 22 4 (18%) (5%, 40%) (8.1, 24.3+)
  Sarcoma 14 3 (21%) (5%, 51%) (35.4+, 57.2+)
  Breast cancer 13 1 (8%) (0%,36%) 24.3+
  OtherIncludes tumor type (n): anal (3), HNSCC (1), nasopharyngeal (1), retroperitoneal (1), testicular (1), vaginal (1), vulvar (1), appendiceal adenocarcinoma, NOS (1), hepatocellular carcinoma (1), and carcinoma of unknown origin (1). Includes 1 pediatric patient with abdominal adenocarcinoma. 13 4 (31%) (9%, 61%) (6.2+, 32.3+)
  Cervical cancer 11 1 (9%) (0%, 41%) 63.9+
  Neuroendocrine cancer 11 1 (9%) (0%, 41%) 13.3
  Prostate cancer 8 1 (13%) (0%, 53%) 24.5+
  Adrenocortical cancer 7 1 (14%) (0%, 58%) 4.2
  Mesothelioma 7 0 (0%) (0%, 41%)
  Thyroid cancer 7 1 (14%) (0%, 58%) 8.2
  Small cell lung cancer 6 2 (33%) (4%, 78%) (20.0, 47.5)
  Bladder cancer 6 3 (50%) (12%, 88%) (35.6+, 57.5+)
  Salivary cancer 5 2 (40%) (5%, 85%) (42.6+, 57.8+)
  Renal cell cancer 4 1 (25%) (0%, 81%) 22.0
Exploratory analysis by TMB In an exploratory analysis performed in 138 patients (Cohort K of KEYNOTE-158) who were tested retrospectively for tumor mutation burden (TMB) using an FDA-authorized test, 45 (33%) had tumors with TMB score of <10 mut/Mb; ORR in these 45 patients was 6.7% (95% CI: 1.4, 18.3). Among the 45 patients with TMB score of <10 mut/Mb, 39 of the patients were pMMR/not MSI-H when tested using an FDA-authorized test.
14.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-177 (NCT02563002), a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC. MSI or MMR tumor status was determined locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of the following chemotherapy regimens given intravenously every 2 weeks: mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly. FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly. Treatment with KEYTRUDA or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measures were PFS (as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) and OS. Additional efficacy outcome measures were ORR and DoR. A total of 307 patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range: 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an ECOG PS of 0 and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among 154 patients randomized to receive chemotherapy,143 received chemotherapy per the protocol. Of the 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI. The trial demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA compared with chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy in the final OS analysis. Sixty percent of the patients who had been randomized to receive chemotherapy had crossed over to receive subsequent anti-PD-1/PD-L1 therapies including KEYTRUDA. The median follow-up time at the final analysis was 38.1 months (range: 0.2 to 58.7 months). Table 88 and Figure 22 summarize the key efficacy measures for KEYNOTE-177.
Table 88: Efficacy Results in Patients with MSI-H or dMMR CRC in KEYNOTE-177
Endpoint KEYTRUDA
200 mg every 3 weeks
n=153 		Chemotherapy
 
n=154
+ Denotes ongoing response
NR = not reached
PFS
  Number (%) of patients with event 82 (54%) 113 (73%)
  Median in months (95% CI) 16.5 (5.4, 32.4) 8.2 (6.1, 10.2)
  Hazard ratio Based on Cox regression model (95% CI) 0.60 (0.45, 0.80)
  p-ValueTwo-sided p-Value based on log-rank test (compared to a significance level of 0.0234) 0.0004
OSFinal OS analysis
  Number (%) of patients with event 62 (41%) 78 (51%)
  Median in months (95% CI) NR (49.2, NR) 36.7 (27.6, NR)
  Hazard ratio (95% CI) 0.74 (0.53, 1.03)
  p-ValueTwo-sided p-Value based on log-rank test (compared to a significance level of 0.0492) 0.0718
Objective Response Rate Based on confirmed response by BICR review
  ORR (95% CI) 44% (35.8, 52.0) 33% (25.8, 41.1)
    Complete response rate 11% 4%
    Partial response rate 33% 29%
Duration of Response , Based on n=67 patients with a response in the KEYTRUDA arm and n=51 patients with a response in the chemotherapy arm
  Median in months (range) NR (2.3+, 41.4+) 10.6 (2.8, 37.5+)
  % with duration ≥12 monthsBased on observed duration of response 75% 37%
  % with duration ≥24 months 43% 18%
Figure 22: Kaplan-Meier Curve for PFS in KEYNOTE-177
Figure 22
14.10 Gastric Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma for Tumors Expressing PD-L1 (CPS≥1) The efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 698 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx assay. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms: KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle. Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. The major outcome measures assessed were PFS by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Additional outcome measures included ORR and DoR, based on BICR using RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 698 patients, randomized, 594 (85%) had tumors that expressed PD-L1 with a CPS ≥1. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx assay. The population characteristics of these 594 patients were: median age of 63 years (range: 19 to 85), 43% age 65 or older; 80% male; 63% White, 33% Asian, and 0.7% Black; 42% ECOG PS of 0 and 58% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease (Stage IV) and 2% had locally advanced unresectable disease. Ninety-five percent (n=562) had tumors that were not MSI-H, 1% (n=8) had tumors that were MSI-H, and in 4% (n=24) the status was not known. Eighty-five percent of patients received CAPOX. A statistically significant improvement in OS and PFS was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy; however, an exploratory analysis of OS in the PD-L1 CPS <1 population showed a HR of 1.10 (95% CI: 0.72, 1.68), indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 CPS ≥1. Efficacy results at the final analysis for the subgroup of patients whose tumors expressed PD-L1 with a CPS ≥1 are summarized in Table 89 and Figure 23.
Table 89: Efficacy Results for KEYNOTE-811 with PD-L1 Expression CPS ≥1
Endpoint KEYTRUDA
200 mg every 3 weeks
Trastuzumab
Fluoropyrimidine and Platinum Chemotherapy
n=298		 Placebo

Trastuzumab
Fluoropyrimidine and
Platinum Chemotherapy
n=296
+ Denotes ongoing response
OS
  Number (%) of patients with event 226 (76%) 244 (82%)
  Median in monthsBased on Kaplan-Meier estimation (95% CI) 20.1 (17.9, 22.9) 15.7 (13.5, 18.5)
  Hazard ratioBased on the unstratified Cox proportional hazard model (95% CI) 0.79 (0.66, 0.95)
PFS
  Number (%) of patients with event 221 (74%) 226 (76%)
  Median in months (95% CI) 10.9 (8.5, 12.5) 7.3 (6.8, 8.4)
  Hazard ratio (95% CI) 0.72 (0.60, 0.87)
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 73% (68, 78) 58% (53, 64)
    Complete response rate 17% 10%
    Partial response rate 56% 48%
Duration of Response n=218 n=173
  Median in months (95% CI) 11.3 (9.9, 13.7) 9.6 (7.1, 11.2)
  Range in months 1.1+, 60.8+ 1.4+, 60.5+
Figure 23: Kaplan-Meier Curve for Overall Survival by Treatment Arm in KEYNOTE-811 (CPS ≥1)
First-line Treatment of Locally Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma for Tumors Expressing PD-L1 (CPS≥ 1) The efficacy of KEYTRUDA in combination with fluoropyrimidine- and platinum-containing chemotherapy was investigated in KEYNOTE-859 (NCT03675737), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (FP or CAPOX), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms; treatment was administered prior to chemotherapy on Day 1 of each cycle: KEYTRUDA 200 mg, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). Placebo, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Platinum agents could be administered for 6 or more cycles following local guidelines. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. The major efficacy outcome measure was OS. Additional secondary efficacy outcome measures included PFS, ORR, and DoR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among 1,579 patients, 1,235 (78%) had tumors expressing PD-L1 CPS ≥ 1. The population characteristics in patients with PD-L1 CPS ≥ 1 expressing tumors were: median age of 62 years (range: 24 to 86), 40% age 65 or older; 70% male and 30% female; 55% White, 33% Asian, 4.6% Multiple, 4.3% American Indian or Alaskan Native, 1.3% Black, and 0.2% Native Hawaiian or other Pacific Islander; 76% Not Hispanic or Latino and 21% Hispanic or Latino; 37% ECOG PS of 0 and 63% ECOG PS of 1. Ninety-six percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Five percent (n=66) had tumors that were MSI-H. Eighty-six percent of patients received CAPOX. A statistically significant improvement in OS, PFS, and ORR was demonstrated in patients randomized to KEYTRUDA in combination with chemotherapy compared with placebo in combination with chemotherapy at the time of a pre-specified interim analysis of OS; however, an exploratory analysis of OS in the PD-L1 CPS <1 population showed a HR of 0.92 (95% CI 0.73, 1.17) indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 CPS ≥1. Efficacy results for patients whose tumors expressed PD-L1 CPS ≥1 and CPS ≥10 are summarized in Table 90 and Figures 24 and 25.
Table 90: Efficacy ResultsBased on a pre-specified interim analysis for KEYNOTE-859
Endpoint KEYTRUDA
200 mg every 3
weeks
and
FP or CAPOX
n=618		 Placebo


and
FP or CAPOX
n=617		 KEYTRUDA
200 mg every 3
weeks
and
FP or CAPOX
n=279		 Placebo


and
FP or CAPOX
n=272
CPS ≥1 CPS ≥10
+ Denotes ongoing response
OS
  Number (%) of patients with event 464 (75) 526 (85) 188 (67) 226 (83)
  Median in months (95% CI) 13.0 (11.6, 14.2) 11.4 (10.5, 12.0) 15.7 (13.8, 19.3) 11.8 (10.3, 12.7)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.74 (0.65, 0.84) 0.65 (0.53, 0.79)
  p-Value (stratified log-rank)One-sided p-Value based on stratified log-rank test <0.0001 <0.0001
PFS
  Number (%) of patients with event 443 (72%) 483 (78%) 190 (68) 210 (77)
  Median in months (95% CI) 6.9 (6.0, 7.2) 5.6 (5.4, 5.7) 8.1 (6.8, 8.5) 5.6 (5.4, 6.7)
  Hazard ratio (95% CI) 0.72 (0.63, 0.82) 0.62 (0.51, 0.76)
  p-Value (stratified log-rank) <0.0001 <0.0001
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 52% (48, 56) 43% (39, 47) 61% (55, 66) 43% (37, 49)
    Complete response rate 10% 6% 13% 5%
    Partial response rate 42% 37% 48% 38%
  p-ValueOne-sided p-Value based on stratified Miettinen & Nurminen method 0.0004 <0.0001
Duration of Response n=322 n=263 n=169 n=117
  Median in monthsBased on Kaplan-Meier estimates (95% CI) 8.3 (7.0, 10.9) 5.6 (5.4, 6.9) 10.9 (8.0, 13.8) 5.8 (5.3, 7.0)
  Range in months 1.2+, 41.5+ 1.3+, 34.2+ 1.2+, 41.5+ 1.4+, 31.2+
Figure 24: Kaplan-Meier Curve for Overall Survival in KEYNOTE-859 (CPS≥1)
Figure 25: Kaplan-Meier Curve for Overall Survival in KEYNOTE-859 (CPS≥10)
An exploratory analysis of OS in the 74 patients with MSI-H tumors irrespective of PD-L1 status showed a HR of 0.34 (95% CI: 0.18, 0.66). Figure 23 Figure 24 Figure 25
14.11 Esophageal Cancer
First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal/Gastroesophageal Junction Cancer for Tumors Expressing PD-L1 (CPS≥ 1) KEYNOTE-590 The efficacy of KEYTRUDA was investigated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx assay. Patients with active autoimmune disease, a medical condition that required immunosuppression, or who received prior systemic therapy in the locally advanced or metastatic setting were ineligible. Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: KEYTRUDA 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months. Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months. Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, CPS ≥10, and in all patients. Additional efficacy outcome measures were ORR and DoR, according to modified RECIST v1.1, as assessed by the investigator. Additional analyses of efficacy outcome measures were also conducted based on PD-L1 CPS ≥1. Among 749 patients, 647 (86%) had tumors expressing PD-L1 CPS ≥ 1. The study population characteristics in patients with PD-L1 CPS ≥ 1 expressing tumors were: median age of 63 years (range: 27 to 89), 41% age 65 or older; 83% male; 36% White, 54% Asian, and 1% Black; 40% had an ECOG PS of 0 and 59% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-four percent had a tumor histology of squamous cell carcinoma, and 26% had adenocarcinoma. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy compared to chemotherapy; however, an exploratory analysis of OS in the PD-L1 CPS <1 population showed an HR of 0.96 (0.59, 1.55), indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 CPS ≥1. Table 91 and Figures 26 and 27 summarize the efficacy results for KEYNOTE-590 in patients whose tumors expressed PD-L1 CPS ≥1 and CPS ≥10.
Table 91: Efficacy Results in Patients with Locally Advanced Unresectable or Metastatic Esophageal Cancer in KEYNOTE-590
Endpoint KEYTRUDA
200 mg every 3 weeks
Cisplatin
FU
n=320		 Placebo
Cisplatin
FU

n=327		 KEYTRUDA
200 mg every 3 weeks
Cisplatin
FU
n=186		 Placebo
Cisplatin
FU

n=197
CPS ≥ 1 CPS ≥ 10
OS
  Number (%) of events 222 (69) 271 (83) 124 (67) 165 (84)
  Median in months
  (95% CI)		 12.7
(10.5, 14.4)		 9.8
(8.8, 10.8)		 13.5
(11.1, 15.6)		 9.4
(8.0, 10.7)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.71 (0.59, 0.84) 0.62 (0.49, 0.78)
  p-ValueBased on a stratified log-rank test; p-Value for CPS ≥ 1 not included (not pre-specified subgroup) <0.0001
PFS
  Number of events (%) 252 (79) 291 (89) 140 (75) 174 (88)
  Median in months
  (95% CI)		 6.3
(6.2, 7.1)		 5.7
(4.6, 6.0)		 7.5
(6.2, 8.2)		 5.5
(4.3, 6.0)
  Hazard ratio (95% CI) 0.62 (0.52, 0.73) 0.51 (0.41, 0.65)
  p-Value <0.0001
Objective Response Rate
  ORR, %Confirmed complete response or partial response
  (95% CI)		 45
(40, 51)		 29
(24, 34)		 51
(44, 59)		 27
(21, 34)
    Number (%) of complete responses 19 (6) 9 (2.8) 11 (6) 5 (2.5)
    Number (%) of partial responses 126 (39) 85 (26) 84 (45) 48 (24)
Duration of Response
  Median in months
  (range) 		8.6
(1.2+, 31.0+)		 5.8
(1.5+, 25.0+)		 10.4
(1.9+, 28.9+)		 5.6
(1.5+, 25.0+)
Figure 26: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590 (CPS ≥1)
Figure 27: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590 (CPS ≥10)
In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n=383), the median was 13.5 months (95% CI: 11.1, 15.6) for the KEYTRUDA arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n=347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the KEYTRUDA arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10). Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer for Tumors Expressing PD-L1 (CPS≥ 10) KEYNOTE-181 The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx assay. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator's choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator's treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS ≥10. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator's treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirty-three percent of patients received prior treatment with a taxane. The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 92 and Figure 28 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10.
Table 92: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS ≥10) in KEYNOTE-181
Endpoint KEYTRUDA
200 mg every 3 weeks
n=85		 Chemotherapy
 
n=82
OS
  Number (%) of patients with event 68 (80%) 72 (88%)
  Median in months (95% CI) 10.3 (7.0, 13.5) 6.7 (4.8, 8.6)
  Hazard ratioBased on the Cox regression model stratified by geographic region (Asia vs. ex-Asia) (95% CI) 0.64 (0.46, 0.90)
PFS
  Number (%) of patients with event 76 (89%) 76 (93%)
  Median in months (95% CI) 3.2 (2.1, 4.4) 2.3 (2.1, 3.4)
  Hazard ratio (95% CI) 0.66 (0.48, 0.92)
Objective Response Rate
  ORR (95% CI) 22 (14, 33) 7 (3, 15)
  Number (%) of complete responses 4 (5) 1 (1)
  Number (%) of partial responses 15 (18) 5 (6)
  Median duration of response in months (range) 9.3 (2.1+, 18.8+) 7.7 (4.3, 16.8+)
Figure 28: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS ≥10)
Figure 26 Figure 27 Figure 28
KEYNOTE-180 The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, non-randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS ≥10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease. The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer.
14.12 Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer The efficacy of KEYTRUDA in combination with CRT (cisplatin and external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1060 patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. There were 599 patients with FIGO 2014 Stage III-IVA disease (tumor involves the lower third of the vagina or the pelvic sidewall, or there is hydronephrosis/non-functioning kidney or spread to adjacent pelvic organs, all without spread to distant organs), and 459 patients with FIGO 2014 Stage IB2-IIB disease (clinical lesion >4 cm confined to the cervix, or clinical lesion of any size with extension beyond the uterus, but which has not extended to the pelvic wall or lower third of the vagina) with positive nodes. Two patients had FIGO 2014 Stage IVB disease. Randomization was stratified by planned type of EBRT (Intensity-modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT] vs. non-IMRT and non-VMAT), stage at screening of cervical cancer (FIGO 2014 Stage IB2-IIB vs. FIGO 2014 Stage III-IVA), and planned total radiotherapy dose (EBRT + brachytherapy dose of <70 Gy vs. ≥70 Gy as per equivalent dose [EQD2]). Patients were randomized (1:1) to one of two treatment arms: KEYTRUDA 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by KEYTRUDA 400 mg IV every 6 weeks (15 cycles) Placebo IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by placebo IV every 6 weeks (15 cycles) Treatment continued until RECIST v1.1-defined progression of disease as determined by investigator or unacceptable toxicity. Assessment of tumor status was performed every 12 weeks from completion of CRT for the first two years, followed by every 24 weeks in year 3, and then annually. The major efficacy outcome measures were PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, or histopathologic confirmation, and OS. Among the 599 patients with FIGO 2014 Stage III-IVA disease, the baseline characteristics were: median age of 52 years (range: 22 to 87), 17% age 65 or older; 36% White, 34% Asian, 2% Black; 38% Hispanic or Latino; 68% ECOG PS 0 and 32% ECOG PS 1; 93% with CPS ≥1; 71% had positive pelvic and/or positive para-aortic lymph node(s) and 29% had neither positive pelvic nor para-aortic lymph node(s); 83% had squamous cell carcinoma and 17% had non-squamous histology. Regarding radiation, 86% of patients received IMRT or VMAT EBRT, and the median EQD2 dose was 87 Gy (range: 7 to 114). The trial demonstrated statistically significant improvements in PFS and OS in the ITT population. Exploratory analyses of PFS and OS by the stratification factor of FIGO 2014 stage showed that the improvement in the ITT population was primarily attributed to the results seen in the patients with FIGO 2014 Stage III-IVA disease. Table 93 and Figures 29 and 30 summarize the results in exploratory subgroup analyses of 599 patients with FIGO 2014 Stage III-IVA disease.
Table 93: Efficacy Results in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer)
Endpoint KEYTRUDA
200 mg every 3 weeks and
400 mg every 6 weeks
with CRT
n=295		 Placebo


with CRT
n=304
CRT = Chemoradiotherapy
NR = not reached
OSResults at the time of pre-specified final analysis for OS
  Number of patients with event (%) 61 (21) 90 (30)
  Hazard ratioBased on the unstratified Cox proportional hazard model (95% CI) 0.65 (0.47, 0.90)
PFS by InvestigatorResults at the time of first pre-specified interim analysis for PFS
  Number of patients with event (%) 61 (21) 94 (31)
  Median in months (95% CI) NR (NR, NR) NR (18.8, NR)
  12-month PFS rate (95% CI) 81% (75, 85) 70% (64, 76)
  Hazard ratio (95% CI) 0.59 (0.43, 0.81)
Figure 29: Kaplan-Meier Curve for Overall Survival in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer)
Figure 30: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer)
Persistent, Recurrent, or Metastatic Cervical Cancer for Tumors Expressing PD-L1 (CPS≥ 1) The efficacy of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups: Treatment Group 1: KEYTRUDA 200 mg plus chemotherapy with or without bevacizumab Treatment Group 2: Placebo plus chemotherapy with or without bevacizumab The investigator selected one of the following four treatment regimens prior to randomization: Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg All study medications were administered as an intravenous infusion. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each 3-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every 9 weeks for the first year, followed by every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by investigator. Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. The baseline characteristics of the 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, 6% American Indian or Alaska Native, and 1% Black; 37% Hispanic or Latino; 56% ECOG performance status 0 and 43% ECOG performance status 1. Seventy-five percent had squamous cell carcinoma, 21% adenocarcinoma, and 5% adenosquamous histology, and 32% of patients had metastatic disease at diagnosis. At study entry, 21% of patients had metastatic disease only and 79% had persistent or recurrent disease with or without distant metastases, of whom 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery. A statistically significant improvement in OS and PFS was demonstrated in patients randomized to receive KEYTRUDA compared with patients randomized to receive placebo. An updated OS analysis was conducted at the time of final analysis when 354 deaths in the CPS ≥1 population were observed. Table 94 and Figure 31 summarize the key efficacy measures for KEYNOTE-826 for patients with tumors expressing PD-L1 (CPS ≥1).
Table 94: Efficacy Results in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-826
Endpoint KEYTRUDA
200 mg every 3 weeks
and chemotherapyChemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab
n=273		 Placebo

and chemotherapy with or without bevacizumab
n=275
+ Denotes ongoing response
NR = not reached
OS
  Number of patients with event (%) 118 (43.2) 154 (56.0)
  Median in months (95% CI) NR (19.8, NR) 16.3 (14.5, 19.4)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.64 (0.50, 0.81)
  p-Valuep-Value (one-sided) is compared with the allocated alpha of 0.0055 for this interim analysis (with 72% of the planned number of events for final analysis) 0.0001
Updated OS
  Number of patients with event (%) 153 (56.0%) 201 (73.1%)
  Median in months (95% CI) 28.6 (22.1, 38.0) 16.5 (14.5, 20.0)
  Hazard ratio (95% CI) 0.60 (0.49, 0.74)
PFS
  Number of patients with event (%) 157 (57.5) 198 (72.0)
  Median in months (95% CI) 10.4 (9.7, 12.3) 8.2 (6.3, 8.5)
  Hazard ratio (95% CI) 0.62 (0.50, 0.77)
  p-Valuep-Value (one-sided) is compared with the allocated alpha of 0.0014 for this interim analysis (with 82% of the planned number of events for final analysis) < 0.0001
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 68% (62, 74) 50% (44, 56)
    Complete response rate 23% 13%
    Partial response rate 45% 37%
Duration of Response
  Median in months (range) 18.0 (1.3+, 24.2+) 10.4 (1.5+, 22.0+)
Figure 31: Kaplan-Meier Curve for Overall Survival in KEYNOTE-826 (CPS ≥1)Treatment arms include KEYTRUDA plus chemotherapy, with or without bevacizumab, versus placebo plus chemotherapy, with or without bevacizumab. , Based on the protocol-specified final OS analysis
Previously Treated Recurrent or Metastatic Cervical Cancer for Tumors Expressing PD-L1 (CPS≥ 1) The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx assay. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). Efficacy results are summarized in Table 95 for patients with PD-L1 expression (CPS ≥1).
Table 95: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158
Endpoint KEYTRUDA
200 mg every 3 weeks
n=77Median follow-up time of 11.7 months (range 0.6 to 22.7 months)
+ Denotes ongoing response
NR = not reached
Objective Response Rate
  ORR (95% CI) 14.3% (7.4, 24.1)
    Complete response rate 2.6%
    Partial response rate 11.7%
Duration of Response
  Median in months (range) NR (4.1, 18.6+)Based on patients (n=11) with a response by independent review
  % with duration ≥6 months 91%
Figure 29 Figure 30 Figure 31
14.13 Hepatocellular Carcinoma Previously Treated HCC The efficacy of KEYTRUDA was investigated in KEYNOTE-394 (NCT03062358), a multicenter, randomized, placebo-controlled, double-blind trial conducted in Asia in patients with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC, who were previously treated with sorafenib or oxaliplatin-based chemotherapy and who were not amenable to or were refractory to local-regional therapy. Patients were also required to have Child-Pugh A liver function. Patients with hepatitis B had treated controlled disease (HBV viral load <2000 IU/mL or <104 copies/mL). Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Patients with hepatic encephalopathy, main branch portal venous invasion, clinically apparent ascites, or esophageal or gastric variceal bleeding within the last 6 months were also ineligible. Randomization was stratified by prior treatment: sorafenib vs. oxaliplatin-based chemotherapy, macrovascular invasion, and etiology (active HBV vs. others (active HCV, non-infected)). Patients were randomized (2:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or placebo. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks. The main efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR, and DoR, as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study enrolled 453 patients, and 360 (79%) had active hepatitis B. The population characteristics in patients with active hepatitis B were: median age of 52 years (range: 23 to 82), 16% age 65 or older; 86% male; 100% Asian; 42% ECOG PS of 0 and 58% ECOG PS of 1; 90% received prior sorafenib and 10% received prior oxaliplatin-based chemotherapy. Patient characteristics also included extrahepatic disease (77%), macrovascular invasion (10%), BCLC stage C (93%) and B (7%), and baseline AFP ≥200 ng/mL (57%). KEYNOTE-394 demonstrated improved OS in patients with HCC secondary to hepatitis B randomized to KEYTRUDA compared with placebo. Efficacy results are summarized in Table 96 and Figure 32.
Table 96: Efficacy Results in Patients with Hepatocellular Carcinoma in KEYNOTE-394
Endpoint KEYTRUDA
200 mg every 3 weeks

n=236		 Placebo


n=124
+ Denotes ongoing response
OS Results at the pre-specified final OS analysis
  Number (%) of patients with events 172 (73) 105 (85)
  Median in months (95% CI) 13.9 (12.5, 17.9) 13.0 (10.1, 15.6)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.78 (0.61, 0.99)
PFS Results at pre-specified interim OS analysis
  Number (%) of patients with events 189 (80) 108 (87)
  Median in months (95% CI) 2 (1.4, 2.7) 2.3 (1.4, 2.8)
  Hazard ratio (95% CI) 0.78 (0.61, 1.00)
Objective Response Rate
  ORRConfirmed complete response or partial response (95% CI) 11% (7, 16) 1.6% (0.2, 5.7)
    Number (%) of complete responses 2 (0.9%) 1 (0.8%)
    Number (%) of partial responses 24 (10%) 1 (0.8%)
Duration of Response n=28 n=2
  Median in monthsBased on Kaplan-Meier estimate (range) 23.9 (2.6+, 44.4+) 5.6 (3.0+, 5.6)
Figure 32: Kaplan-Meier Curve for Overall Survival in KEYNOTE-394
14.14 Biliary Tract Cancer The efficacy of KEYTRUDA in combination with gemcitabine and cisplatin chemotherapy was investigated in KEYNOTE-966 (NCT04003636), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1069 patients with locally advanced unresectable or metastatic BTC, who had not received prior systemic therapy in the advanced disease setting. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by region (Asia vs. non-Asia), locally advanced versus metastatic, and site of origin (gallbladder, intrahepatic or extrahepatic cholangiocarcinoma). Patients were randomized (1:1) to KEYTRUDA 200 mg on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks, or placebo on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks. Study medications were administered via intravenous infusion. Treatment continued until unacceptable toxicity or disease progression. For pembrolizumab, treatment continued for a maximum of 35 cycles, or approximately 24 months. For gemcitabine, treatment could be continued beyond 8 cycles while for cisplatin, treatment could be administered for a maximum of 8 cycles. Administration of KEYTRUDA with chemotherapy was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Assessment of tumor status was performed at baseline and then every 6 weeks through 54 weeks, followed by every 12 weeks thereafter. Study population characteristics were median age of 64 years (range: 23 to 85), 47% age 65 or older; 52% male; 49% White, 46% Asian, 1.3% Black or African American; 10% Hispanic or Latino; 46% ECOG PS of 0 and 54% ECOG PS of 1; 31% of patients had a history of hepatitis B infection, and 3% had a history of hepatitis C infection. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Table 97 and Figure 33 summarize the efficacy results for KEYNOTE-966.
Table 97: Efficacy Results in KEYNOTE-966
Endpoint KEYTRUDA
200 mg every 3 weeks
with
gemcitabine/cisplatin
n=533		 Placebo with
gemcitabine/cisplatin


n=536
NS = not significant
OSResults at the pre-specified final OS analysis
  Number of patients with event (%) 414 (78%) 443 (83%)
  Median in months (95% CI) 12.7 (11.5, 13.6) 10.9 (9.9, 11.6)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.83 (0.72, 0.95)
  p-ValueOne-sided p-Value based on a stratified log-rank test 0.0034
PFS Results at pre-specified final analysis of PFS and ORR
  Number (%) of patients with event 361 (68%) 391 (73%)
  Median in months (95% CI) 6.5 (5.7, 6.9) 5.6 (5.1, 6.6)
  Hazard ratio (95% CI) 0.86 (0.75, 1.00)
  p-Value NS
Objective Response Rate
  ORRConfirmed complete response or partial response (95% CI) 29% (25, 33) 29% (25, 33)
    Number (%) of complete responses 11 (2.1%) 7 (1.3%)
    Number (%) of partial responses 142 (27%) 146 (27%)
    p-Value One-sided p-Value based on the stratified Miettinen and Nurminen analysis NS
Duration of Response n=156 n=152
  Median in months Based on Kaplan-Meier estimate (95% CI) 8.3 (6.9, 10.2) 6.8 (5.7, 7.1)
Figure 33: Kaplan-Meier Curve for Overall Survival in KEYNOTE-966
Figure 32 Figure 33
14.15 Merkel Cell Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603) and KEYNOTE-913 (NCT03783078), two multicenter, non-randomized, open-label trials that enrolled 105 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 2 mg/kg (KEYNOTE-017) or 200 mg (KEYNOTE-913) every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1. Among the 105 patients enrolled, the median age was 73 years (range: 38 to 91), 79% were age 65 or older; 62% were male; 80% were White, race in 19% was unknown or missing, and 1% were Asian; 53% had ECOG PS of 0, and 47% had ECOG PS of 1. Thirteen percent had stage IIIB disease and 84% had stage IV. Seventy-six percent of patients had prior surgery and 51% had prior radiation therapy. Efficacy results are summarized in Table 98.
Table 98: Efficacy Results in KEYNOTE-017 and KEYNOTE-913
Endpoint KEYNOTE-017
KEYTRUDA
2 mg/kg every
3 weeks
n=50		 KEYNOTE-913
KEYTRUDA
200 mg or 2 mg/kg every
3 weeks
n=55
+ Denotes ongoing response
NR = not reached
Objective Response Rate
  ORR (95% CI) 56% (41, 70) 49% (35, 63)
    Complete responses, n (%) 12 (24%) 9 (16%)
    Partial responses, n (%) 16 (32%) 18 (33%)
Duration of Response n=28 n=27
  Median DoR in months (range) NR (5.9, 34.5+) NR (4.8, 25.4+)
  Patients with duration ≥6 months, n (%) 27 (96%) 25 (93%)
  Patients with duration ≥12 months, n (%) 15 (54%) 19 (70%)
14.16 Renal Cell Carcinoma First-line treatment with axitinib KEYNOTE-426 The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus "Rest of the World"). Patients were randomized (1:1) to one of the following treatment arms: KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity. Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks. Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter. The study population characteristics were: median age of 62 years (range: 26 to 90), 38% age 65 or older; 73% male; 79% White and 16% Asian; 20% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate, and 13% poor. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the first pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. An updated OS analysis was conducted when 418 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 99 and Figure 34 summarize the efficacy results for KEYNOTE-426.
Table 99: Efficacy Results in KEYNOTE-426
Endpoint KEYTRUDA
200 mg every 3 weeks and Axitinib		 Sunitinib
n=432 n=429
NR = not reached
OS
  Number of patients with event (%) 59 (14%) 97 (23%)
  Median in months (95% CI) NR (NR, NR) NR (NR, NR)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.53 (0.38, 0.74)
  p-ValueBased on stratified log-rank test <0.0001p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis).
Updated OS
  Number of patients with event (%) 193 (45%) 225 (52%)
  Median in months (95% CI) 45.7 (43.6, NR) 40.1 (34.3, 44.2)
  Hazard ratio (95% CI) 0.73 (0.60, 0.88)
PFS
  Number of patients with event (%) 183 (42%) 213 (50%)
  Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5)
  Hazard ratio (95% CI) 0.69 (0.56, 0.84)
  p-Value 0.0001p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis).
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 59% (54, 64) 36% (31, 40)
    Complete response rate 6% 2%
    Partial response rate 53% 34%
  p-ValueBased on Miettinen and Nurminen method stratified by IMDC risk group and geographic region <0.0001
Figure 34: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-426
In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR of 1.17 (95% CI: 0.76, 1.80), 0.67 (95% CI: 0.52, 0.86), 0.64 (95% CI: 0.52, 0.80), and 0.51 (95% CI: 0.32, 0.81), respectively. First-line treatment with lenvatinib KEYNOTE-581 The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-581 (NCT02811861), a multicenter, open-label, randomized trial conducted in 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America versus Western Europe versus "Rest of the World") and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable versus intermediate versus poor risk). Patients were randomized (1:1:1) to one of the following treatment arms: KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with lenvatinib 20 mg orally once daily. Lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily. Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks. Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks. The study population characteristics were: median age of 62 years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate, and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%). The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. KEYTRUDA in combination with lenvatinib demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. An updated OS analysis was conducted when 304 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 100 and Figures 35 and 36 summarize the efficacy results for KEYNOTE-581.
Table 100: Efficacy Results in KEYNOTE-581
Endpoint KEYTRUDA
200 mg every 3 weeks
and Lenvatinib		 Sunitinib
n=355 n=357
Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR.
Data cutoff date = 28 Aug 2020, Updated OS cutoff date = 31 July 2022
CI = confidence interval; NR= Not reached
Progression-Free Survival (PFS)
  Number of events, n (%) 160 (45%) 205 (57%)
  Progressive disease 145 (41%) 196 (55%)
  Death 15 (4%) 9 (3%)
  Median PFS in months (95% CI) 23.9 (20.8, 27.7) 9.2 (6.0, 11.0)
  Hazard ratioHazard ratio is based on a Cox Proportional Hazards Model. Stratified by geographic region and MSKCC prognostic groups. (95% CI) 0.39 (0.32, 0.49)
  p-ValueTwo-sided p-Value based on stratified log-rank test. <0.0001
Overall Survival (OS)
  Number of deaths, n (%) 80 (23%) 101 (28%)
  Median OS in months (95% CI) NR (33.6, NR) NR (NR, NR)
  Hazard ratio (95% CI) 0.66 (0.49, 0.88)
  p-Value 0.0049
Updated OS
  Number of deaths, n (%) 149 (42%) 159 (45%)
  Median OS in months (95% CI) 53.7 (48.7, NR) 54.3 (40.9, NR)
  Hazard ratio (95% CI) 0.79 (0.63, 0.99)
Objective Response Rate (Confirmed)
  ORR, n (%) 252 (71%) 129 (36%)
  (95% CI) (66, 76) (31, 41)
    Complete response rate 16% 4%
    Partial response rate 55% 32%
    p-ValueTwo-sided p-Value based upon CMH test. <0.0001
Figure 35: Kaplan-Meier Curve for PFS in KEYNOTE-581
Figure 36: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-581
KEYNOTE-B61 The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-B61 (NCT04704219), a multicenter, single-arm trial that enrolled 160 patients with advanced or metastatic non-clear cell RCC in the first-line setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 400 mg every 6 weeks in combination with lenvatinib 20 mg orally once daily. KEYTRUDA was continued for a maximum of 24 months; however, lenvatinib could be continued beyond 24 months. Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit. Among the 158 treated patients, the baseline characteristics were: median age of 60 years (range: 24 to 87 years); 71% male; 86% White, 8% Asian, and 3% Black; <1% Hispanic or Latino; 22% and 78% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; histologic subtypes were 59% papillary, 18% chromophobe, 4% translocation, <1% medullary, 13% unclassified, and 6% other; patient distribution by IMDC risk categories was 35% favorable, 54% intermediate, and 10% poor. Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%). The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures included DOR as assessed by BICR using RECIST 1.1. Efficacy results are summarized in Table 101.
Table 101: Efficacy Results in KEYNOTE-B61
Endpoint KEYTRUDA
400 mg every 6 weeks
and Lenvatinib
n=158
CI = confidence interval
+ Denotes ongoing response
Objective Response Rate (Confirmed)
  ORR (95% CI) 51% (43, 59)
    Complete response 8%
    Partial response 42%
Duration of ResponseBased on Kaplan-Meier estimates
  Median in months (range) 19.5 (1.5+, 23.5+)
Adjuvant Treatment of RCC (KEYNOTE‑564) The efficacy of KEYTRUDA was investigated as adjuvant therapy for RCC in KEYNOTE-564 (NCT03142334), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease (NED). The intermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Grade without nodal involvement (N0) or distant metastases (M0). The high risk category included: pT4, any Grade N0 and M0; any pT, any Grade with nodal involvement and M0. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins ≥4 weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. Patients were randomized to KEYTRUDA 200 mg administered intravenously every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Randomization was stratified by metastasis status (M0, M1 NED); M0 group was further stratified by ECOG PS (0,1) and geographic region (US, non-US). The study population characteristics were: median age of 60 years (range: 25 to 84), 33% age 65 or older; 71% male; 75% White, 14% Asian, 9% Unknown, 1% Black or African American, 1% American Indian or Alaska Native, 1% Multiracial; 13% Hispanic or Latino, 78% Not Hispanic or Latino, 8% Unknown; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-four percent of patients enrolled had N0 disease; 11% had sarcomatoid features; 86% were intermediate-high risk; 8% were high risk; and 6% were M1 NED. Ninety-two percent of patients had a radical nephrectomy, and 8% had a partial nephrectomy. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS), defined as time to recurrence, metastasis, or death. An additional outcome measure was OS. Statistically significant improvements in DFS and OS were demonstrated at pre-specified interim analyses in patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 102 and Figures 37 and 38.
Table 102: Efficacy Results in KEYNOTE-564
Endpoint KEYTRUDA
200 mg every 3 weeks
n=496		 Placebo

n=498
NR = not reached
DFS
  Number (%) of patients with event 109 (22%) 151 (30%)
  Median in months (95% CI) NR NR
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.68 (0.53, 0.87)
  p-ValueBased on stratified log-rank test 0.0010p-Value (one-sided) is compared with a boundary of 0.0114.
  24-month DFS rate (95% CI) 77% (73, 81) 68% (64, 72)
OS
  Number (%) of patients with event 55 (11%) 86 (17%)
  Median in months (95% CI) NR (NR, NR) NR (NR, NR)
  Hazard ratio (95% CI) 0.62 (0.44, 0.87)
  p-Value 0.0024p-Value (one-sided) is compared with a boundary of 0.0072.
  48-month OS rate (95% CI) 91% (88, 93) 86% (83, 89)
Figure 37: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-564
Figure 38: Kaplan-Meier Curve for Overall Survival in KEYNOTE-564
Figure 34 Figure 35 Figure 36 Figure 37 Figure 38
14.17 Endometrial Carcinoma In Combination with Paclitaxel and Carboplatin for the Treatment of Primary Advanced or Recurrent Endometrial Carcinoma The efficacy of KEYTRUDA in combination with paclitaxel and carboplatin was investigated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial in 810 patients with advanced or recurrent endometrial carcinoma. The study design included two separate cohorts based on MMR status; 222 (27%) patients were in dMMR cohort, 588 (73%) patients were in pMMR cohort. The trial enrolled measurable Stage III, measurable Stage IVA, Stage IVB or recurrent endometrial cancer (with or without measurable disease). Patients who had not received prior systemic therapy or had received prior chemotherapy in the adjuvant setting were eligible. Patients who had received prior adjuvant chemotherapy were only eligible if their chemotherapy-free interval was at least 12 months. Patients with endometrial sarcoma, including carcinosarcoma, or patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified according to MMR status, ECOG PS (0 or 1 vs. 2), and prior adjuvant chemotherapy. Patients were randomized (1:1) to one of the following treatment arms: KEYTRUDA 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by KEYTRUDA 400 mg every 6 weeks for up to 14 cycles. Placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles. All study medications were administered as an intravenous infusion on Day 1 of each treatment cycle. Treatment continued until disease progression, unacceptable toxicity, or a maximum of 20 cycles (up to approximately 24 months). Patients with measurable disease who had RECIST-defined stable disease or partial response at the completion of cycle 6 were permitted to continue receiving paclitaxel and carboplatin with KEYTRUDA or placebo for up to 10 cycles as determined by the investigator. Assessment of tumor status was performed every 9 weeks for the first 9 months and then every 12 weeks thereafter. The major efficacy outcome measure was PFS as assessed by the investigator according to RECIST 1.1. An additional efficacy outcome measure was OS. The dMMR population characteristics were: median age of 66 years (range: 37 to 86), 55% age 65 or older; 79% White, 9% Black, and 3% Asian; 5% Hispanic or Latino; 64% ECOG PS of 0, 33% ECOG PS of 1, and 3% ECOG PS of 2; 61% had recurrent disease and 39% had primary or persistent disease; 5% received prior adjuvant chemotherapy and 43% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (81%), adenocarcinoma NOS (11%), serous carcinoma (2%), and other (6%). The pMMR population characteristics were: median age of 66 years (range: 29 to 94), 54% age 65 or older; 72% White, 16% Black, and 5% Asian; 6% Hispanic or Latino; 67% ECOG PS of 0, 30% ECOG PS of 1, and 3% ECOG PS of 2; 56% had recurrent disease and 44% had primary or persistent disease; 26% received prior adjuvant chemotherapy and 41% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (52%), serous carcinoma (26%), adenocarcinoma NOS (10%), clear cell carcinoma (7%), and other (5%). The trial demonstrated statistically significant improvements in PFS for patients randomized to KEYTRUDA in combination with paclitaxel and carboplatin compared to placebo in combination with paclitaxel and carboplatin in both the dMMR and pMMR populations. Table 103 and Figures 39 and 40 summarize the efficacy results for KEYNOTE-868 by MMR status. At the time of the PFS analysis, OS data were not mature with 12% deaths in the dMMR population and 17% deaths in the pMMR population.
Table 103: Efficacy Results in KEYNOTE-868
Endpoint dMMR Population pMMR Population
KEYTRUDA
with paclitaxel and
carboplatin
n=110		 Placebo
with paclitaxel and
carboplatin
n=112		 KEYTRUDA
with paclitaxel and
carboplatin
n=294		 Placebo
with paclitaxel and
carboplatin
n=294
NR = not reached
PFSBased on interim PFS analysis; the information fractions for interim analyses were 49% for dMMR and 55% for pMMR.
  Number (%) of patients with event 26 (24%) 57 (51%) 91 (31%) 124 (42%)
  Median in months (95% CI) NR (30.7, NR) 6.5 (6.4, 8.7) 11.1 (8.7, 13.5) 8.5 (7.2, 8.8)
  Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.30 (0.19, 0.48) 0.60 (0.46, 0.78)
  p-ValueBased on the stratified log-rank test <0.0001 <0.0001
Figure 39: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-868 (dMMR Population)
Figure 40: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-868 (pMMR Population)
Lack of Effectiveness for Adjuvant Treatment of Patients with Endometrial Carcinoma The efficacy of KEYTRUDA in combination with carboplatin and paclitaxel, with or without radiation, was investigated in KEYNOTE‑B21 (NCT04634877), a randomized, multicenter, double-blind, placebo-controlled trial in 1,095 patients with newly diagnosed, high‑risk endometrial cancer with no evidence of disease on imaging following curative intent surgery. High-risk disease was defined as any of the following (staging per FIGO 2009): Stage I/II with myometrial invasion and either non-endometrioid histology or aberrant p53 expression or p53 mutation, or Stage III/IVA. The trial did not meet the prespecified primary endpoint for investigator-assessed DFS, with a HR of 1.02 (95% CI: 0.79, 1.32). In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775 (NCT03517449), a multicenter, open-label, randomized, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were pMMR (using the VENTANA MMR RxDx Panel test) or not MSI-H were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomized (1:1) to one of the following treatment arms: KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily. Investigator’s choice, consisting of either doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off. Treatment with KEYTRUDA and lenvatinib continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for KEYTRUDA, a maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit, and the treatment was tolerated. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR and DoR, as assessed by BICR. Among the 697 pMMR patients, 346 patients were randomized to KEYTRUDA in combination with lenvatinib, and 351 patients were randomized to investigator’s choice of doxorubicin (n=254) or paclitaxel (n=97). The pMMR population characteristics were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy. Efficacy results for the pMMR or not MSI-H patients are summarized in Table 104 and Figures 41 and 42.
Table 104: Efficacy Results in KEYNOTE-775
Endometrial Carcinoma (pMMR or not MSI-H)
Endpoint KEYTRUDA
200 mg every 3 weeks
and Lenvatinib
n=346		 Doxorubicin or Paclitaxel

n=351
OS
  Number (%) of patients with event 165 (48%) 203 (58%)
  Median in months (95% CI) 17.4 (14.2, 19.9) 12.0 (10.8, 13.3)
  Hazard ratioBased on the stratified Cox regression model (95% CI) 0.68 (0.56, 0.84)
  p-ValueBased on stratified log-rank test 0.0001
PFS
  Number (%) of patients with event 247 (71%) 238 (68%)
  Median in months (95% CI) 6.6 (5.6, 7.4) 3.8 (3.6, 5.0)
  Hazard ratio (95% CI) 0.60 (0.50, 0.72)
  p-Value <0.0001
Objective Response Rate
  ORRResponse: Best objective response as confirmed complete response or partial response (95% CI) 30% (26, 36) 15% (12, 19)
    Complete response rate 5% 3%
    Partial response rate 25% 13%
  p-ValueBased on Miettinen and Nurminen method stratified by ECOG performance status, geographic region, and history of pelvic radiation <0.0001
Duration of Response n=105 n=53
  Median in months (range) 9.2 (1.6+, 23.7+) 5.7 (0.0+, 24.2+)
Figure 41: Kaplan-Meier Curve for Overall Survival in KEYNOTE-775 (pMMR or Not MSI-H)
Figure 42: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-775 (pMMR or Not MSI-H)
As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial enrolled 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in Cohorts D and K. MSI or MMR tumor status was determined using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 90 patients evaluated, the baseline characteristics were: median age of 64 years (range: 42 to 86); 83% White, 8% Asian, and 3% Black; 12% Hispanic or Latino; 39% ECOG PS of 0 and 61% ECOG PS of 1; 96% had M1 disease and 4% had M0 disease at study entry; and 51% had one and 48% had two or more prior lines of therapy. Nine patients received only adjuvant therapy and one patient received only neoadjuvant and adjuvant therapy before participating in the study. Efficacy results are summarized in Table 105.
Table 105: Efficacy Results in Patients with Advanced MSI-H or dMMR Endometrial Carcinoma in KEYNOTE-158
Endpoint KEYTRUDA
n=90Median follow-up time of 16.0 months (range 0.5 to 62.1 months)
+ Denotes ongoing response
NR = not reached
Objective Response Rate
  ORR (95% CI) 46% (35, 56)
    Complete response rate 12%
    Partial response rate 33%
Duration of Response n=41
  Median in months (range) NR (2.9, 55.7+)
  % with duration ≥12 months 68%
  % with duration ≥24 months 44%
Figure 39 Figure 40 Figure 41 Figure 42
14.18 Tumor Mutational Burden-High Cancer The efficacy of KEYTRUDA was investigated in a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with high tumor mutation burden (TMB-H) who were enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumor status was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The statistical analysis plan pre-specified ≥10 and ≥13 mutations per megabase using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The major efficacy outcome measures were ORR and DoR in patients who received at least one dose of KEYTRUDA as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mutations per megabase. Among the 102 patients with TMB-H advanced solid tumors, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older; 34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy. Efficacy results are summarized in Tables 106 and 107.
Table 106: Efficacy Results for Patients with TMB-H Cancer in KEYNOTE-158

  Endpoint		 KEYTRUDA
200 mg every 3 weeks
TMB ≥10 mut/Mb
n=102Median follow-up time of 11.1 months 		TMB ≥13 mut/Mb
n=70
+ Denotes ongoing response
NR = not reached
Objective Response Rate
  ORR (95% CI) 29% (21, 39) 37% (26, 50)
    Complete response rate 4% 3%
    Partial response rate 25% 34%
Duration of Response n=30 n=26
  Median in months (range)From product-limit (Kaplan-Meier) method for censored data NR (2.2+, 34.8+) NR (2.2+, 34.8+)
  % with duration ≥12 months 57% 58%
  % with duration ≥24 months 50% 50%
Table 107: Response by Tumor Type (TMB ≥10 mut/Mb)
Objective Response Rate Duration of Response range
N n (%) 95% CI (months)
CR = complete response
PR = partial response
SD = stable disease
PD = progressive disease
OverallNo TMB-H patients were identified in the cholangiocarcinoma cohort 102 30 (29%) (21%, 39%) (2.2+, 34.8+)
  Small cell lung cancer 34 10 (29%) (15%, 47%) (4.1, 32.5+)
  Cervical cancer 16 5 (31%) (11%, 59%) (3.7+, 34.8+)
  Endometrial cancer 15 7 (47%) (21%, 73%) (8.4+, 33.9+)
  Anal cancer 14 1 (7%) (0.2%, 34%) 18.8+
  Vulvar cancer 12 2 (17%) (2%, 48%) (8.8, 11.0)
  Neuroendocrine cancer 5 2 (40%) (5%, 85%) (2.2+, 32.6+)
  Salivary cancer 3 PR, SD, PD 31.3+
  Thyroid cancer 2 CR, CR (8.2, 33.2+)
  Mesothelioma cancer 1 PD
In an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses.
14.19 Cutaneous Squamous Cell Carcinoma The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC or locally advanced cSCC enrolled in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every 6 weeks during the first year, and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 105 patients with recurrent or metastatic cSCC treated, the study population characteristics were: median age of 72 years (range: 29 to 95), 71% age 65 or older; 76% male; 70% White, 25% race unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty-seven percent received one or more prior lines of therapy; 73% received prior radiation therapy. Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range: 35 to 95), 80% age 65 or older; 72% male; 83% White, 13% race unknown; 41% ECOG PS of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy. Efficacy results are summarized in Table 108.
Table 108: Efficacy Results in KEYNOTE-629
Endpoint KEYTRUDA
Recurrent or Metastatic cSCC
n=105		 KEYTRUDA
Locally Advanced cSCC
n=54
+ Denotes ongoing response
Objective Response Rate
  ORR (95% CI) 35% (26, 45) 52% (38, 66)
    Complete response rate 12% 22%
    Partial response rate 23% 30%
Duration of ResponseMedian follow-up time: recurrent or metastatic cSCC: 23.8 months; locally advanced cSCC: 48.0 months n=37 n=28
    Median in months (range) NR (2.7, 64.2+) 47.2 (1.0+, 49.9+)
    % with duration ≥6 months 76% 89%
    % with duration ≥12 months 68% 75%
14.20 Triple-Negative Breast Cancer Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522 (NCT03036488), a randomized (2:1), multicenter, double-blind, placebo-controlled trial conducted in 1174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 cm but ≤2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by nodal status (positive vs. negative), tumor size (T1/T2 vs. T3/T4), and choice of carboplatin (dosed every 3 weeks vs. weekly). Patients were randomized (2:1) to one of the following two treatment arms; all study medications were administered intravenously: Arm 1: Four cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: Carboplatin AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen
-or- AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen
-and- Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen Followed by four additional cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -and- Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen Following surgery, nine cycles of KEYTRUDA 200 mg every 3 weeks were administered. Arm 2: Four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: Carboplatin AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen
-or- AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen
-and- Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen Followed by four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -and- Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen Following surgery, nine cycles of placebo every 3 weeks were administered. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. The main efficacy outcomes were pCR rate and EFS. pCR was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause. An additional efficacy outcome was overall survival (OS). The study population characteristics were: median age of 49 years (range: 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 4.5% Black, and 1.8% American Indian or Alaska Native; 87% ECOG PS of 0 and 13% ECOG PS of 1; 56% were pre-menopausal status and 44% were post-menopausal status; 7% were primary Tumor 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall Stage II and 25% were Stage III. Statistically significant improvements in pCR, EFS, and OS were demonstrated at pre-specified interim analyses for patients randomized to KEYTRUDA in combination with chemotherapy followed by KEYTRUDA as a single agent compared with patients randomized to placebo in combination with chemotherapy followed by placebo alone. Table 109 and Figures 43 and 44 summarize the efficacy results for KEYNOTE-522.
Table 109: Efficacy Results in KEYNOTE-522
Endpoint KEYTRUDA
200 mg every 3 weeks
with chemotherapy/KEYTRUDA
n=784		 Placebo
with chemotherapy/Placebo

n=390
pCR (ypT0/Tis ypN0) Based on the entire intention-to-treat population n=1174 patients
  Number of patients with pCR 494 217
  pCR rate (%), (95% CI) 63.0 (59.5, 66.4) 55.6 (50.6, 60.6)
  Treatment difference (%) estimate (95% CI)Based on a pre-specified pCR interim analysis in n=602 patients, the pCR rate difference was statistically significant (p=0.00055 compared to a significance level of 0.003). , Based on Miettinen and Nurminen method stratified by nodal status, tumor size, and choice of carboplatin 7.5 (1.6, 13.4)
EFS
  Number of patients with event (%) 123 (16%) 93 (24%)
  Hazard ratio (95% CI)Based on stratified Cox regression model 0.63 (0.48, 0.82)
  p-ValueBased on a pre-specified EFS interim analysis (compared to a significance level of 0.0052) , Based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin 0.00031
OS
  Number of patients with event (%) 115 (15%) 85 (22%)
  Hazard ratio (95% CI) 0.66 (0.50, 0.87)
  p-Value , Based on a pre-specified OS interim analysis (compared to a significance level of 0.0050) 0.00150
Figure 43: Kaplan-Meier Curve for Event-Free Survival in KEYNOTE-522
Figure 44: Kaplan-Meier Curve for Overall Survival in KEYNOTE-522
Locally Recurrent Unresectable or Metastatic TNBC for Tumors Expressing PD-L1 (CPS≥ 10) The efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs. gemcitabine and carboplatin), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx assay, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Patients were randomized (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: KEYTRUDA 200 mg on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. Placebo on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. Assessment of tumor status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, tested in the subgroup of patients with CPS ≥10. Additional efficacy outcome measures were ORR and DoR as assessed by BICR. The study population characteristics for patients were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal status. Seventy-five percent of patients had tumor PD-L1 expression CPS ≥1 and 38% had tumor PD-L1 expression CPS ≥10. Table 110 and Figures 45 and 46 summarize the efficacy results for KEYNOTE-355.
Table 110: Efficacy Results in KEYNOTE-355 (CPS ≥10)
Endpoint KEYTRUDA
200 mg every 3 weeks
with chemotherapy
n=220		 Placebo
every 3 weeks
with chemotherapy
n=103
OSBased on the pre-specified final analysis
  Number of patients with event (%) 155 (70%) 84 (82%)
  Median in months (95% CI) 23 (19.0, 26.3) 16.1 (12.6, 18.8)
  Hazard ratioBased on stratified Cox regression model (95% CI) 0.73 (0.55, 0.95)
  p-ValueOne-sided p-Value based on stratified log-rank test (compared to a significance level of 0.0113) 0.0093
PFSBased on a pre-specified interim analysis
  Number of patients with event
  (%)		 136 (62%) 79 (77%)
  Median in months (95% CI) 9.7 (7.6, 11.3) 5.6 (5.3, 7.5)
  Hazard ratio (95% CI) 0.65 (0.49, 0.86)
  p-ValueOne-sided p-Value based on stratified log-rank test (compared to a significance level of 0.00411) 0.0012
Objective Response Rate (Confirmed)
  ORR (95% CI) 53% (46, 59) 41% (31, 51)
    Complete response rate 17% 14%
    Partial response rate 35% 27%
Duration of Response n=116 n=42
  Median in months (95% CI) 12.8 (9.9, 25.9) 7.3 (5.5, 15.4)
Figure 45: Kaplan-Meier Curve for Overall Survival in KEYNOTE-355 (CPS ≥10)
Figure 46: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-355 (CPS ≥10)
Figure 43 Figure 44 Figure 45 Figure 46
14.21 Ovarian Cancer The efficacy of KEYTRUDA in combination with paclitaxel, with or without bevacizumab, was evaluated in KEYNOTE-B96 (NCT05116189), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 643 patients with platinum-resistant, epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who received one or two prior lines of systemic therapy for ovarian carcinoma. Patients must have received at least one line of platinum-based chemotherapy for ovarian cancer with radiographic evidence of disease progression within 6 months after the last dose. Prior therapy with an anti-PD-1/PD-L1 inhibitor, PARP inhibitor, or bevacizumab was permitted. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by investigator decision to use bevacizumab, geographic region (U.S. or European Union or Rest of World), and PD-L1 status according to the PD-L1 IHC 22C3 pharmDx assay (CPS <1 or CPS 1 to <10 or CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups: KEYTRUDA 400 mg every 6 weeks plus paclitaxel 80 mg/m2 with or without bevacizumab 10 mg/kg Placebo every 6 weeks plus paclitaxel 80 mg/m2 with or without bevacizumab 10 mg/kg All study medications were administered as an intravenous infusion. KEYTRUDA 400 mg or placebo were administered on Day 1 of each 6-week treatment cycle and paclitaxel 80 mg/m2 was administered on Days 1, 8, and 15 of each 3-week treatment cycle. The option to use bevacizumab was by investigator choice prior to randomization. Bevacizumab 10 mg/kg was administered on Day 1 of a 2-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every 9 weeks for the first year, followed by every 12 weeks thereafter. The major efficacy outcome measure was PFS as assessed by investigator according to RECIST v1.1. An additional efficacy outcome measure was OS. Among the 643 patients randomized, 466 patients (72%) had tumors expressing PD-L1 with a CPS ≥1. The population characteristics of these 466 patients were: median age of 62 years (range: 37 to 85), 38% age 65 or older; 67% White, 20% Asian, 8% Missing, 3% Multiple, 2% Black, 0.4% Native Hawaiian or other Pacific Islander; 13% Hispanic or Latino; 55% and 44% ECOG performance status of 0 or 1, respectively; 73% received bevacizumab as study treatment; 36% of patients had received one prior line and 64% had received two prior lines of therapy; prior systemic therapy included: 46% with bevacizumab; 39% with a PARP inhibitor, or 3% with an anti-PD-1/PD-L1 inhibitor. The platinum-free interval following the most recent line of therapy was <3 months in 47% of patients, and 3 to 6 months in 53% of patients. The study demonstrated statistically significant improvement in PFS and OS for patients randomized to KEYTRUDA in combination with paclitaxel with or without bevacizumab compared to placebo in combination with paclitaxel with or without bevacizumab in patients whose tumors expressed PD-L1 CPS ≥1. Efficacy results are summarized in Table 111 and Figures 47 and 48.
Table 111: Efficacy Results in KEYNOTE-B96 (CPS ≥1)
Endpoint KEYTRUDA
400 mg every 6 weeks
plus paclitaxel with or without
bevacizumab

n=234		 Placebo

plus paclitaxel with or without
bevacizumab

n=232
PFS
  Number of patients with event (%) 162 (69) 180 (78)
  Median in months (95% CI) 8.3 (7.0, 9.4) 7.2 (6.2, 8.1)
  Hazard ratio (95% CI) 0.72 (0.58, 0.89)
  p-Value 0.0014Based on stratified log-rank test (p-Value [one-sided] is compared to an alpha boundary of 0.0116)
OS
  Number of patients with event (%) 157 (67) 175 (75)
  Median in months (95% CI) 18.2 (15.3, 21.0) 14.0 (12.5, 16.1)
  Hazard ratio (95% CI) 0.76 (0.61, 0.94)
  p-Value 0.0053Based on stratified log-rank test (p-Value [one sided] is compared to an alpha boundary of 0.0083)
Figure 47: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-B96 (CPS ≥1)
Figure 48: Kaplan-Meier Curve for Overall Survival in KEYNOTE-B96 (CPS ≥1)
Figure 47 Figure 48
16 HOW SUPPLIED/STORAGE AND HANDLING KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution): Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02)
Carton containing two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04)
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include: Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)]. Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.1)]. Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus [see Warnings and Precautions (5.1)]. Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.1)]. Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.1)]. Other immune-mediated adverse reactions: Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)]. Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)].
Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].
Complications of Allogeneic HSCT Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.3)].
Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].
Lactation Advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.2)].
Laboratory Tests Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.1)].
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA Manufactured by: MSD International Business GmbH
6005 Luzern, Switzerland
U.S. License No. 2405 For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. Copyright © 2014-2026 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved. uspi-mk3475-iv-2602r093
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: February 2026
MEDICATION GUIDE
KEYTRUDA® (key-true-duh)
(pembrolizumab)
injection
What is the most important information I should know about KEYTRUDA?
KEYTRUDA is a medicine that may treat certain cancers by working with your immune system. KEYTRUDA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.
Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:
Lung problems
cough shortness of breath chest pain
Intestinal problems
diarrhea (loose stools) or more frequent bowel movements than usual stools that are black, tarry, sticky, or have blood or mucus severe stomach-area (abdomen) pain or tenderness
Liver problems
yellowing of your skin or the whites of your eyes severe nausea or vomiting pain on the right side of your stomach area (abdomen) dark urine (tea colored) bleeding or bruising more easily than normal
Hormone gland problems
headaches that will not go away or unusual headaches eye sensitivity to light eye problems rapid heartbeat increased sweating extreme tiredness weight gain or weight loss feeling more hungry or thirsty than usual urinating more often than usual hair loss feeling cold constipation your voice gets deeper dizziness or fainting changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Kidney problems
decrease in your amount of urine blood in your urine swelling of your ankles loss of appetite
Skin problems
rash itching skin blistering or peeling painful sores or ulcers in your mouth or in your nose, throat, or genital area fever or flu-like symptoms swollen lymph nodes
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with KEYTRUDA. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:
chest pain, irregular heartbeat, shortness of breath, swelling of ankles confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight persistent or severe muscle pain or weakness, muscle cramps low red blood cells, bruising
Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:
chills or shaking itching or rash flushing shortness of breath or wheezing dizziness feeling like passing out fever back pain
Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you depending on the type of organ or tissue transplant that you have had.
Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with KEYTRUDA. Your healthcare provider will monitor you for these complications.
Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during treatment with KEYTRUDA. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with KEYTRUDA if you have severe side effects.
What is KEYTRUDA?
KEYTRUDA is a prescription medicine used to treat:
a kind of skin cancer called melanoma. KEYTRUDA may be used: when your melanoma has spread or cannot be removed by surgery (advanced melanoma), or in adults and children 12 years of age and older with Stage IIB, Stage IIC, or Stage III melanoma, to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery. a kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer: has spread (advanced NSCLC), and is a type called “nonsquamous”, and your tumor does not have an abnormal “EGFR” or “ALK” gene. KEYTRUDA may be used with the chemotherapy medicines carboplatin and either paclitaxel or paclitaxel protein-bound as your first treatment when your lung cancer: has spread (advanced NSCLC), and is a type called “squamous”. KEYTRUDA may be used alone as your first treatment when your lung cancer: has not spread outside your chest (Stage III) and you cannot have surgery or chemotherapy with radiation or your NSCLC has spread to other areas of your body (advanced NSCLC), and your tumor tests positive for “PD-L1”, and does not have an abnormal “EGFR” or “ALK” gene. KEYTRUDA may also be used alone when: you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and your tumor tests positive for “PD-L1”, and if your tumor has an abnormal “EGFR” or “ALK” gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working. KEYTRUDA may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine: before surgery when you have early-stage NSCLC which can be removed by surgery, and then continued alone after surgery to help prevent your lung cancer from coming back. KEYTRUDA may be used alone as a treatment in adults for your lung cancer: to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and you have Stage IB and your tumor(s) is 4 cm or greater in size, Stage II, or Stage IIIA NSCLC. a kind of cancer in adults called malignant pleural mesothelioma (MPM) that affects the lining of the lungs and chest wall. KEYTRUDA may be used in combination with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your cancer has spread or cannot be removed by surgery (advanced MPM). a kind of cancer called head and neck squamous cell cancer (HNSCC). KEYTRUDA may be used alone in adults with HNSCC before surgery: when your cancer can be removed by surgery, has spread to nearby tissues, and your tumor tests positive for “PD-L1”, and then continued in combination with radiation with or without cisplatin after surgery, and then continued alone to help prevent your head and neck cancer from coming back. KEYTRUDA may be used with the chemotherapy medicines fluorouracil and a platinum as your first treatment when your head and neck cancer has spread or returned and cannot be removed by surgery. KEYTRUDA may be used alone as your first treatment when your head and neck cancer: has spread or returned and cannot be removed by surgery, and your tumor tests positive for “PD-L1”. KEYTRUDA may be used alone when your head and neck cancer: has spread or returned, and you have received chemotherapy that contains platinum and it did not work or is no longer working. a kind of cancer called classical Hodgkin lymphoma (cHL): in adults when: your cHL has returned or you have tried a treatment and it did not work, or in children when: you have tried a treatment and it did not work or your cHL has returned after you received 2 or more types of treatment. a kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when: you have tried a treatment and it did not work or your PMBCL has returned after you received 2 or more types of treatment. a kind of bladder and urinary tract cancer called urothelial cancer. KEYTRUDA may be used with the medicine enfortumab vedotin in adults when your bladder or urinary tract cancer has spread or cannot be removed by surgery (locally advanced or metastatic urothelial cancer). KEYTRUDA may be used alone when your bladder or urinary tract cancer: has spread or cannot be removed by surgery (locally advanced or metastatic urothelial cancer), and you are not able to receive chemotherapy that contains platinum (medicines called either cisplatin or carboplatin), or you have received chemotherapy that contains platinum, and it did not work or is no longer working. KEYTRUDA may be used with the medicine enfortumab vedotin in adults before and after the surgical removal of your bladder when: your bladder cancer has spread into the muscle layer of the bladder (muscle invasive bladder cancer [MIBC]) but not to other parts of the body, and you are not able to receive chemotherapy that contains cisplatin. KEYTRUDA may be used alone when your cancer has not spread to nearby tissue in the bladder, but is at high-risk for spreading (high-risk non-muscle-invasive bladder cancer [NMIBC]) when: your tumor is a type called “carcinoma in situ” (CIS), and you have tried treatment with Bacillus Calmette-Guerin (BCG) and it did not work, and you are not able to or have decided not to have surgery to remove your bladder. a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. KEYTRUDA may be used in adults and children to treat: cancer that has spread or cannot be removed by surgery (advanced cancer), and has progressed following treatment, and you have no satisfactory treatment options. a kind of cancer called colon or rectal cancer. KEYTRUDA may be used when your cancer: has spread or cannot be removed by surgery (advanced colon or rectal cancer), and has been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). a kind of stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma. KEYTRUDA may be used in adults in combination with the medicine trastuzumab along with fluoropyrimidine and platinum chemotherapy as your first treatment when your stomach cancer: is HER2-positive, and your tumor tests positive for “PD-L1”, and has spread or cannot be removed by surgery (advanced gastric cancer). KEYTRUDA may be used in adults in combination with fluoropyrimidine and platinum chemotherapy as your first treatment when your stomach cancer: is HER2-negative, and your tumor tests positive for “PD-L1”, and has spread or cannot be removed by surgery (advanced gastric cancer). a kind of cancer called esophageal or certain gastroesophageal junction (GEJ) carcinomas that cannot be cured by surgery or a combination of chemotherapy and radiation therapy. KEYTRUDA may be used in combination with platinum- and fluoropyrimidine-based chemotherapy medicines when your tumor tests positive for “PD-L1”. KEYTRUDA may be used alone when: you have received one or more types of treatment, and it did not work or it is no longer working, and your tumor is a type called “squamous”, and your tumor tests positive for “PD-L1”. a kind of cancer called cervical cancer. KEYTRUDA may be used with chemotherapy and radiation therapy when your cervical cancer has spread nearby to the lower part of your vagina or to pelvic organs or has affected your kidneys (Stage III to IVA FIGO 2014 classification). KEYTRUDA may be used with chemotherapy medicines, with or without the medicine bevacizumab, when: your cervical cancer does not go away (persistent), has returned, or has spread (advanced cervical cancer), and your tumor tests positive for “PD-L1”. KEYTRUDA may be used alone when your cervical cancer: has returned, or has spread (advanced cervical cancer), and you have received chemotherapy, and it did not work or is no longer working, and your tumor tests positive for “PD-L1”. a kind of liver cancer called hepatocellular carcinoma (HCC). KEYTRUDA may be used when: you have HCC after having hepatitis B, and you have received anti-cancer treatment that did not contain a “PD-1” or “PD-L1” blocking medicine. a kind of bile duct or gallbladder cancer called biliary tract cancer (BTC). KEYTRUDA may be used with chemotherapy medicines gemcitabine and cisplatin when your biliary tract cancer has spread or cannot be removed by surgery. a kind of skin cancer called Merkel cell carcinoma (MCC) in adults and children. KEYTRUDA may be used to treat your skin cancer when it has spread or returned. a kind of kidney cancer called renal cell carcinoma (RCC). KEYTRUDA may be used in adults with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC). KEYTRUDA may be used in adults with the medicine lenvatinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC). KEYTRUDA may be used alone if you are at intermediate-high or high risk of your kidney cancer (RCC) coming back after surgery to: remove all or part of your kidney, or remove all or part of your kidney and also surgery to remove cancer that has spread to other parts of the body (metastatic lesions). a kind of uterine cancer called advanced endometrial carcinoma. KEYTRUDA may be used with the chemotherapy medicines carboplatin and paclitaxel, and then KEYTRUDA may be used alone, in adults: when your cancer has spread (advanced), or if your cancer has returned. KEYTRUDA may be used with the medicine lenvatinib in adults: when a laboratory test shows that your tumor is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), and you have received anti-cancer treatment, and it is no longer working, and your cancer cannot be cured by surgery or radiation. KEYTRUDA may be used alone in adults: if your cancer is shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and you have received anti-cancer treatment and it is no longer working, and your cancer cannot be cured by surgery or radiation. a kind of cancer that is shown by a test to be tumor mutational burden-high (TMB-H). KEYTRUDA may be used in adults and children to treat: solid tumors that have spread or cannot be removed by surgery (advanced cancer), and you have received anti-cancer treatment, and it did not work or is no longer working, and you have no satisfactory treatment options. It is not known if KEYTRUDA is safe and effective in children with TMB-H cancers of the brain or spinal cord (central nervous system cancers). a kind of skin cancer called cutaneous squamous cell carcinoma (cSCC). KEYTRUDA may be used when your skin cancer: has returned or spread, and cannot be cured by surgery or radiation. a kind of cancer called triple-negative breast cancer (TNBC). KEYTRUDA may be used with chemotherapy medicines as treatment before surgery and then continued alone after surgery when you: have early-stage breast cancer, and are at high risk of your breast cancer coming back. KEYTRUDA may be used with chemotherapy medicines when your breast cancer: has returned and cannot be removed by surgery or has spread, and tests positive for “PD-L1”. a kind of cancer called ovarian cancer. KEYTRUDA may be used in adults with the chemotherapy medicine paclitaxel, with or without the medicine bevacizumab, when your ovarian, fallopian tube, or primary peritoneal cancer: is resistant to chemotherapy that contains platinum, and tests positive for “PD-L1”, and you have received 1or 2 types of treatment.
Before receiving KEYTRUDA, tell your healthcare provider about all of your medical conditions, including if you: have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus have received an organ or tissue transplant, including corneal transplant have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) have received radiation treatment to your chest area have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome are pregnant or plan to become pregnant. KEYTRUDA can harm your unborn baby.
Females who are able to become pregnant: Your healthcare provider will give you a pregnancy test before you start treatment with KEYTRUDA. You should use an effective method of birth control during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA. Talk to your healthcare provider about birth control methods that you can use during this time. Tell your healthcare provider right away if you think you may be pregnant or if you become pregnant during treatment with KEYTRUDA. are breastfeeding or plan to breastfeed. It is not known if KEYTRUDA passes into your breast milk. Do not breastfeed during treatment with KEYTRUDA and for 4 months after your last dose of KEYTRUDA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive KEYTRUDA?
Your healthcare provider will give you KEYTRUDA into your vein through an intravenous (IV) line over 30 minutes. In adults, KEYTRUDA is usually given every 3 weeks or 6 weeks depending on the dose of KEYTRUDA that you are receiving. In children, KEYTRUDA is usually given every 3 weeks. Your healthcare provider will decide how many treatments you need. Your healthcare provider will do blood tests to check you for side effects. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of KEYTRUDA?
KEYTRUDA can cause serious side effects. See “What is the most important information I should know about KEYTRUDA?”
Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, rash, diarrhea, fever, cough, decreased appetite, itching, shortness of breath, constipation, bones or joints and stomach-area (abdominal) pain, nausea, and low levels of thyroid hormone.
Side effects of KEYTRUDA when used alone that are more common in children than in adults include: fever, vomiting, headache, stomach area (abdominal) pain, and low levels of white blood cells.
Common side effects of KEYTRUDA when given with certain chemotherapy or chemotherapy with radiation therapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, mouth sores, headache, weight loss, stomach-area (abdominal) pain, joint and muscle pain, trouble sleeping, blisters or rash on the palms of your hands and soles of your feet, urinary tract infection, low levels of thyroid hormone, skin irritation in the radiation area, trouble swallowing and dry mouth.
Common side effects of KEYTRUDA when given with chemotherapy and bevacizumab include: tingling or numbness of the arms or legs, hair loss, low red blood cell count, feeling tired or weak, nausea, low white blood cell count, diarrhea, high blood pressure, decreased platelet count, constipation, joint aches, vomiting, urinary tract infection, rash, low levels of thyroid hormone, decreased appetite, fever, mouth sores and nosebleed.
Common side effects of KEYTRUDA when given with axitinib include: diarrhea, feeling tired or weak, high blood pressure, liver problems, low levels of thyroid hormone, decreased appetite, blisters or rash on the palms of your hands and soles of your feet, nausea, mouth sores or swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, hoarseness, rash, cough, and constipation.
Common side effects of KEYTRUDA when given with lenvatinib include: low levels of thyroid hormone, high blood pressure, feeling tired, diarrhea, joint and muscle pain, nausea, decreased appetite, vomiting, mouth sores, weight loss, stomach-area (abdominal) pain, urinary tract infection, protein in your urine, constipation, headache, bleeding, blisters or rash on the palms of your hands and soles of your feet, hoarseness, rash, liver problems, and kidney problems.
Common side effects of KEYTRUDA when given with enfortumab vedotin include: rash, tingling or numbness of the arms or legs, feeling tired, itching, diarrhea, hair loss, weight loss, decreased appetite, dry eye, nausea, constipation, changes in sense of taste, and urinary tract infection.
These are not all the possible side effects of KEYTRUDA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of KEYTRUDA
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about KEYTRUDA that is written for health professionals.
What are the ingredients in KEYTRUDA?
Active ingredient: pembrolizumab
Inactive ingredients: L-histidine, polysorbate 80, sucrose, and Water for Injection.
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA

Manufactured by: MSD International Business GmbH
6005 Luzern, Switzerland		 U.S. License No. 2405
For patent information: www.msd.com/research/patent
Copyright © 2014-2026 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved.
usmg-mk3475-iv-2602r073

For more information, go to www.keytruda.com .
PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton NDC 0006-3029-02 Keytruda ®
(pembrolizumab)
for Injection 50 mg /vial For Intravenous Infusion Only Dispense the enclosed Medication Guide to each patient. Sterile lyophilized powder must be reconstituted with Sterile Water for
Injection, USP. Reconstituted solution requires further dilution prior
to administration. Rx only Single-dose vial. Discard unused portion. PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton
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Injection 100 mg /4 mL
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