İHALE DÜNYASI
İHALE DÜNYASI
KEYTRUDA QLEX is a fixed-combination drug product containing pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. Berahyaluronidase alfa is an endoglycosidase used to enhance dispersion and permeation, which facilitates delivery of increased volume of pembrolizumab that is co-administered subcutaneously. It is produced by mammalian CHO (Chinese Hamster Ovary) cells containing a DNA plasmid encoding a variant of human hyaluronidase PH20. It is a glycosylated protein with an approximate molecular weight of 49 kDa under nonreducing, deglycosylated conditions. KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution supplied in single-dose vials for subcutaneous administration. KEYTRUDA QLEX is supplied as two different configurations: Each KEYTRUDA QLEX 2.4 mL single-dose vial contains 395 mg of pembrolizumab and 4,800 units of berahyaluronidase alfa, and histidine (0.7 mg), histidine hydrochloride monohydrate (4.1 mg), methionine (3.6 mg), polysorbate 80 (0.5 mg), sucrose (168 mg), and Water for Injection, USP. The pH is 5.3-5.9. Each KEYTRUDA QLEX 4.8 mL single-dose vial contains 790 mg of pembrolizumab and 9,600 units of berahyaluronidase alfa, and histidine (1.4 mg), histidine hydrochloride monohydrate (8.2 mg), methionine (7.2 mg), polysorbate 80 (1 mg), sucrose (336 mg), and Water for Injection, USP. The pH is 5.3-5.9.
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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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 approved test. ( 1.18 , 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 TM 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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 approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved 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-approved test [see Dosage and Administration (2.1) ] .
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-approved tests for intravenous pembrolizumab. Information on FDA-approved 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-approved tests, confirmation of MSI-H or dMMR status is recommended by an FDA-approved 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-approved 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-approved 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) ] . 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 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.
KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. ( 4 )
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, and decreased appetite. ( 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, and decreased appetite. 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 <10% of patients who received KEYTRUDA QLEX included local injection site reactions (2.4%). Table 5: Laboratory Abnormalities Worsened from Baseline Occurring in ?20% of Patients with Metastatic NSCLC Receiving KEYTRUDA QLEX in Study MK-3475A-D77 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: KEYTRUDA QLEX plus platinum doublet chemotherapy (range: 240 to 246 patients) and intravenous pembrolizumab plus platinum doublet chemotherapy (range: 124 to 125 patients). KEYTRUDA QLEX and Platinum Doublet Chemotherapy Intravenous Pembrolizumab and Platinum Doublet Chemotherapy All Grades Graded per NCI CTCAE V5.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Anemia 80 22 86 26 Leukopenia 61 13 52 10 Neutropenia 58 28 49 19 Lymphopenia 55 22 54 18 Thrombocytopenia 43 11 41 6 Chemistry Increased AST 43 2.5 38 3.2 Hypoalbuminemia 38 0.4 39 0 Increased ALT 37 2.1 36 0.8 Hyponatremia 35 4.1 42 7 Increased creatinine 33 4.5 38 6 Hypocalcemia 31 2.1 31 2.4 Increased alkaline phosphatase 29 0.4 34 0 Hypokalemia 21 5 24 6 Adverse Reactions in Adult and Pediatric Patients Treated with Intravenous Pembrolizumab The safety of KEYTRUDA QLEX for its approved indications [see Indications and Usage (1) ] has been established in adequate and well-controlled studies of KEYTRUDA QLEX in combination with platinum doublet chemotherapy (Study MK-3475A-D77) and intravenous pembrolizumab, as a single agent or in combination therapy, across tumor types. Below is a description of adverse reactions of intravenous pembrolizumab in these adequate and well-controlled studies. Melanoma Ipilimumab-Naive Melanoma The safety of intravenous pembrolizumab for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received intravenous pembrolizumab 10 mg/kg every 2 weeks (n=278) or intravenous pembrolizumab 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.2) ] . Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for intravenous pembrolizumab and similar in both treatment arms. Fifty-one and 46% of patients received intravenous pembrolizumab 10 mg/kg every 2 or 3 weeks, respectively, for ?6 months. No patients in either arm received treatment for more than one year. The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%). In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both intravenous pembrolizumab arms. Adverse reactions leading to permanent discontinuation of intravenous pembrolizumab occurred in 9% of patients. Adverse reactions leading to discontinuation of intravenous pembrolizumab in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 21% of patients; the most common (?1%) was diarrhea (2.5%). Tables 6 and 7 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-006. Table 6: Selected Adverse reactions occurring at same or higher incidence than in the ipilimumab arm Adverse Reactions Occurring in ?10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-006 Adverse Reaction Intravenous Pembrolizumab 10 mg/kg every 2 or 3 weeks Ipilimumab n=555 n=256 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 28 0.9 28 3.1 Skin and Subcutaneous Tissue Rash Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. 24 0.2 23 1.2 Vitiligo Includes skin hypopigmentation 13 0 2 0 Musculoskeletal and Connective Tissue Arthralgia 18 0.4 10 1.2 Back pain 12 0.9 7 0.8 Respiratory, Thoracic and Mediastinal Cough 17 0 7 0.4 Dyspnea 11 0.9 7 0.8 Metabolism and Nutrition Decreased appetite 16 0.5 14 0.8 Nervous System Headache 14 0.2 14 0.8 Other clinically important adverse reactions occurring in ?10% of patients receiving intravenous pembrolizumab were diarrhea (26%), nausea (21%), and pruritus (17%). Table 7: Selected Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Laboratory Abnormalities Worsened from Baseline Occurring in ?20% of Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-006 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 (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: intravenous pembrolizumab n=429 and ipilimumab n=183; hypercholesterolemia: intravenous pembrolizumab n=484 and ipilimumab n=205. Intravenous Pembrolizumab 10 mg/kg every 2 or 3 weeks Ipilimumab All Grades Graded per NCI CTCAE v4.0 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 45 4.2 45 3.8 Hypertriglyceridemia 43 2.6 31 1.1 Hyponatremia 28 4.6 26 7 Increased AST 27 2.6 25 2.5 Hypercholesterolemia 20 1.2 13 0 Hematology Anemia 35 3.8 33 4.0 Lymphopenia 33 7 25 6 Other laboratory abnormalities occurring in ?20% of patients receiving intravenous pembrolizumab were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4). Ipilimumab-Refractory Melanoma The safety of intravenous pembrolizumab in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (intravenous pembrolizumab dose), randomized (1:1:1), active-controlled trial in which 528 patients received intravenous pembrolizumab 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.2) ] . Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure to intravenous pembrolizumab 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to intravenous pembrolizumab 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the intravenous pembrolizumab 2 mg/kg arm, 36% of patients were exposed to intravenous pembrolizumab for ?6 months and 4% were exposed for ?12 months. In the 10 mg/kg arm, 41% of patients were exposed to intravenous pembrolizumab for ?6 months and 6% of patients were exposed to intravenous pembrolizumab for ?12 months. The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis. In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both intravenous pembrolizumab arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving intravenous pembrolizumab; the most common (?1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 14% of patients; the most common (?1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-002. Table 8: Selected Adverse reactions occurring at same or higher incidence than in chemotherapy arm Adverse Reactions Occurring in ?10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-002 Adverse Reaction Intravenous Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin n=357 n=171 All Grades Graded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Pruritus 28 0 8 0 Rash Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic 24 0.6 8 0 Gastrointestinal Constipation 22 0.3 20 2.3 Diarrhea 20 0.8 20 2.3 Abdominal pain 13 1.7 8 1.2 Respiratory, Thoracic and Mediastinal Cough 18 0 16 0 General Pyrexia 14 0.3 9 0.6 Asthenia 10 2.0 9 1.8 Musculoskeletal and Connective Tissue Arthralgia 14 0.6 10 1.2 Other clinically important adverse reactions occurring in patients receiving intravenous pembrolizumab were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%). Table 9: Selected Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Laboratory Abnormalities Worsened from Baseline Occurring in ?20% of Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-002 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: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: intravenous pembrolizumab n=247 and chemotherapy n=116; decreased bicarbonate: intravenous pembrolizumab n=263 and chemotherapy n=123. Intravenous Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy All Grades Graded per NCI CTCAE v4.0 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 49 6 44 6 Hypoalbuminemia 37 1.9 33 0.6 Hyponatremia 37 7 24 3.8 Hypertriglyceridemia 33 0 32 0.9 Increased alkaline phosphatase 26 3.1 18 1.9 Increased AST 24 2.2 16 0.6 Decreased bicarbonate 22 0.4 13 0 Hypocalcemia 21 0.3 18 1.9 Increased ALT 21 1.8 16 0.6 Other laboratory abnormalities occurring in ?20% of patients receiving intravenous pembrolizumab were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4). Adjuvant Treatment of Resected Stage IIB or IIC Melanoma Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.2) ] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent. Adjuvant Treatment of Stage III Resected Melanoma The safety of intravenous pembrolizumab as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of 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 pa
Immune-Mediated Adverse Reactions ( 5.1 ) Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue based on severity and type of reaction. Hypersensitivity and Administration-Related Reactions: Interrupt injection and resume upon symptom resolution, or permanently discontinue KEYTRUDA QLEX based on the severity of reaction. ( 5.2 ) Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. ( 5.3 ) Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. ( 5.4 ) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA QLEX is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4) ] . In general, if KEYTRUDA QLEX requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis KEYTRUDA QLEX can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions. Intravenous Pembrolizumab as a Single Agent Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving intravenous pembrolizumab, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of intravenous pembrolizumab in 1.3% (36) of patients and withholding of intravenous pembrolizumab in 0.9% (26) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients. In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received intravenous pembrolizumab as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of intravenous pembrolizumab in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted intravenous pembrolizumab, 63% discontinued intravenous pembrolizumab, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA QLEX can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%), and Grade 2 (0.4%) adverse reactions. Intravenous Pembrolizumab as a Single Agent Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of intravenous pembrolizumab in 0.5% (15) of patients and withholding of intravenous pembrolizumab in 0.5% (13) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA QLEX can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions. Intravenous Pembrolizumab as a Single Agent Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of intravenous pembrolizumab in 0.2% (6) of patients and withholding of intravenous pembrolizumab in 0.3% (9) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients. In Combination with Axitinib KEYTRUDA QLEX in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA QLEX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA QLEX and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.4) ] . Intravenous Pembrolizumab in Combination with Axitinib With the combination of intravenous pembrolizumab and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ?3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either intravenous pembrolizumab (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ?3 times ULN was observed in 1 patient receiving intravenous pembrolizumab, 16 patients receiving axitinib, and 24 patients receiving both intravenous pembrolizumab and axitinib. All patients with a recurrence of ALT ?3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4) ]. Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%), and Grade 2 (0.8%) adverse reactions. Intravenous Pembrolizumab as a Single Agent Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of intravenous pembrolizumab in <0.1% (1) of patients and withholding of intravenous pembrolizumab in 0.3% (8) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. Hypophysitis KEYTRUDA QLEX can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4) ] . Intravenous Pembrolizumab as a Single Agent Hypophysitis occurred in 0.6% (17/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of intravenous pembrolizumab in 0.1% (4) of patients and withholding of intravenous pembrolizumab in 0.3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. Thyroid Disorders KEYTRUDA QLEX can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4) ]. Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%). Intravenous Pembrolizumab as a Single Agent Thyroiditis occurred in 0.6% (16/2799) of patients receiving intravenous pembrolizumab, including Grade 2 (0.3%). No patients discontinued intravenous pembrolizumab due to thyroiditis. Intravenous pembrolizumab was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of intravenous pembrolizumab in <0.1% (2) of patients and withholding of intravenous pembrolizumab in 0.3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving intravenous pembrolizumab as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism. Hypothyroidism occurred in 8% (237/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of intravenous pembrolizumab in <0.1% (1) of patients and withholding of intravenous pembrolizumab in 0.5% (14) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving intravenous pembrolizumab as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving intravenous pembrolizumab as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4) ] . Type 1 diabetes mellitus occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy. Intravenous Pembrolizumab as a Single Agent Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving intravenous pembrolizumab. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of intravenous pembrolizumab in <0.1% (1) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy. Immune-Mediated Nephritis with Renal Dysfunction KEYTRUDA QLEX can cause immune-mediated nephritis. Intravenous Pembrolizumab as a Single Agent Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of intravenous pembrolizumab in 0.1% (3) of patients and withholding of intravenous pembrolizumab in 0.1% (3) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA QLEX can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4) ] . Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%), and Grade 3 (0.8%) adverse reactions. Intravenous Pembrolizumab as a Single Agent Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of intravenous pembrolizumab in 0.1% (2) of patients and withholding of intravenous pembrolizumab in 0.6% (16) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA QLEX, intravenous pembrolizumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis (2.8%), duodenitis Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica Endocrine: Hypoparathyroidism Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection 5.2 Hypersensitivity and Administration-Related Reactions KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. In Study MK-3475A-D77, hypersensitivity and administration-related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX, including Grade 2 (2.8%). Monitor patients for signs and symptoms of administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate hypersensitivity and administration-related systemic reactions. For severe or life-threatening hypersensitivity and administration-related systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX [see Dosage and Administration (2.4) ] . 5.3 Complications of Allogeneic HSCT Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Increased Mortality in Patients with Multiple Myeloma when Pembrolizumab is Added to a Thalidomide Analogue and Dexamethasone In two randomized trials in patients with multiple myeloma, the addition of intravenous pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, KEYTRUDA QLEX can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA QLEX and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ].
