KEYTRUDA QLEX

1 INDICATIONS AND USAGE KEYTRUDA QLEX is a combination of pembrolizumab, a programmed death receptor-1 (PD-1)-blocking antibody, and berahyaluronidase alfa, an endoglycosidase, indicated: Melanoma for the treatment of adult patients with unresectable or metastatic melanoma. ( 1.1 ) for the adjuvant treatment of adult and pediatric patients 12 years and older 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 adult 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 adult patients with metastatic squamous NSCLC. ( 1.2 ) as a single agent for the first-line treatment of adult 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 adult 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 QLEX. ( 1.2 , 2.1 ) for the treatment of adult 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 adult patients with metastatic or with unresectable, recurrent HNSCC. ( 1.4 ) as a single agent for the first-line treatment of adult 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 adult patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. ( 1.4 ) Urothelial Cancer in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. ( 1.5 ) as a single agent for the treatment of adult 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. ( 1.5 ) 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. ( 1.5 ) as a single agent for the treatment of adult 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. ( 1.5 ) Microsatellite Instability-High or Mismatch Repair Deficient Cancer for the treatment of adult and pediatric patients 12 years and older 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. ( 1.6 , 2.1 ) Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC) for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test. ( 1.7 , 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. ( 1.8 ) 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. ( 1.8 ) Esophageal Cancer for the treatment of adult 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. ( 1.9 , 2.1 ) Cervical Cancer in combination with chemoradiotherapy, for the treatment of adult 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). ( 1.10 ) in combination with chemotherapy, with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. ( 1.10 , 2.1 ) as a single agent for the treatment of adult 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. ( 1.10 , 2.1 ) Hepatocellular Carcinoma (HCC) for the treatment of adult patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. ( 1.11 ) Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer. ( 1.12 ) Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients 12 years and older with recurrent locally advanced or metastatic Merkel cell carcinoma. ( 1.13 ) Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. ( 1.14 ) in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. ( 1.14 ) for the adjuvant treatment of adult patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. ( 1.14 ) Endometrial Carcinoma in combination with carboplatin and paclitaxel, followed by KEYTRUDA QLEX as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. ( 1.15 ) 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. ( 1.15 , 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. ( 1.15 , 2.1 ) Tumor Mutational Burden-High (TMB-H) Cancer for the treatment of adult and pediatric patients 12 years and older 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 ( 1.16 , 2.1 ) Limitations of Use : The safety and effectiveness of KEYTRUDA QLEX in pediatric patients 12 years and older with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of adult patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. ( 1.17 ) Triple-Negative Breast Cancer (TNBC) for the treatment of adult 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. ( 1.18 ) in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. ( 1.18 , 2.1 ) Ovarian Cancer 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, and who have received one or two prior systemic treatment regimens. ( 1.19 , 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 QLEX ™ is indicated for the treatment of adult patients with unresectable or metastatic melanoma. KEYTRUDA QLEX is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with Stage IIB, IIC, or III melanoma following complete resection. 1.2 Non-Small Cell Lung Cancer KEYTRUDA QLEX, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA QLEX, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of adult patients with metastatic squamous NSCLC. KEYTRUDA QLEX, as a single agent, is indicated for the first-line treatment of adult 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 QLEX, as a single agent, is indicated for the treatment of adult 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 QLEX. KEYTRUDA QLEX is indicated for the treatment of adult 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 QLEX, 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 QLEX, 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 QLEX 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 QLEX, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of adult patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA QLEX, as a single agent, is indicated for the first-line treatment of adult 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 QLEX, as a single agent, is indicated for the treatment of adult patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. 1.5 Urothelial Cancer KEYTRUDA QLEX, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA QLEX, as a single agent, is indicated for the treatment of adult 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 QLEX, 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 QLEX, as a single agent, is indicated for the treatment of adult 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. 1.6 Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA QLEX is indicated for the treatment of adult and pediatric patients 12 years and older 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) ] . 1.7 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA QLEX is indicated for the treatment of adult 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) ] . 1.8 Gastric Cancer KEYTRUDA QLEX, 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 QLEX, 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) ] . 1.9 Esophageal Cancer KEYTRUDA QLEX is indicated for the treatment of adult 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) ] . 1.10 Cervical Cancer KEYTRUDA QLEX, in combination with chemoradiotherapy (CRT), is indicated for the treatment of adult 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 QLEX, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of adult 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 QLEX, as a single agent, is indicated for the treatment of adult 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) ] . 1.11 Hepatocellular Carcinoma KEYTRUDA QLEX is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. 1.12 Biliary Tract Cancer KEYTRUDA QLEX, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). 1.13 Merkel Cell Carcinoma KEYTRUDA QLEX is indicated for the treatment of adult and pediatric patients 12 years and older with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 1.14 Renal Cell Carcinoma KEYTRUDA QLEX, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA QLEX, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC. KEYTRUDA QLEX is indicated for the adjuvant treatment of adult patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [see Clinical Studies (14.15) ] . 1.15 Endometrial Carcinoma KEYTRUDA QLEX, in combination with carboplatin and paclitaxel, followed by KEYTRUDA QLEX as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA QLEX, 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 QLEX, 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) ] . 1.16 Tumor Mutational Burden-High Cancer KEYTRUDA QLEX is indicated for the treatment of adult and pediatric patients 12 years and older 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 (14.17) ] . 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 QLEX in pediatric patients 12 years and older with TMB-H central nervous system cancers have not been established. 1.17 Cutaneous Squamous Cell Carcinoma KEYTRUDA QLEX is indicated for the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. 1.18 Triple-Negative Breast Cancer KEYTRUDA QLEX is indicated for the treatment of adult 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 QLEX, in combination with chemotherapy, is indicated for the treatment of adult 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) ] . 1.19 Ovarian Cancer KEYTRUDA QLEX, 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 KEYTRUDA QLEX has different recommended dosage and administration than intravenous pembrolizumab. ( 2.2 ) KEYTRUDA QLEX is for subcutaneous use in the thigh or abdomen only. ( 2.2 ) Do not administer KEYTRUDA QLEX intravenously. ( 2.2 ) KEYTRUDA QLEX must be administered by a healthcare provider. ( 2.2 ) The recommended dose for adults and pediatric patients 12 years and older who weigh greater than 40 kg is: Every 3-week dosing (395 mg/4,800 units): Inject 2.4 mL subcutaneously in the abdomen or thigh over 1 minute. ( 2.3 ) Every 6-week dosing (790 mg/9,600 units): Inject 4.8 mL subcutaneously in the abdomen or thigh over 2 minutes. ( 2.3 ) For RCC, administer KEYTRUDA QLEX 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. ( 2.3 ) For Endometrial Carcinoma, administer KEYTRUDA QLEX: 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. ( 2.3 ) See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. ( 2.4 , 2.5 ) 2.1 Patient Selection See information on FDA-authorized tests for intravenous pembrolizumab. 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 QLEX 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 (14.3) ] . metastatic NSCLC [see Clinical Studies (14.3) ]. first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.5) ] . previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.10) ] . recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.11) ] . For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA QLEX as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.7 , 14.8) ]. For the TMB-H indication, select patients for treatment with KEYTRUDA QLEX as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.17) ]. 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 (14.7) ] . Patient Selection for Combination Therapy For use of KEYTRUDA QLEX 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 (14.5) ] . For use of KEYTRUDA QLEX 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 (14.9) , (14.10) ]. 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 QLEX 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 (14.11) ]. For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with KEYTRUDA QLEX in combination with lenvatinib based on MMR or MSI status in tumor specimens [see Clinical Studies (14.16) ] . For use of KEYTRUDA QLEX 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 (14.19) ] . For use of KEYTRUDA QLEX 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 (14.20) ] . 2.2 Important Dosage and Administration Information KEYTRUDA QLEX has different recommended dosage and administration instructions than intravenous pembrolizumab. To reduce the risk of medication errors, check the vial labels to ensure that the drug being prepared and administered is KEYTRUDA QLEX for subcutaneous use and not intravenous pembrolizumab. Do not substitute KEYTRUDA QLEX with intravenous pembrolizumab because they have different recommended dosages and routes of administration. Patients receiving intravenous pembrolizumab can switch to subcutaneous KEYTRUDA QLEX at their next scheduled dose. Patients receiving subcutaneous KEYTRUDA QLEX can switch to intravenous pembrolizumab at their next scheduled dose. Administer KEYTRUDA QLEX as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel. Every 3-week dosing (395 mg/4,800 units) : inject 2.4 mL subcutaneously over 1 minute. Treatment duration is provided in Recommended Dosage (Table 1). Every 6-week dosing (790 mg/9,600 units): inject 4.8 mL subcutaneously over 2 minutes. Treatment duration is provided in Recommended Dosage (Table 1). Inject into healthy skin and never into areas where the skin is red, bruised, tender, or hard. Ensure the injection site is at least 2.5 cm from the previous injection site. During treatment with KEYTRUDA QLEX, do not administer other medications for subcutaneous use at the same site as KEYTRUDA QLEX. Do not administer KEYTRUDA QLEX intravenously. KEYTRUDA QLEX must be administered by a healthcare provider. 2.3 Recommended Dosage The recommended dosages of KEYTRUDA QLEX are presented in Table 1. Every 3-week dosing (395 mg pembrolizumab and 4,800 units berahyaluronidase alfa): inject 2.4 mL subcutaneously over 1 minute. Every 6-week dosing (790 mg pembrolizumab and 9,600 units berahyaluronidase alfa): inject 4.8 mL subcutaneously over 2 minutes. Table 1: Recommended Dosage Indication Recommended Dosage of KEYTRUDA QLEX Duration/Timing of Treatment Monotherapy Adult patients with unresectable or metastatic melanoma 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until disease progression or unacceptable toxicity Adjuvant treatment of adult patients with melanoma, NSCLC, or RCC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until disease recurrence, unacceptable toxicity, or up to 12 months Adult patients with NSCLC, HNSCC, 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 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with high-risk BCG- unresponsive NMIBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until persistent or recurrent high-risk NMIBC, disease progression, unacceptable toxicity, or up to 24 months Pediatric patients The recommended dosage for melanoma, MSI-H or dMMR cancer, MCC and TMB-H cancer has not been established in pediatric patients 12 years and older who weigh 40 kg or less [see Use in Specific Populations (8.4) ] . (12 years and older who weigh greater than 40 kg) with MSI-H or dMMR Cancer, MCC, or TMB- H Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until disease progression, unacceptable toxicity, or up to 24 months Pediatric patients (12 years and older who weigh greater than 40 kg) for adjuvant treatment of melanoma 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks 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 QLEX for recommended dosing information, as appropriate. Adult patients with resectable NSCLC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX 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 QLEX 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 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX 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 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX after enfortumab vedotin when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with locally advanced HNSCC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to cisplatin when given on the same day. Neoadjuvant: Administer KEYTRUDA QLEX for 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity. Adjuvant: Administer KEYTRUDA QLEX in combination with RT with or without cisplatin. Continue KEYTRUDA QLEX as a single agent. Continue KEYTRUDA QLEX until disease recurrence or unacceptable toxicity or up to one year Adult patients with MIBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX after enfortumab vedotin when given on the same day. Neoadjuvant: Administer KEYTRUDA QLEX 395 mg/4,800 units 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 QLEX 395 mg/4,800 units every 3 weeks for 14 doses or 790 mg/9,600 units every 6 weeks for 7 doses in combination with enfortumab vedotin or until disease recurrence or unacceptable toxicity Adult patients with HER2-positive Gastric Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX 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 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX 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 QLEX, up to 24 months Adult patients with RCC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX in combination with axitinib 5 mg orally twice daily When axitinib is used in combination with KEYTRUDA QLEX, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. or Administer KEYTRUDA QLEX in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA QLEX, up to 24 months Adult patients with Endometrial Carcinoma 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to carboplatin and paclitaxel when given on the same day. or Administer KEYTRUDA QLEX in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA QLEX, up to 24 months Adult patients with high-risk early-stage TNBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 395 mg/4,800 units every 3 weeks or 4 doses of 790 mg/9,600 units every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA QLEX as a single agent for up to 27 weeks (9 doses of 395 mg/4,800 units every 3 weeks or 5 doses of 790 mg/9,600 units every 6 weeks) or until disease recurrence or unacceptable toxicity Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA QLEX with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA QLEX. Adult patients with locally recurrent unresectable or metastatic TNBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with Ovarian Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to paclitaxel with or without bevacizumab when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months 2.4 Dosage Modifications No dose reduction for KEYTRUDA QLEX is recommended. In general, withhold KEYTRUDA QLEX for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA QLEX 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 QLEX 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 Severity Based 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 Withhold Resume 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 liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA QLEX 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 Other Adverse Reactions Hypersensitivity and Administration-Related Systemic Reactions [see Warnings and Precautions (5.2) ] Grade 1 or 2 Interrupt injection (if not already fully administered). If symptoms resolve, resume injection Grade 3 or 4 Permanently discontinue The following table represents dosage modifications that are different from those described above for KEYTRUDA QLEX or in the Full Prescribing Information for the drug administered in combination. Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA QLEX in Combination with Axitinib Treatment Adverse Reaction Severity Dosage Modification ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal KEYTRUDA QLEX in combination with axitinib Liver enzyme elevations Consider 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 QLEX and axitinib until resolution to Grades 0 or 1 Based 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 QLEX and axitinib Recommended Dose Modifications for Adverse Reactions for KEYTRUDA QLEX in Combination with Lenvatinib When administering KEYTRUDA QLEX in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA QLEX as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information. 2.5 Preparation KEYTRUDA QLEX is a ready-to-use solution. Do not dilute KEYTRUDA QLEX. Do not shake. Preparation of the Syringe Remove KEYTRUDA QLEX vial from refrigerated storage [2°C to 8°C (36°F to 46°F)] and allow it to equilibrate to room temperature [20°C to 25°C (68°F to 77°F)] for at least 30 minutes. Prior to preparation for administration, if needed, the unpunctured vial may be stored at room temperature for up to 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed. Use a sterile, polypropylene or polycarbonate syringe and a stainless steel transfer needle (18 to 21 gauge) to withdraw KEYTRUDA QLEX from the vial. Every 3-week dosing (395 mg pembrolizumab/4,800 units berahyaluronidase alfa) : withdraw 2.4 mL into the syringe. Every 6-week dosing (790 mg pembrolizumab/9,600 units berahyaluronidase alfa) : withdraw 4.8 mL into the syringe. To avoid needle clogging, change the needle to a 25 to 30 gauge, ½-inch, stainless steel hypodermic injection needle immediately prior to subcutaneous injection. Discard any unused portion left in the vial. Storage of Prepared Syringe The product does not contain a preservative and should be used immediately after withdrawing from the vial. If not used immediately, store the syringe containing KEYTRUDA QLEX with the transfer needle and cap in place: At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours, or In the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours. The 24-hour period may include up to 8 hours at room temperature. Discard if storage time exceeds these limits. If refrigerated, allow the filled syringe to come to room temperature for at least 30 minutes prior to administration. Do not freeze.

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) ] . Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.2) ]. The most common adverse reactions (≥20%) in patients treated with KEYTRUDA QLEX in combination with chemotherapy were nausea, fatigue, and musculoskeletal pain. ( 6.1 ) The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines. The most common adverse reactions (reported in ≥20% of patients) with intravenous pembrolizumab were: As a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. ( 6.1 ) 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 ) 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 ) 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 ) 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 ) 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 intravenous pembrolizumab 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 QLEX in combination with platinum doublet chemotherapy in a randomized, open-label, active-controlled trial (Study MK-3475A-D77), which enrolled 251 patients with NSCLC; intravenous pembrolizumab 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 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, patients were administered either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks or intravenous pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Among the 2799 patients who received intravenous pembrolizumab, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. The most common adverse reactions (≥20%) in patients who received KEYTRUDA QLEX in combination with chemotherapy were nausea (25%), fatigue (25%), and musculoskeletal pain (21%). The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines. The most common adverse reactions (≥20%) in patients who received intravenous pembrolizumab were: as a single agent : fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. 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. 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. in combination with axitinib : diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. 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. 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. Adverse Reactions in Patients with NSCLC Treated with KEYTRUDA QLEX The safety of KEYTRUDA QLEX compared to intravenous pembrolizumab in patients with previously untreated, metastatic NSCLC with no EGFR, ALK or ROS1 genomic tumor aberrations was evaluated in Study MK-3475A-D77 [see Clinical Studies (14.1) ]. A total of 377 patients received either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks in combination with platinum doublet chemotherapy (n=251) or intravenous pembrolizumab 400 mg every 6 weeks in combination with platinum doublet chemotherapy (n=126). Among patients who received KEYTRUDA QLEX, 58% were exposed for 6 months or longer and 3.2% were exposed for greater than one year. The median age of patients who received KEYTRUDA QLEX was 65 years (range: 39 to 87); 73% male, 63% White; 29% Asian, 4.8% multiple races, 2% Black or African American, 0.8% Alaska Native or American Indian; and 29% were of Hispanic or Latino ethnicity. Serious adverse reactions occurred in 39% of patients who received KEYTRUDA QLEX in combination with chemotherapy. Serious adverse reactions in ≥1% of patients who received KEYTRUDA QLEX were pneumonia (10%), thrombocytopenia (4%), febrile neutropenia (4%), neutropenia (2.8%), musculoskeletal pain (2%), pneumonitis (2%), diarrhea (1.6%), rash (1.2%), respiratory failure (1.2%), and anemia (1.2%). Fatal adverse reactions occurred in 10% of patients who received KEYTRUDA QLEX in combination with chemotherapy including pneumonia (3.2%), neutropenic sepsis (2%), death not otherwise specified (1.6%), respiratory failure (1.2%), parotitis (0.4%), pneumonitis (0.4%), pneumothorax (0.4%), pulmonary embolism (0.4%), neutropenic colitis (0.4%), and seizure (0.4%). Permanent discontinuation of KEYTRUDA QLEX due to an adverse reaction occurred in 16% of patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥2% of patients included pneumonia and pneumonitis. Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase. Tables 4 and 5 summarize the adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA QLEX in Study MK-3475A-D77. Table 4: Adverse Reactions Occurring in ≥10% of Patients with Metastatic NSCLC Receiving KEYTRUDA QLEX in Study MK-3475A-D77 Adverse Reaction KEYTRUDA QLEX and Platinum Doublet Chemotherapy Intravenous Pembrolizumab and Platinum Doublet Chemotherapy (n=251) (n=126) All Grades Graded per NCI CTCAE V5.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Nausea 25 1.2 25 0.8 Diarrhea Includes diarrhea, colitis, and enterocolitis. 16 2 14 0.8 Constipation 14 0 18 1.6 General Fatigue Includes fatigue, asthenia. 25 3.6 26 3.2 Musculoskeletal and Connective Tissue Musculoskeletal pain Includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, non-cardiac chest pain, and pain in extremity. 21 2.4 30 2.4 Skin and Subcutaneous Tissue Rash Includes rash, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, eczema, erythema multiforme, immune-mediated dermatitis, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin exfoliation. 18 2 19 0.8 Pruritus 12 0 13 0.8 Endocrine Hypothyroidism 14 0 12 0 Infections Pneumonia Includes pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung abscess, pneumocystis jirovecii pneumonia, pneumonia bacterial, and pneumonia mycoplasmal. 17 10 16 7 Nervous System Peripheral neuropathy Includes neuropathy peripheral, hypoaesthesia, neuralgia, paraesthesia, and peripheral sensory neuropathy. 11 0.4 14 0 Metabolism and Nutrition Decreased appetite 11 0.8 21 2.4 Hyperglycemia 11 0.8 11 0.8 Respiratory, Thoracic and Mediastinal Cough Includes cough, productive cough, and upper-airway cough syndrome. 10 0 11 0.8 Clinically relevant adverse reactions in 1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of intravenous pembrolizumab by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.2) ] . 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving intravenous pembrolizumab; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of intravenous pembrolizumab 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 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-054. Table 10: Selected Adverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-054 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks n=509 Placebo n=502 All Grades Graded 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 11: Selected Laboratory abnormalities occurring at same or higher incidence than placebo. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-054 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 502 to 505 patients) and placebo (range: 491 to 497 patients). Intravenous Pembrolizumab 200 mg every 3 weeks Placebo All Grades Graded 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 intravenous pembrolizumab 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 (14.3) ] . A total of 607 patients received intravenous pembrolizumab 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by intravenous pembrolizumab 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 intravenous pembrolizumab 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 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. Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-189. Table 12: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 All Grades Graded 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 Fatigue Includes 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 Rash Includes 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 13: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab /pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). Intravenous Pembrolizumab 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy All Grades Graded 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 intravenous pembrolizumab 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 (14.3) ] . Safety data are available for the first 203 patients who received intravenous pembrolizumab 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 intravenous pembrolizumab was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 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. Intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. Previously Untreated NSCLC The safety of intravenous pembrolizumab 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 (14.3) ]. Patients received intravenous pembrolizumab 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 intravenous pembrolizumab was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 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. Intravenous pembrolizumab was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-042. Table 14: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks n=636 Chemotherapy n=615 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-5 (%) All Grades (%) Grades 3-5 (%) General Fatigue Includes 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 Rash Includes 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 15: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 598 to 610 patients) and chemotherapy (range: 585 to 598 patients); increased prothrombin INR: intravenous pembrolizumab n=203 and chemotherapy n=173. Intravenous Pembrolizumab 200 mg every 3 weeks Chemotherapy All Grades Graded 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 intravenous pembrolizumab 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 (14.3) ] . A total of 991 patients received intravenous pembrolizumab 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m 2 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 intravenous pembrolizumab 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to intravenous pembrolizumab 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to intravenous pembrolizumab 2 mg/kg in 31% of patients exposed to intravenous pembrolizumab for ≥6 months. In the intravenous pembrolizumab 10 mg/kg arm, 34% of patients were exposed to intravenous pembrolizumab 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 intravenous pembrolizumab. The most common adverse events resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.8%). Adverse reactions leading to interruption of intravenous pembrolizumab 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 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-010. Table 16: Selected Adverse reactions occurring at same or higher incidence than in docetaxel arm Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-010 Adverse Reaction Intravenous Pembrolizumab 2 or 10 mg/kg every 3 weeks n=682 Docetaxel 75 mg/m 2 every 3 weeks n=309 All Grades Graded 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 Rash Includes 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 intravenous pembrolizumab were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%). Table 17: Selected Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving Intravenous Pembrolizumab in KEYNOTE-010 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 631 to 638 patients) and docetaxel (range: 271 to 277 patients). Intravenous Pembrolizumab 2 or 10 mg/kg every 3 weeks Docetaxel 75 mg/m 2 every 3 weeks All Grades Graded 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with intravenous pembrolizumab 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 (14.3) ]. 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with chemotherapy. Neoadjuvant Phase of KEYNOTE-671 A total of 396 patients received at least 1 dose of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab-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 intravenous pembrolizumab arm was interstitial lung disease (1%). Of the 325 intravenous pembrolizumab-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 intravenous pembrolizumab-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 intravenous pembrolizumab arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent intravenous pembrolizumab 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 intravenous pembrolizumab due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous pembrolizumab were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%). Adjuvant Treatment of Resected NSCLC The safety of intravenous pembrolizumab 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 (14.3) ] . A total of 1161 patients received intravenous pembrolizumab 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 intravenous pembrolizumab was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months. The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving intravenous pembrolizumab 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 intravenous pembrolizumab 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 (14.4) ] . A total of 473 patients received intravenous pembrolizumab 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by intravenous pembrolizumab (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 intravenous pembrolizumab 200 mg every 3 weeks was 6.9 months (range: 1 day to 25.2 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months. Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy. HNSCC Neoadjuvant and Adjuvant Treatment of Locally Advanced HNSCC The safety of intravenous pembrolizumab 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 (14.5) ]. Intravenous pembrolizumab 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 intravenous pembrolizumab and adjuvant RT for high-risk disease pathology. A total of 361 patients received treatment on the intravenous pembrolizumab arm and 315 patients received treatment on the SOC therapy arm. The median duration of exposure to intravenous pembrolizumab in the neoadjuvant phase was 3.1 weeks (range: 1 day to 4.9 weeks). The median duration of exposure to intravenous pembrolizumab in the adjuvant phase was 42 weeks (range: 1 day to 82 weeks). The median age of patients who received intravenous pembrolizumab 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 intravenous pembrolizumab 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 18 and Table 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-689. Table 18: Adverse Reactions in ≥20% of Patients with HNSCC Who Received Intravenous Pembrolizumab in KEYNOTE-689 Adverse Reaction Intravenous Pembrolizumab Neoadjuvant then adjuvant beginning with RT with or without cisplatin n=361 Standard of Care Adjuvant RT with or without cisplatin n=315 All Grades Graded per NCI CTCAE v4.03 (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Stomatitis Includes 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 Diarrhea Includes 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 Hypothyroidism Includes blood thyroid stimulating hormone increased 26 0 6 0 General Fatigue Includes asthenia 33 2.2 27 1.6 Skin and subcutaneous tissue disorders Rash Includes 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 19: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with HNSCC Who Received Intravenous Pembrolizumab in KEYNOTE-689 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Pembrolizumab + CRT/RT (range: 342 to 357 patients) and CRT/RT (range: 300 to 309 patients) Intravenous Pembrolizumab Neoadjuvant then adjuvant beginning with radiation with or without cisplatin Radiation with or without cisplatin All Grades Graded 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 intravenous pembrolizumab 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 intravenous pembrolizumab including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 2.8% of patients who received intravenous pembrolizumab as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant intravenous pembrolizumab in more than one patient was arthralgia (0.6%). Of the 361 patients who received intravenous pembrolizumab as neoadjuvant treatment, 11% (n=38) did not receive surgery. Surgical cancellation on the intravenous pembrolizumab 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 intravenous pembrolizumab-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 intravenous pembrolizumab) 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 intravenous pembrolizumab-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 intravenous pembrolizumab arm and 275 patients in the SOC arm started the adjuvant phase of treatment. On the intravenous pembrolizumab arm, 100 patients received intravenous pembrolizumab and cisplatin with concurrent RT, 154 patients received intravenous pembrolizumab alone with concurrent RT, 7 patients received cisplatin alone with concurrent RT, and 13 patients received RT alone. One patient received intravenous pembrolizumab alone. On the SOC arm, 139 patients received cisplatin with concurrent RT while 136 patients received RT alone. For the intravenous pembrolizumab arm, a total of 222 patients received single-agent intravenous pembrolizumab following RT. Of the 255 patients who received at least one dose of intravenous pembrolizumab in the adjuvant phase, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of intravenous pembrolizumab-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 intravenous pembrolizumab due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous pembrolizumab 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 intravenous pembrolizumab, 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 (14.5) ] . 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 intravenous pembrolizumab 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 intravenous pembrolizumab, 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 intravenous pembrolizumab was 3.5 months (range: 1 day to 24.2 months) in the intravenous pembrolizumab 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 intravenous pembrolizumab single agent arm and 18% of patients in the combination arm were exposed to intravenous pembrolizumab for ≥12 months. Fifty-seven percent of patients receiving intravenous pembrolizumab in combination with chemotherapy started treatment with carboplatin. Intravenous pembrolizumab was discontinued for adverse reactions in 12% of patients in the intravenous pembrolizumab single agent arm. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 31% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%). Intravenous pembrolizumab was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 45% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%). Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-048. Table 20: Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-048 Intravenous Pembrolizumab 200 mg every 3 weeks Intravenous Pembrolizumab 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU Adverse Reaction n=300 n=276 n=287 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue Includes 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 Diarrhea Includes 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 Rash Includes 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 Cough Includes cough, productive cough 18 0.3 22 0 15 0 Dyspnea Includes 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 Pneumonia Includes 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 neuropathy Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia 1 0 14 1.1 7 1 Musculoskeletal Myalgia Includes 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 21: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-048 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/chemotherapy (range: 240 to 267 patients), intravenous pembrolizumab (range: 245 to 292 patients), cetuximab/chemotherapy (range: 249 to 282 patients). Intravenous Pembrolizumab 200 mg every 3 weeks Intravenous Pembrolizumab 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU All Grades Graded 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 (14.5) ] , the median duration of exposure to intravenous pembrolizumab 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. Intravenous pembrolizumab was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. 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 intravenous pembrolizumab 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) ] . Urothelial Cancer Patients with urothelial cancer in combination with enfortumab vedotin The safety of intravenous pembrolizumab in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.6) ]. A total of 440 patients received intravenous pembrolizumab 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 intravenous pembrolizumab and enfortumab vedotin, the median duration of exposure to intravenous pembrolizumab was 8.5 months (range: 9 days to 28.5 months). Fatal adverse reactions occurred in 3.9% of patients treated with intravenous pembrolizumab 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 intravenous pembrolizumab in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis/ILD (4.8%) and rash (3.4%). Dose interruptions of intravenous pembrolizumab occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of intravenous pembrolizumab 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 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39. Table 22: Adverse Reactions ≥20% (All Grades) in Patients Treated with Intravenous Pembrolizumab in Combination with Enfortumab Vedotin in KEYNOTE-A39 Adverse Reaction Intravenous Pembrolizumab in combination with Enfortumab Vedotin n=440 Chemotherapy n=433 All Grades Graded per NCI CTCAE v4.03 % Grades 3-4 % All Grades % Grades 3-4 % Skin and subcutaneous tissue disorders Rash Includes 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 (1%) adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab 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 intravenous pembrolizumab in the neoadjuvant phase occurred in 20% of patients. The most common adverse reactions (≥2%) leading to dose interruption of intravenous pembrolizumab were rash (4.8%) and neutropenia (2.4%). Of the 167 patients in the intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab due to an adverse reaction occurred in 28% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were diarrhea (5%), and peripheral neuropathy, acute kidney injury, and pneumonitis (2% each). Adverse reactions leading to dose interruption of intravenous pembrolizumab in the adjuvant phase occurred in 38% of patients. The most common adverse reactions (≥2%) leading to dose interruption of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab was 4.3 months (range: 1 day to 25.6 months). Intravenous pembrolizumab was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of intravenous pembrolizumab-treated patients. The most frequent serious adverse reactions (≥2%) in intravenous pembrolizumab-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-057. Table 31: Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-057 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks N=148 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3–4 (%) General Fatigue Includes asthenia, fatigue, malaise 29 0.7 Peripheral edema Includes edema peripheral, peripheral swelling 11 0 Gastrointestinal Diarrhea Includes diarrhea, gastroenteritis, colitis 24 2.0 Nausea 13 0 Constipation 12 0 Skin and Subcutaneous Tissue Rash Includes 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 pain Includes 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 Cough Includes cough, productive cough 19 0 Infections Urinary tract infection 12 2.0 Nasopharyngitis 10 0 Endocrine Hypothyroidism 11 0 Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of BCG-unresponsive NMIBC Patients Receiving Intravenous Pembrolizumab in KEYNOTE-057 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 124 to 147 patients) Intravenous Pembrolizumab 200 mg every 3 weeks All Grades Graded 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 intravenous pembrolizumab was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.7) ]. The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 (14.8) ] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab was evaluated in 696 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 350 patients treated with intravenous pembrolizumab 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 intravenous pembrolizumab was 9.2 months (range: 1 day to 33.6 months). Fatal adverse reactions occurred in 3 patients who received intravenous pembrolizumab in combination with trastuzumab and CAPOX or FP and included pneumonitis in 2 patients and hepatitis in 1 patient. Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. Adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 71% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 intravenous pembrolizumab arm versus placebo, there was a difference of ≥5% incidence between patients treated with intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with intravenous pembrolizumab 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 (14.9) ] . The median duration of exposure to intravenous pembrolizumab was 6.2 months (range: 1 day to 33.7 months). Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. 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 intravenous pembrolizumab, including infection (2.3%) and thromboembolism (1.3%). Permanent discontinuation of intravenous pembrolizumab due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab in ≥1% were infections (1.8%) and diarrhea (1.0%). Dosage interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-859. Table 33: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-859 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks and FP or CAPOX n=785 Placebo and FP or CAPOX n=787 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Nervous System Peripheral neuropathy Includes 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 Pain Includes 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 Fatigue Includes 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 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-859 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/FP or CAPOX (range: 210 to 766 patients) and placebo/FP or CAPOX (range: 190 to 762 patients) Intravenous Pembrolizumab 200 mg every 3 weeks and FP or CAPOX Placebo and FP or CAPOX All Grades Graded 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 intravenous pembrolizumab, 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 (14.10) ] . A total of 740 patients received either intravenous pembrolizumab 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 intravenous pembrolizumab combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 67% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥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 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-590. Table 35: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-590 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks Cisplatin FU n=370 Placebo Cisplatin FU n=370 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-4 One 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 Fatigue Includes 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 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving Intravenous Pembrolizumab in KEYNOTE-590 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/cisplatin/FU (range: 353 to 365 patients) and placebo/cisplatin/FU (range: 347 to 359 patients) Intravenous Pembrolizumab 200 mg every 3 weeks Cisplatin FU Chemotherapy (Cisplatin and FU) All Grades Graded 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 (14.10) ] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent. Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy The safety of intravenous pembrolizumab 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 (14.11) ] . Two hundred ninety-four patients received intravenous pembrolizumab in combination with chemoradiotherapy and 303 patients received placebo in combination with chemoradiotherapy. The median duration of exposure to intravenous pembrolizumab was 20 months (range: 1 day to 32 months). Fatal adverse reactions occurred in 1.4% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of patients included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%). Intravenous pembrolizumab 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 intravenous pembrolizumab occurred in 47% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥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 37 and Table 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-A18. Table 37: Adverse Reactions Occurring in ≥10% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving Intravenous Pembrolizumab in KEYNOTE-A18 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy n=294 Placebo with chemoradiotherapy n=303 All Grades Graded 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 infection Includes 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 Fatigue Includes fatigue, asthenia 28 1.0 28 1.3 Pyrexia 14 0.7 15 0 Endocrine Hypothyroidism Includes 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 Rash Includes 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 38: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving Intravenous Pembrolizumab in KEYNOTE-A18 Laboratory Test 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: Intravenous pembrolizumab + chemoradiotherapy (range: 288 to 293 patients) and placebo + chemoradiotherapy (range: 299 to 301 patients) Intravenous Pembrolizumab 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy Placebo with chemoradiotherapy All Grades Graded 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 intravenous pembrolizumab 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 (14.11) ] . A total of 616 patients, regardless of tumor PD-L1 expression, received intravenous pembrolizumab 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 intravenous pembrolizumab was 9.9 months (range: 1 day to 26 months). Fatal adverse reactions occurred in 4.6% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab 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%). Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) was colitis (1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 intravenous pembrolizumab, 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 39 and Table 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-826. Table 39: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-826 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks and chemotherapy Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab n=307 Placebo and chemotherapy with or without bevacizumab n=309 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Nervous System Peripheral neuropathy Includes 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 Rash Includes rash, rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular 22 3.6 15 0.3 General Fatigue Includes 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 40: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-826 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab plus chemotherapy (range: 296 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients) Intravenous Pembrolizumab 200 mg every 3 weeks and chemotherapy Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab n=307 Placebo and chemotherapy with or without bevacizumab n=309 All Grades Graded 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 (14.11) ] , the median duration of exposure to intravenous pembrolizumab was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving intravenous pembrolizumab. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-158. Table 41: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks N=98 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3–4 (%) General Fatigue Includes asthenia, fatigue, lethargy, malaise 43 5 Pain Includes 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 peripheral Includes edema peripheral, peripheral swelling 15 2.0 Musculoskeletal and Connective Tissue Musculoskeletal pain Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity 27 5 Gastrointestinal Diarrhea Includes colitis, diarrhea, gastroenteritis 23 2.0 Abdominal pain Includes 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 Hemorrhage Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage 19 5 Infections UTI Includes 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 Rash Includes 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 42: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 76 to 79 patients) Intravenous Pembrolizumab 200 mg every 3 weeks All Grades Graded 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.12) ] . The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the intravenous pembrolizumab arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab was ascites (2.3%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%). Tables 43 and 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-394. Table 43: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving Intravenous Pembrolizumab in KEYNOTE-394 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks n=299 Placebo n=153 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-5 (%) All Grades (%) Grades 3-5 (%) General Pyrexia 18 0.7 14 0 Skin and Subcutaneous Tissue Rash Includes 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 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with HCC Receiving Intravenous Pembrolizumab in KEYNOTE-394 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 223 to 297 patients) and placebo (range: 144 to 151 patients). Intravenous Pembrolizumab Placebo All Grades Graded 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 intravenous pembrolizumab 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 (14.13) ] . A total of 1063 patients received either intravenous pembrolizumab 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 intravenous pembrolizumab was 6 months (range: 1 day to 28 months). Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥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 intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with intravenous pembrolizumab 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 intravenous pembrolizumab 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 (14.14) ] , the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.15) ] . 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab or axitinib occurred in 31% of patients; 13% intravenous pembrolizumab only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of intravenous pembrolizumab, 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 intravenous pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving intravenous pembrolizumab in combination with axitinib. This includes interruption of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with intravenous pembrolizumab and axitinib in KEYNOTE-426. Table 45: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Axitinib in KEYNOTE-426 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks and Axitinib n=429 Sunitinib n=425 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Diarrhea Includes 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 Hypertension Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension 48 24 48 20 Hepatobiliary Hepatotoxicity Includes 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 Rash Includes 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 46: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Axitinib in KEYNOTE-426 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 421 patients). Intravenous Pembrolizumab 200 mg every 3 weeks and Axitinib Sunitinib All Grades Graded 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 Hypocalcemia Corrected for albumin 22 0.2 29 0.7 Blood bilirubin increased 22 2.1 21 1.9 Activated partial thromboplastin time prolonged Two 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 intravenous pembrolizumab was evaluated in KEYNOTE-581 [see Clinical Studies (14.15) ]. Patients received intravenous pembrolizumab 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 intravenous pembrolizumab and lenvatinib was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients treated with intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving intravenous pembrolizumab in combination with lenvatinib; 29% intravenous pembrolizumab only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of intravenous pembrolizumab, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of intravenous pembrolizumab, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving intravenous pembrolizumab in combination with lenvatinib. Intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with intravenous pembrolizumab and lenvatinib in KEYNOTE-581. Table 47: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Lenvatinib in KEYNOTE-581 Adverse Reaction Intravenous Pembrolizumab 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 Fatigue Includes asthenia, fatigue, lethargy, malaise 63 9 56 8 Gastrointestinal Diarrhea Includes diarrhea, gastroenteritis 62 10 50 6 Stomatitis Includes 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 pain Includes 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 disorders Includes 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 Hypothyroidism Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism 57 1 32 0 Vascular Hypertension Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure 56 29 43 20 Hemorrhagic events Includes 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 appetite Includes decreased appetite, early satiety 41 4 31 1 Skin and Subcutaneous Tissue Rash Includes 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 syndrome Includes 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 Proteinuria Includes hemoglobinuria, nephrotic syndrome, proteinuria 30 8 13 3 Acute kidney injury Includes 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 Hepatotoxicity Includes 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 intravenous pembrolizumab with lenvatinib were myocardial infarction (3%) and angina pectoris (1%). Table 48: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving Intravenous Pembrolizumab with Lenvatinib in KEYNOTE-581 Laboratory Test With at least one Grade increase from baseline Intravenous Pembrolizumab 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: intravenous pembrolizumab 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 intravenous pembrolizumab and lenvatinib (n=38) and was not observed on rechallenge with intravenous pembrolizumab alone (n=3). Adjuvant treatment of RCC The safety of intravenous pembrolizumab 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 intravenous pembrolizumab by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.15) ] . The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab. 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 intravenous pembrolizumab, including one case of pneumonia. Discontinuation of intravenous pembrolizumab 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 intravenous pembrolizumab 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 49 and 50 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-564. Table 49: Selected Adverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in ≥10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-564 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks n=488 Placebo n=496 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal pain Includes 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 Fatigue Includes asthenia, fatigue 40 1.2 31 0.2 Skin and Subcutaneous Tissue Rash Includes 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 Diarrhea Includes diarrhea, colitis, enterocolitis, frequent bowel movements, enteritis 27 2.7 23 0.2 Nausea 16 0.4 10 0 Abdominal pain Includes 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 Headache Includes tension headache, headache, sinus headache, migraine with aura 15 0.2 13 0 Hepatobiliary Hepatotoxicity Includes 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 injury Includes acute kidney injury, blood creatinine increased, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic 13 1.2 10 0.2 Table 50: Selected Laboratory abnormalities occurring at same or higher incidence than placebo Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-564 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: intravenous pembrolizumab n=199 and placebo n=224. Intravenous Pembrolizumab 200 mg every 3 weeks Placebo All Grades Graded 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 intravenous pembrolizumab 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 (14.16) ] . A total of 759 patients received intravenous pembrolizumab 200 mg every 3 weeks and chemotherapy for 6 cycles followed by intravenous pembrolizumab 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 intravenous pembrolizumab was 5.6 months (range: 1 day to 24.0 months). Serious adverse reactions occurred in 35% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab in combination with chemotherapy, including COVID-19 (0.5%), and cardiac arrest (0.3%). Intravenous pembrolizumab was discontinued for an adverse reaction in 14% of patients. Chemotherapy dose reduction was required in 29% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab and chemotherapy were generally similar to those observed with intravenous pembrolizumab 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 intravenous pembrolizumab 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 (14.16) ]. Patients with endometrial carcinoma that is pMMR or not MSI-H received intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of intravenous pembrolizumab (≥1%) was increased ALT (1.2%). Dose interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%). Tables 51 and 52 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with lenvatinib in KEYNOTE-775. Table 51: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks and Lenvatinib n=342 Doxorubicin or Paclitaxel n=325 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Endocrine Hypothyroidism Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, secondary hypothyroidism 67 0.9 0.9 0 Vascular Hypertension Includes hypertension, blood pressure increased, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, blood pressure fluctuation 67 39 6 2.5 Hemorrhagic events Includes 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 Fatigue Includes fatigue, asthenia, malaise, lethargy 58 11 54 6 Gastrointestinal Diarrhea Includes diarrhea, gastroenteritis 55 8 20 2.8 Nausea 49 2.9 47 1.5 Vomiting 37 2.3 21 2.2 Stomatitis Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration 35 2.6 26 1.2 Abdominal pain Includes 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 disorders Includes 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 appetite Includes decreased appetite, early satiety 44 7 21 0 Investigations Weight loss 34 10 6 0.3 Renal and Urinary Proteinuria Includes proteinuria, protein urine present, hemoglobinuria 29 6 3.4 0.3 Infections Urinary tract infection Includes 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 erythrodysesthesia Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema 23 2.9 0.9 0 Rash Includes 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 52: Laboratory Abnormalities Worsened from Baseline With 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 Test 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: intravenous pembrolizumab and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). Intravenous Pembrolizumab 200 mg every 3 weeks and Lenvatinib Doxorubicin or Paclitaxel All Grades Graded 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 (14.16) ] treated with intravenous pembrolizumab as a single agent, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent. TMB-H Cancer The safety of intravenous pembrolizumab was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.17) ]. The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 (14.18) ] , the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with intravenous pembrolizumab 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 intravenous pembrolizumab arm received at least 1 dose of intravenous pembrolizumab in combination with neoadjuvant chemotherapy followed by intravenous pembrolizumab 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 (14.19) ]. The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab, 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 intravenous pembrolizumab. Serious adverse reactions in ≥2% of patients who received intravenous pembrolizumab included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of intravenous pembrolizumab were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 57% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥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 53 and 54 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-522. Table 53: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-522 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide / Intravenous Pembrolizumab n=778 Placebo with chemotherapy /Placebo n=389 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue Includes 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 Stomatitis Includes 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 pain Includes 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 Rash Includes 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 neuropathy Includes 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 Cough Includes 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 54: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-522 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab in combination with chemotherapy followed by intravenous pembrolizumab as a single agent (range: 762 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 381 to 389 patients). Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide /Intravenous Pembrolizumab Placebo with chemotherapy /Placebo All Grades Graded 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 intravenous pembrolizumab 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 (14.19) ] . A total of 596 patients (including 34 patients from a safety run-in) received intravenous pembrolizumab 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. The median duration of exposure to intravenous pembrolizumab was 5.7 months (range: 1 day to 33.0 months). Fatal adverse reactions occurred in 2.5% of patients receiving intravenous pembrolizumab in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving intravenous pembrolizumab 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%). Intravenous pembrolizumab was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 50% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥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 55 and 56 summarize the adverse reactions and laboratory abnormalities in patients on intravenous pembrolizumab in KEYNOTE-355. Table 55: Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Chemotherapy in KEYNOTE-355 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy n=596 Placebo every 3 weeks with chemotherapy n=281 All Grades Graded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue Includes 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 Rash Includes 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 Cough Includes 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 Headache Includes headache, migraine, tension headache 20 0.7 23 0.7 Table 56: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Chemotherapy in KEYNOTE-355 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients). Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy Placebo every 3 weeks with chemotherapy All Grades Graded 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 intravenous pembrolizumab 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 (14.20) ]. Among patients who received intravenous pembrolizumab, 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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%). Intravenous pembrolizumab was permanently discontinued for adverse reactions in 16% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) were colitis (1.3%) and increased alanine aminotransferase (1.3%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 44% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 post-approval use of intravenous pembrolizumab. 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

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