Pembrolizumab and Berahyaluronidase Alfa-pmph

INDICATIONS AND USAGE KEYTRUDA QLEX is a combination of pembrolizumab, a programmed death receptor-1 (PD-1)-blocking antibody, and berahyaluronidase alfa, an endoglycosidase, indicated: Melanoma for the treatment of adult patients with unresectable or metastatic melanoma. ( 1.1 ) for the adjuvant treatment of adult and pediatric patients 12 years and older with Stage IIB, IIC, or III melanoma following complete resection. ( 1.1 ) Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. ( 1.2 ) in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of adult patients with metastatic squamous NSCLC. ( 1.2 ) as a single agent for the first-line treatment of adult patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. ( 1.2 , 2.1 ) as a single agent for the treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-authorized test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA QLEX. ( 1.2 , 2.1 ) for the treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. ( 1.2 ) as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. ( 1.2 ) Malignant Pleural Mesothelioma (MPM) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with unresectable advanced or metastatic MPM. ( 1.3 ) Head and Neck Squamous Cell Cancer (HNSCC) for the treatment of adult patients with resectable locally advanced HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent. ( 1.4 ) in combination with platinum and FU for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC. ( 1.4 ) as a single agent for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test. ( 1.4 , 2.1 ) as a single agent for the treatment of adult patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. ( 1.4 ) Urothelial Cancer in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. ( 1.5 ) as a single agent for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who: are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. ( 1.5 ) in combination with enfortumab vedotin, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment of adult patients with muscle invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy. ( 1.5 ) as a single agent for the treatment of adult patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. ( 1.5 ) Microsatellite Instability-High or Mismatch Repair Deficient Cancer for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. ( 1.6 , 2.1 ) Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC) for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test. ( 1.7 , 2.1 ) Gastric Cancer in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. ( 1.8 ) in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. ( 1.8 ) Esophageal Cancer for the treatment of adult patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy for patients whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. ( 1.9 , 2.1 ) Cervical Cancer in combination with chemoradiotherapy, for the treatment of adult patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA). ( 1.10 ) in combination with chemotherapy, with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. ( 1.10 , 2.1 ) as a single agent for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. ( 1.10 , 2.1 ) Hepatocellular Carcinoma (HCC) for the treatment of adult patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. ( 1.11 ) Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer. ( 1.12 ) Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients 12 years and older with recurrent locally advanced or metastatic Merkel cell carcinoma. ( 1.13 ) Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. ( 1.14 ) in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. ( 1.14 ) for the adjuvant treatment of adult patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. ( 1.14 )

DOSAGE AND ADMINISTRATION KEYTRUDA QLEX has different recommended dosage and administration than intravenous pembrolizumab. ( 2.2 ) KEYTRUDA QLEX is for subcutaneous use in the thigh or abdomen only. ( 2.2 ) Do not administer KEYTRUDA QLEX intravenously. ( 2.2 ) KEYTRUDA QLEX must be administered by a healthcare provider. ( 2.2 ) The recommended dose for adults and pediatric patients 12 years and older who weigh greater than 40 kg is: Every 3-week dosing (395 mg/4,800 units): Inject 2.4 mL subcutaneously in the abdomen or thigh over 1 minute. ( 2.3 ) Every 6-week dosing (790 mg/9,600 units): Inject 4.8 mL subcutaneously in the abdomen or thigh over 2 minutes. ( 2.3 ) For RCC, administer KEYTRUDA QLEX as a single agent in the adjuvant setting, or in the advanced setting with either: axitinib 5 mg orally twice daily or lenvatinib 20 mg orally once daily. ( 2.3 ) For Endometrial Carcinoma, administer KEYTRUDA QLEX: in combination with carboplatin and paclitaxel regardless of MMR or MSI status, or in combination with lenvatinib 20 mg orally once daily for pMMR or not MSI-H tumors, or as a single agent for MSI-H or dMMR tumors. ( 2.3 ) See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. ( 2.4 , 2.5 ) 2.1 Patient Selection See information on FDA-authorized tests for intravenous pembrolizumab. Information on FDA-authorized tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics . Patient Selection for Single-Agent Treatment Select patients for treatment with KEYTRUDA QLEX as a single agent based on the presence of positive PD-L1 expression in: Stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.4) ] . metastatic NSCLC [see Clinical Studies (14.4) ]. first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.6) ] . previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.11) ] . recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.12) ] . For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA QLEX as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.8 , 14.9) ]. For the TMB-H indication, select patients for treatment with KEYTRUDA QLEX as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.18) ]. Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas. Additional Patient Selection Information for MSI-H or dMMR in Patients with non-CRC Solid Tumors Due to discordance between local tests and FDA-authorized tests, confirmation of MSI-H or dMMR status is recommended by an FDA-authorized test in patients with MSI-H or dMMR solid tumors, if feasible. If unable to perform confirmatory MSI-H/dMMR testing, the presence of TMB ≥10 mut/Mb, as determined by an FDA-authorized test, may be used to select patients for treatment [see Clinical Studies (14.8) ] . Patient Selection for Combination Therapy For use of KEYTRUDA 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 (14.6) ] . 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 (14.10) , (14.11) ]. 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 (14.12) ]. 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 (14.17) ] . 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 (14.20) ] . For use of KEYTRUDA QLEX in combination with paclitaxel, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma [see Clinical Studies (14.21) ] . 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, unacc

WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions ( 5.1 ) Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue based on severity and type of reaction. 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.

CONTRAINDICATIONS 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 )

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1) ] . Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.2) ]. The most common adverse reactions (≥20%) in patients treated with KEYTRUDA QLEX in combination with chemotherapy were nausea, fatigue, and musculoskeletal pain. ( 6.1 ) The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines. The most common adverse reactions (reported in ≥20% of patients) with intravenous pembrolizumab were: As a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. ( 6.1 ) In combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth and musculoskeletal pain. ( 6.1 ) In combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, decreased appetite, pyrexia, epistaxis, decreased white blood cell count, and stomatitis. ( 6.1 ) In combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. ( 6.1 ) In combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury. ( 6.1 ) In combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS reflect exposure to intravenous pembrolizumab as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA QLEX in combination with platinum doublet chemotherapy in a randomized, open-label, active-controlled trial (Study MK-3475A-D77), which enrolled 251 patients with NSCLC; intravenous pembrolizumab as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC; a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, patients were administered either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks or intravenous pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Among the 2799 patients who received intravenous pembrolizumab, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. The most common adverse reactions (≥20%) in patients who received KEYTRUDA QLEX in combination with chemotherapy were nausea (25%), fatigue (25%), and musculoskeletal pain (21%). The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines. The most common adverse reactions (≥20%) in patients who received intravenous pembrolizumab were: as a single agent : fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. in combination with chemotherapy or chemoradiotherapy : fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain. in combination with chemotherapy and bevacizumab : peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, decreased appetite, pyrexia, epistaxis, decreased white blood cell count, and stomatitis. in combination with axitinib : diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. in combination with lenvatinib : hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury. in combination with enfortumab vedotin : rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. Adverse Reactions in Patients with NSCLC Treated with KEYTRUDA QLEX The safety of KEYTRUDA QLEX compared to intravenous pembrolizumab in patients with previously untreated, metastatic NSCLC with no EGFR, ALK or ROS1 genomic tumor aberrations was evaluated in Study MK-3475A-D77 [see Clinical Studies (14.1) ]. A total of 377 patients received either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks in combination with platinum doublet chemotherapy (n=251) or intravenous pembrolizumab 400 mg every 6 weeks in combination with platinum doublet chemotherapy (n=126). Among patients who received KEYTRUDA QLEX, 58% were exposed for 6 months or longer and 3.2% were exposed for greater than one year. The median age of patients who received KEYTRUDA QLEX was 65 years (range: 39 to 87); 73% male, 63% White; 29% Asian, 4.8% multiple races, 2% Black or African Am

Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. In syngeneic mouse tumor models, combination treatment of a PD-1 blocking antibody and kinase inhibitor lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth compared to either treatment alone. Berahyaluronidase alfa, an endoglycosidase, is a variant of human hyaluronidase PH20 that temporarily and locally breaks down hyaluronan. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, the effects of berahyaluronidase alfa are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.