DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial (3)

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Immune-mediated pneumonitis: Withhold for moderate, and permanently discontinue for severe, life-threatening or recurrent moderate pneumonitis. (5.1) Immune-mediated colitis: Withhold for moderate or severe, and permanently discontinue for life-threatening colitis. (5.2) Immune-mediated hepatitis (KEYTRUDA) and hepatotoxicity (KEYTRUDA in combination with axitinib): Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA, axitinib, or KEYTRUDA and axitinib. Consider corticosteroid therapy. (2.3, 5.3) Immune-mediated endocrinopathies (5.4): Adrenal insufficiency: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening adrenal insufficiency. Hypophysitis: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening hypophysitis. Thyroid disorders: Monitor for changes in thyroid function. Withhold or permanently discontinue for severe or life-threatening hyperthyroidism. Type 1 diabetes mellitus: Monitor for hyperglycemia. Withhold KEYTRUDA in cases of severe hyperglycemia. Immune-mediated nephritis: Monitor for changes in renal function. Withhold for moderate, and permanently discontinue for severe or life-threatening nephritis. (5.5) Immune-mediated skin adverse reactions including, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN): Withhold for severe and permanently discontinue for life-threatening skin reactions. (5.6) Other immune-mediated adverse reactions: In organ transplant recipients, consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection. (5.7) Infusion-related reactions: Stop infusion and permanently discontinue KEYTRUDA for severe or life-threatening infusion reactions. (5.8) Complications of allogeneic HSCT (5.9): Allogeneic HSCT after treatment with KEYTRUDA: Monitor for hepatic veno-occlusive disease, grade 3-4 acute GVHD including hyperacute GVHD, steroid-requiring febrile syndrome, and other immune-mediated adverse reactions. Transplant-related mortality has occurred. Allogeneic HSCT prior to treatment with KEYTRUDA: In patients with a history of allogeneic HSCT, consider the benefit of treatment with KEYTRUDA versus the risk of GVHD. 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. (5.10) 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. (5.11, 8.1, 8.3) 5.1 Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. In clinical studies enrolling 2799 patients with various cancers who received KEYTRUDA as a single agent, pneumonitis occurred in 94 (3.4%) patients, including Grade 1 (0.8%), Grade 2 (1.3%), Grade 3 (0.9%), Grade 4 (0.3%), and Grade 5 (0.1%) pneumonitis. The median time to onset was 3.3 months (range: 2 days to 19.3 months), and the median duration was 1.5 months (range: 1 day to 17.2+ months). Sixty-three (67%) of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) followed by a corticosteroid taper. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.9%) than in patients who did not receive prior thoracic radiation (2.9%). Pneumonitis led to discontinuation of KEYTRUDA in 36 (1.3%) patients. Pneumonitis resolved in 55 (59%) of the 94 patients. In clinical studies enrolling 790 patients with NSCLC who received KEYTRUDA as a single agent as first-line therapy for advanced disease, pneumonitis occurred in 65 (8.2%) patients, including Grades 3-4 in 3.2% of patients. Forty-eight of the 65 patients received high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days). Pneumonitis occurred in 17% of patients with a history of prior thoracic radiation and 7.7% of patients who did not receive prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 29 (3.7%) patients. Pneumonitis resolved in 51% of the patients. In KEYNOTE-048 enrolling 300 patients with HNSCC who received KEYTRUDA as a single agent pneumonitis occurred in 18 (6%) patients, including Grade 3 (1.3%), Grade 4 (0%), and Grade 5 (0.3%). Eight of the 18 patients received high-dose corticosteroids for a median duration of 14 days (range: 1 to 77 days). Pneumonitis led to discontinuation of KEYTRUDA in 2 (0.7%) patients. Pneumonitis resolved in 12 (66%) of the patients. Pneumonitis occurred in 15 (5.4%) patients of 276 patients with HNSCC receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3 (1.1%), Grade 4 (0%), and Grade 5 (0.4%) pneumonitis. Four of the 15 patients received high-dose corticosteroids for a median duration of 16 days (range: 2 to 32 days). Pneumonitis led to discontinuation of KEYTRUDA in 5 (1.8%) patients. Pneumonitis resolved in 12 (80%) of the patients. 5.2 Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), Grade 3 (1.1%), and Grade 4 (3 times ULN. 5.4 Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause adrenal insufficiency (primary and secondary). Monitor for signs and symptoms of adrenal insufficiency. Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for moderate (Grade 2) adrenal insufficiency and withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adrenal insufficiency. The median time to onset was 5.3 months (range: 26 days to 16.6 months), and the median duration was not reached (range: 4 days to 1.9+ years). Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% of patients and withholding of KEYTRUDA in 0.3% of patients. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency, including 9% who received high-dose corticosteroids (prednisone 40 mg per day or equivalent) for median duration of 4 days (range: 1 to 6 days) followed by corticosteroid taper. Adrenal insufficiency resolved in 23% of the patients. Hypophysitis KEYTRUDA can cause hypophysitis. Monitor for signs and symptoms of hypophysitis (including hypopituitarism). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis and withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), Grade 3 (0.3%), and Grade 4 (<0.1%) hypophysitis. The median time to onset was 3.7 months (range: 1 day to 11.9 months), and the median duration was 4.7 months (range: 8+ days to 12.7+ months). Sixteen (94%) of the 17 patients received systemic corticosteroids, with 6 of the 16 receiving high-dose corticosteroids. Hypophysitis led to discontinuation of KEYTRUDA in 4 (0.1%) patients. Hypophysitis resolved in 7 (41%) of the 17 patients. Thyroid Disorders KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and Grade 3 (0.1%) hyperthyroidism. The median time to onset was 1.4 months (range: 1 day to 21.9 months), and the median duration was 2.1 months (range: 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of KEYTRUDA in 2 (<0.1%) patients. Hyperthyroidism resolved in 71 (74%) of the 96 patients. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and Grade 3 (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: 1 day to 18.9 months), and the median duration was not reached (range: 2 days to 27.7+ months). Hypothyroidism led to discontinuation of KEYTRUDA in 1 (<0.1%) patient. Hypothyroidism resolved in 48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months). Type 1 Diabetes mellitus KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. 5.5 Immune-Mediated Nephritis and Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Monitor patients for changes in renal function. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2), and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) nephritis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), Grade 3 (0.1%), and Grade 4 (<0.1%) nephritis. The median time to onset was 5.1 months (range: 12 days to 12.8 months), and the median duration was 3.3 months (range: 12 days to 8.9+ months). Eight (89%) of the 9 patients received systemic corticosteroids, with 7 of the 8 receiving high-dose corticosteroids for a median duration of 15 days (range: 3 days to 4.0 months) followed by a corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in 3 (0.1%) patients. Nephritis resolved in 5 (56%) of the 9 patients. Nephritis occurred in 1.7% of 405 patients receiving KEYTRUDA in combination with pemetrexed and platinum in the KEYNOTE-189 study, including Grade 3 (1%) and Grade 4 (0.5%) nephritis. The median time to onset was 3.2 months (range: 16 days to 11.1 months) and the duration ranged from 1.6 to 16.8+ months. Six (86%) of the 7 patients received systemic corticosteroids, with all 6 receiving high-dose corticosteroids for a median duration of 3 days (range: 1 to 17 days) followed by a corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in 5 (1.2%) patients. Nephritis resolved in 2 (29%) of the 7 patients. 5.6 Immune-Mediated Skin Adverse Reactions Immune-mediated rashes, including SJS, TEN (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and exclude other causes. Based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)]. 5.7 Other Immune-Mediated Adverse Reactions Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA. While immune-mediated adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, they may occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients treated with KEYTRUDA: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other trials, including cHL, and post-marketing use. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients. 5.8 Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)]. 5.9 Complications of Allogeneic HSCT Allogeneic HSCT after treatment with KEYTRUDA Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly. Allogeneic HSCT prior to treatment with KEYTRUDA In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with KEYTRUDA. Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT. 5.10 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials. 5.11 Embryo-Fetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity. Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL - 100 mg/4 mL Vial Carton NDC 0006-3026-02 Keytruda (pembrolizumab) Injection 100 mg/4 mL (25 mg/mL) For Intravenous Infusion Only Dispense the enclosed Medication Guide to each patient. Requires dilution prior to administration. Rx only Single-dose vial. Discard unused portion.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response. 8.2 Lactation Risk Summary There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)]. Contraception KEYTRUDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for at least 4 months following the final dose. 8.4 Pediatric Use The safety and effectiveness of KEYTRUDA have been established in pediatric patients with cHL, PMBCL, and MSI-H cancer. Use of KEYTRUDA in pediatric patients with cHL, PMBCL, and MSI-H cancers is supported by evidence from adequate and well-controlled studies of KEYTRUDA in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Studies (14.5, 14.6, 14.8), Clinical Pharmacology (12.3)]. There is limited experience with KEYTRUDA in pediatric patients. In a trial (NCT02332668), 40 pediatric patients (16 children ages 2 years to less than 12 years and 24 adolescents ages 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range: 1-17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (15% difference) in pediatric patients when compared to adults <65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%) and hyponatremia (18%). The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks. The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)]. 8.5 Geriatric Use Of 3991 patients with melanoma, NSCLC, HNSCC, cHL or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 46% were 65 years and over and 16% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1) 04/2020 Dosage and Administration (2) 04/2020 Warnings and Precautions (5) 01/2020

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include: Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.2)]. Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.3)]. Adrenal Insufficiency: Advise patients to contact their healthcare provider immediately for extreme weakness, dizziness, or fainting [see Warnings and Precautions (5.4)]. Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes [see Warnings and Precautions (5.4)]. Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism [see Warnings and Precautions (5.4)]. Type 1 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 1 diabetes [see Warnings and Precautions (5.4)]. Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.5)]. Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.6)]. Other immune-mediated adverse reactions: Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new signs or symptoms [see Warnings and Precautions (5.7)]. Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection [see Warnings and Precautions (5.7)]. Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.8)]. Complications of Allogeneic HSCT Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.9)]. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. Lactation Advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the final dose [see Use in Specific Populations (8.2)]. Laboratory Tests Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.3, 5.4, 5.5)].

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. Immune-mediated pneumonitis [see Warnings and Precautions (5.1)]. Immune-mediated colitis [see Warnings and Precautions (5.2)]. Immune-mediated hepatitis (KEYTRUDA) and hepatotoxicity (KEYTRUDA in combination with axitinib) [see Warnings and Precautions (5.3)]. Immune-mediated endocrinopathies [see Warnings and Precautions (5.4)]. Immune-mediated nephritis and renal dysfunction [see Warnings and Precautions (5.5)]. Immune-mediated skin adverse reactions [see Warnings and Precautions (5.6)]. Other immune-mediated adverse reactions [see Warnings and Precautions (5.7)]. Infusion-related reactions [see Warnings and Precautions (5.8)]. Most common adverse reactions (reported in 20% of patients) were: KEYTRUDA as a single agent: fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. (6.1) KEYTRUDA in combination with chemotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, and stomatitis. (6.1) KEYTRUDA in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. (6.1) KEYTRUDA in combination with lenvatinib: fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in two randomized, open-label, active-controlled clinical trials (KEYNOTE-042 and KEYNOTE-024), which enrolled 790 patients with NSCLC; in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087), which enrolled 241 patients with cHL; in combination with chemotherapy in a randomized, active-controlled trial (KEYNOTE-189), which enrolled 405 patients with nonsquamous NSCLC; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. The data described in this section were obtained in ten randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-048, KEYNOTE-189, KEYNOTE-407, KEYNOTE-181, and KEYNOTE-426) and eleven non-randomized, open-label trials (KEYNOTE-028, KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-057, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, KEYNOTE-017, and KEYNOTE-146). The data described in this section also included a single randomized, double-blind, placebo-controlled trial (KEYNOTE-054) in which KEYTRUDA was administered for the adjuvant treatment of 509 patients with melanoma with involvement of lymph node(s) following complete surgical resection. In these trials, KEYTRUDA was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks. Melanoma Ipilimumab-Naive Melanoma The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for 6 months. No patients in either arm received treatment for more than one year. The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%). In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (1%) was diarrhea (2.5%). Tables 3 and 4 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006. Table 3: SelectedAdverse reactions occurring at same or higher incidence than in the ipilimumab arm Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-006 Adverse Reaction KEYTRUDA 10 mg/kg every 2 or 3 weeks Ipilimumab n=555 n=256 All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 28 0.9 28 3.1 Skin and Subcutaneous Tissue RashIncludes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. 24 0.2 23 1.2 VitiligoIncludes skin hypopigmentation 13 0 2 0 Musculoskeletal and Connective Tissue Arthralgia 18 0.4 10 1.2 Back pain 12 0.9 7 0.8 Respiratory, Thoracic and Mediastinal Cough 17 0 7 0.4 Dyspnea 11 0.9 7 0.8 Metabolism and Nutrition Decreased appetite 16 0.5 14 0.8 Nervous System Headache 14 0.2 14 0.8 Other clinically important adverse reactions occurring in 10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%). Table 4: SelectedLaboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205. KEYTRUDA 10 mg/kg every 2 or 3 weeks Ipilimumab All GradesGraded per NCI CTCAE v4.0 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 45 4.2 45 3.8 Hypertriglyceridemia 43 2.6 31 1.1 Hyponatremia 28 4.6 26 7 Increased AST 27 2.6 25 2.5 Hypercholesterolemia 20 1.2 13 0 Hematology Anemia 35 3.8 33 4.0 Lymphopenia 33 7 25 6 Other laboratory abnormalities occurring in 20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4). Ipilimumab-Refractory Melanoma The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for 6 months and 4% were exposed for 12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for 6 months and 6% of patients were exposed to KEYTRUDA for 12 months. The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis. In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002. Table 5: SelectedAdverse reactions occurring at same or higher incidence than in chemotherapy arm Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-002 Adverse Reaction KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks ChemotherapyChemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin n=357 n=171 All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Pruritus 28 0 8 0 RashIncludes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic 24 0.6 8 0 Gastrointestinal Constipation 22 0.3 20 2.3 Diarrhea 20 0.8 20 2.3 Abdominal pain 13 1.7 8 1.2 Respiratory, Thoracic and Mediastinal Cough 18 0 16 0 General Pyrexia 14 0.3 9 0.6 Asthenia 10 2.0 9 1.8 Musculoskeletal and Connective Tissue Arthralgia 14 0.6 10 1.2 Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%). Table 6: SelectedLaboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123. KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy All GradesGraded per NCI CTCAE v4.0 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 49 6 44 6 Hypoalbuminemia 37 1.9 33 0.6 Hyponatremia 37 7 24 3.8 Hypertriglyceridemia 33 0 32 0.9 Increased alkaline phosphatase 26 3.1 18 1.9 Increased AST 24 2.2 16 0.6 Decreased bicarbonate 22 0.4 13 0 Hypocalcemia 21 0.3 18 1.9 Increased ALT 21 1.8 16 0.6 Other laboratory abnormalities occurring in 20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4). Adjuvant Treatment of Resected Melanoma The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (4 positive lymph nodes). Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054. Table 7: SelectedAdverse reactions occurring at same or higher incidence than in placebo arm Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-054 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=509 Placebo n=502 All GradesGraded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Diarrhea 28 1.2 26 1.2 Nausea 17 0.2 15 0 Skin and Subcutaneous Tissue Pruritus 19 0 12 0 Rash 13 0.2 9 0 Musculoskeletal and Connective Tissue Arthralgia 16 1.2 14 0 Endocrine Hypothyroidism 15 0 2.8 0 Hyperthyroidism 10 0.2 1.2 0 Respiratory, Thoracic and Mediastinal Cough 14 0 11 0 General Asthenia 11 0.2 8 0 Influenza like illness 11 0 8 0 Investigations Weight loss 11 0 8 0 Table 8: SelectedLaboratory abnormalities occurring at same or higher incidence than placebo. Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 503 to 507 patients) and placebo (range: 492 to 498 patients). KEYTRUDA 200 mg every 3 weeks Placebo All GradesGraded per NCI CTCAE v4.03 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Increased ALT 27 2.4 16 0.2 Increased AST 24 1.8 15 0.4 Hematology Lymphopenia 24 1 16 1.2 NSCLC First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and investigator's choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for 6 months. Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189. Table 9: Adverse Reactions Occurring in 20% of Patients in KEYNOTE-189 Adverse Reaction KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 All GradesGraded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Nausea 56 3.5 52 3.5 Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24 3.7 23 3.0 General FatigueIncludes asthenia and fatigue 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition Decreased appetite 28 1.5 30 0.5 Skin and Subcutaneous Tissue RashIncludes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 25 2.0 17 2.5 Respiratory, Thoracic and Mediastinal Cough 21 0 28 0 Dyspnea 21 3.7 26 5 Table 10: Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Patients in KEYNOTE-189 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy All GradesGraded per NCI CTCAE v4.03 % Grades 3-4 % All Grades % Grades 3-4 % Hematology Anemia 85 17 81 18 Lymphopenia 64 22 64 25 Neutropenia 48 20 41 19 Thrombocytopenia 30 12 29 8 Chemistry Hyperglycemia 63 9 60 7 Increased ALT 47 3.8 42 2.6 Increased AST 47 2.8 40 1.0 Hypoalbuminemia 39 2.8 39 1.1 Increased creatinine 37 4.2 25 1.0 Hyponatremia 32 7 23 6 Hypophosphatemia 30 10 28 14 Increased alkaline phosphatase 26 1.8 29 2.1 Hypocalcemia 24 2.8 17 0.5 Hyperkalemia 24 2.8 19 3.1 Hypokalemia 21 5 20 5 First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The safety of KEYTRUDA in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for 6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin. The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases. KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%). The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. Previously Untreated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for 6 months. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (stage IV), 13% had stage III disease (2% stage IIIA and 11% stage IIIB), and 5% had treated brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042. Table 11: Adverse Reactions Occurring in 10% of Patients in KEYNOTE-042 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=636 Chemotherapy n=615 All GradesGraded per NCI CTCAE v4.03 (%) Grades 3-5 (%) All Grades (%) Grades 3-5 (%) General FatigueIncludes fatigue and asthenia 25 3.1 33 3.9 Pyrexia 10 0.3 8 0 Metabolism and Nutrition Decreased appetite 17 1.7 21 1.5 Respiratory, Thoracic and Mediastinal Dyspnea 17 2.0 11 0.8 Cough 16 0.2 11 0.3 Skin and Subcutaneous Tissue RashIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 15 1.3 8 0.2 Gastrointestinal Constipation 12 0 21 0.2 Diarrhea 12 0.8 12 0.5 Nausea 12 0.5 32 1.1 Endocrine Hypothyroidism 12 0.2 1.5 0 Infections Pneumonia 12 7 9 6 Investigations Weight loss 10 0.9 7 0.2 Table 12: Laboratory Abnormalities Worsened from Baseline in 20% of Patients in KEYNOTE-042 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173. KEYTRUDA 200 mg every 3 weeks Chemotherapy All GradesGraded per NCI CTCAE v4.03 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 52 4.7 51 5 Increased ALT 33 4.8 34 2.9 Hypoalbuminemia 33 2.2 29 1.0 Increased AST 31 3.6 32 1.7 Hyponatremia 31 9 32 8 Increased alkaline phosphatase 29 2.3 29 0.3 Hypocalcemia 25 2.5 19 0.7 Hyperkalemia 23 3.0 20 2.2 Increased prothrombin INR 21 2.0 15 2.9 Hematology Anemia 43 4.4 79 19 Lymphopenia 30 7 41 13 Previously Treated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for 6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for 6 months. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease. In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010. Table 13: SelectedAdverse reactions occurring at same or higher incidence than in docetaxel arm Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-010 Adverse Reaction KEYTRUDA 2 or 10 mg/kg every 3 weeks n=682 Docetaxel 75 mg/m2 every 3 weeks n=309 All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Metabolism and Nutrition Decreased appetite 25 1.5 23 2.6 Respiratory, Thoracic and Mediastinal Dyspnea 23 3.7 20 2.6 Cough 19 0.6 14 0 Gastrointestinal Nausea 20 1.3 18 0.6 Constipation 15 0.6 12 0.6 Vomiting 13 0.9 10 0.6 Skin and Subcutaneous Tissue RashIncludes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic 17 0.4 8 0 Pruritus 11 0 3 0.3 Musculoskeletal and Connective Tissue Arthralgia 11 1.0 9 0.3 Back pain 11 1.5 8 0.3 Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%). Table 14: SelectedLaboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Laboratory Abnormalities Worsened from Baseline Occurring in 20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients). KEYTRUDA 2 or 10 mg/kg every 3 weeks Docetaxel 75 mg/m2 every 3 weeks All GradesGraded per NCI CTCAE v4.0 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyponatremia 32 8 27 2.9 Increased alkaline phosphatase 28 3.0 16 0.7 Increased AST 26 1.6 12 0.7 Increased ALT 22 2.7 9 0.4 Other laboratory abnormalities occurring in 20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% 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). SCLC Among the 131 patients with previously treated SCLC who received KEYTRUDA in KEYNOTE-158 Cohort G (n=107) and KEYNOTE-028 Cohort C1 (n=24) [see Clinical Studies (14.3)], the median duration of exposure to KEYTRUDA was 2 months (range: 1 day to 2.25 years). Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. HNSCC First-line treatment of metastatic or unresectable, recurrent HNSCC The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.4)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab. The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for 12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin. KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%). Tables 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048. Table 15: Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-048 KEYTRUDA 200 mg every 3 weeks KEYTRUDA 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU Adverse Reaction n=300 n=276 n=287 All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General FatigueIncludes fatigue, asthenia 33 4 49 11 48 8 Pyrexia 13 0.7 16 0.7 12 0 Mucosal inflammation 4.3 1.3 31 10 28 5 Gastrointestinal Constipation 20 0.3 37 0 33 1.4 Nausea 17 0 51 6 51 6 DiarrheaIncludes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis 16 0.7 29 3.3 35 3.1 Vomiting 11 0.3 32 3.6 28 2.8 Dysphagia 8 2.3 12 2.9 10 2.1 Stomatitis 3 0 26 8 28 3.5 Skin RashIncludes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis 20 2.3 17 0.7 70 8 Pruritus 11 0 8 0 10 0.3 Respiratory, Thoracic and Mediastinal CoughIncludes cough, productive cough 18 0.3 22 0 15 0 DyspneaIncludes dyspnea, exertional dyspnea 14 2.0 10 1.8 8 1.0 Endocrine Hypothyroidism 18 0 15 0 6 0 Metabolism and Nutrition Decreased appetite 15 1.0 29 4.7 30 3.5 Weight loss 15 2 16 2.9 21 1.4 Infections PneumoniaIncludes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal 12 7 19 11 13 6 Nervous System Headache 12 0.3 11 0.7 8 0.3 Dizziness 5 0.3 10 0.4 13 0.3 Peripheral sensory neuropathyIncludes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia 1 0 14 1.1 7 1 Musculoskeletal MyalgiaIncludes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia 12 1.0 13 0.4 11 0.3 Neck pain 6 0.7 10 1.1 7 0.7 Psychiatric Insomnia 7 0.7 10 0 8 0 Table 16: Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Patients Receiving KEYTRUDA in KEYNOTE-048 KEYTRUDA 200 mg every 3 weeks KEYTRUDA 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 235 to 266 patients), KEYTRUDA (range: 241 to 288 patients), cetuximab/chemotherapy (range: 249 to 282 patients). All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 54 25 69 35 74 45 Anemia 52 7 89 28 78 19 Thrombocytopenia 12 3.8 73 18 76 18 Neutropenia 7 1.4 67 35 71 42 Chemistry Hyperglycemia 47 3.8 55 6 66 4.7 Hyponatremia 46 17 56 20 59 20 Hypoalbuminemia 44 3.2 47 4.0 49 1.1 Increased AST 28 3.1 24 2.0 37 3.6 Increased ALT 25 2.1 22 1.6 38 1.8 Increased alkaline phosphatase 25 2.1 27 1.2 33 1.1 Hypercalcemia 22 4.6 16 4.3 13 2.6 Hypocalcemia 22 1.1 32 4 58 7 Hyperkalemia 21 2.8 27 4.3 29 4.3 Hypophosphatemia 20 5 35 12 48 19 Hypokalemia 19 5 34 12 47 15 Increased creatinine 18 1.1 36 2.3 27 2.2 Hypomagnesemia 16 0.4 42 1.7 76 6 Previously treated recurrent or metastatic HNSCC Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012. The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease. KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.4)]. cHL Among the 210 patients with cHL enrolled in KEYNOTE-087 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). KEYTRUDA was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-087. Table 17: Adverse Reactions in 10% of Patients with cHL in KEYNOTE-087 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=210 All GradesGraded per NCI CTCAE v4.0 (%) Grade 3 (%) General FatigueIncludes fatigue, asthenia 26 1.0 Pyrexia 24 1.0 Respiratory, Thoracic and Mediastinal CoughIncludes cough, productive cough 24 0.5 DyspneaIncludes dyspnea, dyspnea exertional, wheezing 11 1.0 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 21 1.0 Arthralgia 10 0.5 Gastrointestinal DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 20 1.4 Vomiting 15 0 Nausea 13 0 Skin and Subcutaneous Tissue Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrhoeic dermatitis, dermatitis psoriasiform 20 0.5 Pruritus 11 0 Endocrine Hypothyroidism 14 0.5 Infections Upper respiratory tract infection 13 0 Nervous System Headache 11 0.5 Peripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 10 0 Other clinically important adverse reactions that occurred in less than 10% of patients on KEYNOTE-087 included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each). Table 18: Selected Laboratory Abnormalities Worsened from Baseline Occurring in 15% of cHL Patients Receiving KEYTRUDA in KEYNOTE-087 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients) KEYTRUDA 200 mg every 3 weeks All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) Chemistry HypertransaminasemiaIncludes elevation of AST or ALT 34 2 Increased alkaline phosphatase 17 0 Increased creatinine 15 0.5 Hematology Anemia 30 6 Thrombocytopenia 27 4 Neutropenia 24 7 Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4). PMBCL Among the 53 patients with PMBCL treated in KEYNOTE-170 [see Clinical Studies (14.6)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). KEYTRUDA was discontinued due to adverse reactions in 8% of patients, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients, and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-170. Table 19: Adverse Reactions in 10% of Patients with PMBCL in KEYNOTE-170 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=53 All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal painIncludes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain 30 0 Infections Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection 28 0 General Pyrexia 28 0 FatigueIncludes fatigue, asthenia 23 2 Respiratory, Thoracic and Mediastinal CoughIncludes allergic cough, cough, productive cough 26 2 Dyspnea 21 11 Gastrointestinal DiarrheaIncludes diarrhea, gastroenteritis 13 2 Abdominal pain Includes abdominal pain, abdominal pain upper 13 0 Nausea 11 0 Cardiac Arrhythmia Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia 11 4 Nervous System Headache 11 0 Other clinically important adverse reactions that occurred in less than 10% of patients in KEYNOTE-170 included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each). Table 20: Laboratory Abnormalities Worsened from Baseline Occurring in 15% of PMBCL Patients Receiving KEYTRUDA in KEYNOTE-170 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 44 to 48 patients) KEYTRUDA 200 mg every 3 weeks All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) Hematology Anemia 47 0 Leukopenia 35 9 Lymphopenia 32 18 Neutropenia 30 11 Chemistry Hyperglycemia 38 4 Hypophosphatemia 29 10 HypertransaminasemiaIncludes elevation of AST or ALT 27 4 Hypoglycemia 19 0 Increased alkaline phosphatase 17 0 Increased creatinine 17 0 Hypocalcemia 15 4 Hypokalemia 15 4 Urothelial Carcinoma Cisplatin Ineligible Patients with Urothelial Carcinoma The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.7)]. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose 40 mg oral prednisone equivalent. Table 21 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052. Table 21: Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-052 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=370 All GradesGraded per NCI CTCAE v4.0 (%) Grades 34 (%) General FatigueIncludes fatigue, asthenia 38 6 Pyrexia 11 0.5 Weight loss 10 0 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain 24 4.9 Arthralgia 10 1.1 Metabolism and Nutrition Decreased appetite 22 1.6 Hyponatremia 10 4.1 Gastrointestinal Constipation 21 1.1 DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements 20 2.4 Nausea 18 1.1 Abdominal painIncludes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper 18 2.7 Elevated LFTsIncludes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases, hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests 13 3.5 Vomiting 12 0 Skin and Subcutaneous Tissue RashIncludes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized 21 0.5 Pruritus 19 0.3 Edema peripheralIncludes edema peripheral, peripheral swelling 14 1.1 Infections Urinary tract infection 19 9 Blood and Lymphatic System Anemia 17 7 Respiratory, Thoracic, and Mediastinal Cough 14 0 Dyspnea 11 0.5 Renal and Urinary Increased blood creatinine 11 1.1 Hematuria 13 3.0 Previously Treated Urothelial Carcinoma The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator's choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.7)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045. Table 22: Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-045 Adverse Reaction KEYTRUDA 200 mg every 3 weeks ChemotherapyChemotherapy: paclitaxel, docetaxel, or vinflunine n=266 n=255 All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General FatigueIncludes asthenia, fatigue, malaise, lethargy 38 4.5 56 11 Pyrexia 14 0.8 13 1.2 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 32 3.0 27 2.0 Skin and Subcutaneous Tissue Pruritus 23 0 6 0.4 RashIncludes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis 20 0.4 13 0.4 Gastrointestinal Nausea 21 1.1 29 1.6 Constipation 19 1.1 32 3.1 DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 18 2.3 19 1.6 Vomiting 15 0.4 13 0.4 Abdominal pain 13 1.1 13 2.7 Infections Urinary tract infection 15 4.9 14 4.3 Metabolism and Nutrition Decreased appetite 21 3.8 21 1.2 Respiratory, Thoracic and Mediastinal CoughIncludes cough, productive cough 15 0.4 9 0 DyspneaIncludes dyspnea, dyspnea exertional, wheezing 14 1.9 12 1.2 Renal and Urinary Hematuria Includes blood urine present, hematuria, chromaturia 12 2.3 8 1.6 Table 23: Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: KEYTRUDA n=232 and chemotherapy n=222. KEYTRUDA 200 mg every 3 weeks Chemotherapy All GradesGraded per NCI CTCAE v4.0 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 52 8 60 7 Anemia 52 13 68 18 Lymphopenia 45 15 53 25 Hypoalbuminemia 43 1.7 50 3.8 Hyponatremia 37 9 47 13 Increased alkaline phosphatase 37 7 33 4.9 Increased creatinine 35 4.4 28 2.9 Hypophosphatemia 29 8 34 14 Increased AST 28 4.1 20 2.5 Hyperkalemia 28 0.8 27 6 Hypocalcemia 26 1.6 34 2.1 BCG-unresponsive High-risk NMIBC The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057. Table 24: Adverse Reactions Occurring in 10% of Patients Receiving KEYTRUDA in KEYNOTE-057 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=148 All GradesGraded per NCI CTCAE v4.03 (%) Grades 34 (%) General FatigueIncludes asthenia, fatigue, malaise 29 0.7 Peripheral edemaIncludes edema peripheral, peripheral swelling 11 0 Gastrointestinal DiarrheaIncludes diarrhea, gastroenteritis, colitis 24 2.0 Nausea 13 0 Constipation 12 0 Skin and Subcutaneous Tissue RashIncludes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis 24 0.7 Pruritus 19 0.7 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain 19 0 Arthralgia 14 1.4 Renal and Urinary Hematuria 19 1.4 Respiratory, Thoracic, and Mediastinal CoughIncludes cough, productive cough 19 0 Infections Urinary tract infection 12 2.0 Nasopharyngitis 10 0 Endocrine Hypothyroidism 11 0 Table 25: Laboratory Abnormalities Worsened from Baseline Occurring in 20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 124 to 147 patients) KEYTRUDA 200 mg every 3 weeks All GradesGraded per NCI CTCAE v4.03 (%) Grades 3-4 (%) Chemistry Hyperglycemia 59 8 Increased ALT 25 3.4 Hyponatremia 24 7 Hypophosphatemia 24 6 Hypoalbuminemia 24 2.1 Hyperkalemia 23 1.4 Hypocalcemia 22 0.7 Increased AST 20 3.4 Increased creatinine 20 0.7 Hematology Anemia 35 1.4 Lymphopenia 29 1.6 Gastric Cancer Among the 259 patients with gastric cancer enrolled in KEYNOTE-059 [see Clinical Studies (14.9)], the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Esophageal Cancer Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.10)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Cervical Cancer Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.11)], the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 26 and 27 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158. Table 26: Adverse Reactions Occurring in 10% of Patients with Cervical Cancer in KEYNOTE-158 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=98 All GradesGraded per NCI CTCAE v4.0 (%) Grades 34 (%) General FatigueIncludes asthenia, fatigue, lethargy, malaise 43 5 PainIncludes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache 22 2.0 Pyrexia 19 1.0 Edema peripheralIncludes edema peripheral, peripheral swelling 15 2.0 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity 27 5 Gastrointestinal DiarrheaIncludes colitis, diarrhea, gastroenteritis 23 2.0 Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper 22 3.1 Nausea 19 0 Vomiting 19 1.0 Constipation 14 0 Metabolism and Nutrition Decreased appetite 21 0 Vascular HemorrhageIncludes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage 19 5 Infections UTIIncludes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis 18 6 Infection (except UTI)Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis 16 4.1 Skin and Subcutaneous Tissue RashIncludes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular 17 2.0 Endocrine Hypothyroidism 11 0 Nervous System Headache 11 2.0 Respiratory, Thoracic and Mediastinal Dyspnea 10 1.0 Table 27: Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Patients with Cervical Cancer in KEYNOTE-158 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 76 to 79 patients) KEYTRUDA 200 mg every 3 weeks All GradesGraded per NCI CTCAE v4.0 (%) Grades 3-4 (%) Hematology Anemia 54 24 Lymphopenia 47 9 Chemistry Hypoalbuminemia 44 5 Increased alkaline phosphatase 42 2.6 Hyponatremia 38 13 Hyperglycemia 38 1.3 Increased AST 34 3.9 Increased creatinine 32 5 Hypocalcemia 27 0 Increased ALT 21 3.9 Hypokalemia 20 6 Other laboratory abnormalities occurring in 10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (14% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4). HCC Among the 104 patients with HCC who received KEYTRUDA in KEYNOTE-224 [see Clinical Studies (14.12)], the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%). MCC Among the 50 patients with MCC enrolled in KEYNOTE-017 [see Clinical Studies (14.13)], the median duration of exposure to KEYTRUDA was 6.6 months (range 1 day to 23.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%). RCC The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.14)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months). The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80. Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure. Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in 1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%). The most common adverse reactions (20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to 40 mg daily for an immune-mediated adverse reaction. Tables 28 and 29 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426. Table 28: Adverse Reactions Occurring in 20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and Axitinib n=429 Sunitinib n=425 All GradesGraded per NCI CTCAE v4.03 (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic 56 11 45 5 Nausea 28 0.9 32 0.9 Constipation 21 0 15 0.2 General Fatigue/Asthenia 52 5 51 10 Vascular HypertensionIncludes hypertension, blood pressure increased, hypertensive crisis, labile hypertension 48 24 48 20 Hepatobiliary HepatotoxicityIncludes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased 39 20 25 4.9 Endocrine Hypothyroidism 35 0.2 32 0.2 Metabolism and Nutrition Decreased appetite 30 2.8 29 0.7 Skin and Subcutaneous Tissue Palmar-plantar erythrodysaesthesia syndrome 28 5 40 3.8 Stomatitis/Mucosal inflammation 27 1.6 41 4 RashIncludes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrhoeric dermatitis, skin discoloration, skin exfoliation, perineal rash 25 1.4 21 0.7 Respiratory, Thoracic and Mediastinal Dysphonia 25 0.2 3.3 0 Cough 21 0.2 14 0.5 Table 29: Laboratory Abnormalities Worsened from Baseline Occurring in 20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426 Laboratory TestEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients). KEYTRUDA 200 mg every 3 weeks and Axitinib Sunitinib All GradesGraded per NCI CTCAE v4.03 % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 62 9 54 3.2 Increased ALT 60 20 44 5 Increased AST 57 13 56 5 Increased creatinine 43 4.3 40 2.4 Hyponatremia 35 8 29 8 Hyperkalemia 34 6 22 1.7 Hypoalbuminemia 32 0.5 34 1.7 Hypercalcemia 27 0.7 15 1.9 Hypophosphatemia 26 6 49 17 Increased alkaline phosphatase 26 1.7 30 2.7 HypocalcemiaCorrected for albumin 22 0.2 29 0.7 Blood bilirubin increased 22 2.1 21 1.9 Activated partial thromboplastin time prolongedTwo patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity. 22 1.2 14 0 Hematology Lymphopenia 33 11 46 8 Anemia 29 2.1 65 8 Thrombocytopenia 27 1.4 78 14 Endometrial Carcinoma The safety of KEYTRUDA in combination with lenvatinib (20 mg orally once daily) was investigated in KEYNOTE-146, a single-arm, multicenter, open-label trial in 94 patients with endometrial carcinoma whose tumors had progressed following one line of systemic therapy and were not MSI-H or dMMR [see Clinical Studies (14.15)]. The median duration of study treatment was 7 months (range: 0.03 to 37.8 months). The median duration of exposure to KEYTRUDA was 6 months (range: 0.03 to 23.8 months). KEYTRUDA was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Fatal adverse reactions occurred in 3% of patients receiving KEYTRUDA and lenvatinib, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS) with intraventricular hemorrhage, and intracranial hemorrhage. Serious adverse reactions occurred in 52% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in 3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%). KEYTRUDA was discontinued for adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with lenvatinib. The most common adverse reactions ( 2%) leading to discontinuation of KEYTRUDA were adrenal insufficiency (2%), colitis (2%), pancreatitis (2%), and muscular weakness (2%). Adverse reactions leading to interruption of KEYTRUDA occurred in 49% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (2%) were: fatigue (14%), diarrhea (6%), decreased appetite (6%), rash (5%), renal impairment (4%), vomiting (4%), increased lipase (4%), decreased weight (4%), nausea (3%), increased blood alkaline phosphatase (3%), skin ulcer (3%), adrenal insufficiency (2%), increased amylase (2%), hypocalcemia (2%), hypomagnesemia (2%), hyponatremia (2%), peripheral edema (2%), musculoskeletal pain (2%), pancreatitis (2%), and syncope (2%). Tables 30 and 31 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib. Table 30: Adverse Reactions Occurring in 20% of Patients with Endometrial Carcinoma in KEYNOTE-146 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with Lenvatinib N=94 All Grades (%) Grades 3-4 (%) General FatigueIncludes asthenia, fatigue, and malaise 65 17 Musculoskeletal and Connective Tissue Musculoskeletal painIncludes arthralgia, arthritis, back pain, breast pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity 65 3 Vascular HypertensionIncludes essential hypertension, hypertension, and hypertensive encephalopathy 65 38 Hemorrhagic eventsIncludes catheter site bruise, contusion, epistaxis, gastrointestinal hemorrhage, hematemesis, hematuria, hemorrhage intracranial, injection site hemorrhage, intraventricular hemorrhage, large intestinal hemorrhage, metrorrhagia, mouth hemorrhage, uterine hemorrhage, and vaginal hemorrhage 28 4 Gastrointestinal DiarrheaIncludes diarrhea, gastroenteritis, gastrointestinal viral infection, and viral diarrhea 64 4 Nausea 48 5 StomatitisIncludes glossitis, mouth ulceration, oral discomfort, oral mucosal blistering, oropharyngeal pain, and stomatitis 43 0 Vomiting 39 0 Abdominal pain Includes abdominal discomfort, abdominal pain, lower abdominal pain, and upper abdominal pain 33 6 Constipation 32 0 Metabolism Decreased appetiteIncludes decreased appetite and early satiety 52 0 Hypomagnesemia 27 3 Endocrine HypothyroidismIncludes increased blood thyroid stimulating hormone and hypothyroidism 51 1 Investigations Decreased weight 36 3 Nervous System Headache 33 1 Infections Urinary tract infectionIncludes cystitis and urinary tract infection 31 4 Respiratory, Thoracic and Mediastinal Dysphonia 29 0 DyspneaIncludes dyspnea and exertional dyspnea 24 2 Cough 21 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 26 3 RashIncludes rash, rash generalized, rash macular, and rash maculo-papular 21 3 Table 31: Laboratory Abnormalities Worsened from Baseline Occurring in 20% (All Grades) or 3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-146 Laboratory TestWith at least 1 grade increase from baseline KEYTRUDA 200 mg every 3 weeks with Lenvatinib All Grades %Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter (range: 71 to 92 patients). Grade 3-4 % Chemistry Increased creatinine 80 7 Hypertriglyceridemia 58 4 Hyperglycemia 53 1 Hypercholesteremia 49 6 Hypoalbuminemia 48 0 Hypomagnesemia 47 2 Increased aspartate aminotransferase 43 4 Hyponatremia 42 13 Increased lipase 42 18 Increased alanine aminotransferase 35 3 Increased alkaline phosphatase 32 1 Hypokalemia 27 5 Increased amylase 19 6 Hypocalcemia 14 3 Hypermagnesemia 4 3 Hematology Thrombocytopenia 48 0 Leukopenia 38 2 Lymphopenia 36 7 Anemia 35 1 Increased INR 21 3 Neutropenia 12 3 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to pembrolizumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading. Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 27 (2.1%) of 1289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom six (0.5%) patients had neutralizing antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Melanoma Ipilimumab-Naive Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (1% of tumor cells [positive] vs. 1 mm lymph node metastasis), IIIB or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC 4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD-L1 positive melanoma with TPS 1% according to an IUO assay. The trial demonstrated a statistically significant improvement in RFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 34 and Figure 3. Table 34: Efficacy Results in KEYNOTE-054 Endpoint KEYTRUDA 200 mg every 3 weeks n=514 Placebo n=505 NR = not reached RFS Number (%) of patients with event 135 (26%) 216 (43%) Median in months (95% CI) NR 20.4 (16.2, NR) Hazard ratioBased on the stratified Cox proportional hazard model Stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (95% CI) 0.57 (0.46, 0.70) p-Value (log-rank) 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria. The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior auto-HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy. Efficacy results for KEYNOTE-087 are summarized in Table 44. Table 44: Efficacy Results in KEYNOTE-087 Endpoint KEYTRUDA 200 mg every 3 weeks n=210Median follow-up time of 9.4 months Objective Response Rate ORR (95% CI) 69% (62, 75) Complete response rate 22% Partial response rate 47% Duration of Response Median in months (range) 11.1 (0.0+, 11.1) Based on patients (n=145) with a response by independent review 14.6 Primary Mediastinal Large B-Cell Lymphoma The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open-label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR. The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy. For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 45. Table 45: Efficacy Results in KEYNOTE-170 Endpoint KEYTRUDA 200 mg every 3 weeks n=53Median follow-up time of 9.7 months NR = not reached Objective Response Rate ORR (95% CI) 45% (32, 60) Complete response rate 11% Partial response rate 34% Duration of Response Median in months (range) NR (1.1+, 19.2+)Based on patients (n=24) with a response by independent review 14.7 Urothelial Carcinoma Cisplatin Ineligible Patients with Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open-label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 74 years; 77% male; and 89% White. Eighty-seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: 50% with baseline creatinine clearance of <60 mL/min, 32% with ECOG PS of 2, 9% with ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment nave, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. Among the 370 patients, 30% (n = 110) had tumors that expressed PD-L1 with a CPS 10. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The study population characteristics of these 110 patients were: median age of 73 years; 68% male; and 87% White. Eighty-two percent had M1 disease, and 18% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 18% of patients had a primary tumor in the upper tract. Seventy-six percent of patients had visceral metastases, including 11% with liver metastases. Reasons for cisplatin ineligibility included: 45% with baseline creatinine clearance of <60 mL/min, 37% with ECOG PS of 2, 10% with ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 8% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment nave, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. The median follow-up time for 370 patients treated with KEYTRUDA was 7.8 months (range 0.1 to 20 months). Efficacy results are summarized in Table 46. Table 46: Efficacy Results in KEYNOTE-052 Endpoint KEYTRUDA 200 mg every 3 weeks All Subjects n=370 PD-L1 CPS <10 n=260Includes 9 subjects with unknown PD-L1 status PD-L1 CPS 10 n=110 + Denotes ongoing NR = not reached Objective Response Rate ORR (95% CI) 29% (24, 34) 21% (16, 26) 47% (38, 57) Complete response rate 7% 3% 15% Partial response rate 22% 18% 32% Duration of Response Median in months (range) NR (1.4+, 17.8+) NR (1.4+, 16.3+) NR (1.4+, 17.8+) Previously Untreated Urothelial Carcinoma KEYNOTE-361 (NCT02853305) is an ongoing, multicenter, randomized study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study compares KEYTRUDA with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. The trial also enrolled a third arm of monotherapy with KEYTRUDA to compare to platinum-based chemotherapy alone. The independent Data Monitoring Committee (iDMC) for the study conducted a review of early data and found that in patients classified as having low PD-L1 expression (CPS <10), those treated with KEYTRUDA monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended to stop further accrual of patients with low PD-L1 expression in the monotherapy arm, however, no other changes were recommended, including any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm. Previously Treated Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients were randomized to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=90), docetaxel 75 mg/m2 (n=92), or vinflunine 320 mg/m2 (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. The study population characteristics were: median age of 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0 and 56% ECOG PS of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens. The study demonstrated statistically significant improvements in OS and ORR for patients randomized to KEYTRUDA as compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 47 and Figure 11 summarize the efficacy results for KEYNOTE-045. Table 47: Efficacy Results in KEYNOTE-045 KEYTRUDA 200 mg every 3 weeks Chemotherapy n=270 n=272 + Denotes ongoing NR = not reached OS Deaths (%) 155 (57%) 179 (66%) Median in months (95% CI) 10.3 (8.0, 11.8) 7.4 (6.1, 8.3) Hazard ratioHazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI) 0.73 (0.59, 0.91) p-Value (stratified log-rank) 0.004 PFS by BICR Events (%) 218 (81%) 219 (81%) Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.3, 3.5) Hazard ratio (95% CI) 0.98 (0.81, 1.19) p-Value (stratified log-rank) 0.833 Objective Response Rate ORR (95% CI) 21% (16, 27) 11% (8, 16) Complete response rate 7% 3% Partial response rate 14% 8% p-Value (Miettinen-Nurminen) 0.002 Median duration of response in months (range) NR (1.6+, 15.6+) 4.3 (1.4+, 15.4+) Figure 11: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045 BCG-unresponsive High-Risk Non-Muscle Invasive Bladder Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-057 (NCT02625961), a multicenter, open-label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The study population characteristics were: median age of 73 years (range: 44 to 92); 44% age 75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12. The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarized in Table 48. Table 48: Efficacy Results in KEYNOTE-057 Endpoint KEYTRUDA 200 mg every 3 weeks n=96 Complete Response Rate (95% CI) 41% (31, 51) Duration of Response Based on patients (n=39) that achieved a complete response; reflects period from the time complete response was achieved Median in months (range) 16.2 (0.0+, 30.4 Denotes ongoing) % (n) with duration 12 months 46% (18) 14.8 Microsatellite Instability-High Cancer The efficacy of KEYTRUDA was investigated in patients with MSI-H or mismatch repair deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible across the five trials. Patients received either KEYTRUDA 200 mg every 3 weeks or KEYTRUDA 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. A maximum of 24 months of treatment with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity across these 5 trials, the major efficacy outcome measures were ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. Table 49: MSI-H Trials Study Design and Patient Population Number of Patients MSI-H/dMMR Testing Dosage Prior Therapy CRC = colorectal cancer PCR = polymerase chain reaction IHC = immunohistochemistry KEYNOTE-016 NCT01876511 prospective, investigator-initiated 6 sites patients with CRC and other tumors 28 CRC 30 non-CRC local PCR or IHC 10 mg/kg every 2 weeks CRC: 2 prior regimens Non-CRC: 1 prior regimen KEYNOTE-164 NCT02460198 prospective international multi-center CRC 61 local PCR or IHC 200 mg every 3 weeks Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb KEYNOTE-012 NCT01848834 retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer 6 central PCR 10 mg/kg every 2 weeks 1 prior regimen KEYNOTE-028 NCT02054806 retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC 5 central PCR 10 mg/kg every 2 weeks 1 prior regimen KEYNOTE-158 NCT02628067 prospective international multi-center enrollment of patients with MSI-H/dMMR non-CRC retrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts 19 local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts) 200 mg every 3 weeks 1 prior regimen Total 149 A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. Among these 149 patients, the baseline characteristics were: median age of 55 years, 36% age 65 or older; 56% male; 77% White, 19% Asian, and 2% Black; and 36% ECOG PS of 0 and 64% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease and 2% had locally advanced, unresectable disease. The median number of prior therapies for metastatic or unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received two or more prior lines of therapy. The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a total of 415 patients using a central laboratory developed PCR test. Forty-seven patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were identified using both tests. Efficacy results are summarized in Tables 50 and 51. Table 50: Efficacy Results for Patients with MSI-H/dMMR Cancer Endpoint KEYTRUDA n=149 NR = not reached Objective Response Rate ORR (95% CI) 39.6% (31.7, 47.9) Complete response rate 7.4% Partial response rate 32.2% Duration of Response Median in months (range) NR (1.6+, 22.7+) % with duration 6 months 78% Table 51: Response by Tumor Type Objective response rate DoR range N n (%) 95% CI (months) CR = complete response PR = partial response SD = stable disease PD = progressive disease NE = not evaluable CRC 90 32 (36%) (26%, 46%) (1.6+, 22.7+) Non-CRC 59 27 (46%) (33%, 59%) (1.9+, 22.1+) Endometrial cancer 14 5 (36%) (13%, 65%) (4.2+, 17.3+) Biliary cancer 11 3 (27%) (6%, 61%) (11.6+, 19.6+) Gastric or GE junction cancer 9 5 (56%) (21%, 86%) (5.8+, 22.1+) Pancreatic cancer 6 5 (83%) (36%, 100%) (2.6+, 9.2+) Small intestinal cancer 8 3 (38%) (9%, 76%) (1.9+, 9.1+) Breast cancer 2 PR, PR (7.6, 15.9) Prostate cancer 2 PR, SD 9.8+ Bladder cancer 1 NE Esophageal cancer 1 PR 18.2+ Sarcoma 1 PD Thyroid cancer 1 NE Retroperitoneal adenocarcinoma 1 PR 7.5+ Small cell lung cancer 1 CR 8.9+ Renal cell cancer 1 PD 14.9 Gastric Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-059 (NCT02335411), a multicenter, non-randomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet. HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1 with a CPS 1 and microsatellite stable (MSS) tumor status or undetermined MSI or MMR status. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The baseline characteristics of these 143 patients were: median age of 64 years, 47% age 65 or older; 77% male; 82% White and 11% Asian; and 43% ECOG PS of 0 and 57% ECOG PS of 1. Eighty-five percent had M1 disease and 7% had M0 disease. Fifty-one percent had two and 49% had three or more prior lines of therapy in the recurrent or metastatic setting. For the 143 patients, the ORR was 13.3% (95% CI: 8.2, 20.0); 1.4% had a complete response and 11.9% had a partial response. Among the 19 responding patients, the DoR ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and 5 patients (26%) having responses of 12 months or longer. Among the 259 patients enrolled in KEYNOTE-059, 7 (3%) had tumors that were determined to be MSI-H. An objective response was observed in 4 patients, including 1 complete response. The DoR ranged from 5.3+ to 14.1+ months. 14.10 Esophageal Cancer KEYNOTE-181 The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator's choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS 10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator's treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS 10. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator's treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirty-three percent of patients received prior treatment with a taxane. The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS 10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS 10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 52 and Figure 12 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS 10. Table 52: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS 10) in KEYNOTE-181 Endpoint KEYTRUDA 200 mg every 3 weeks n=85 Chemotherapy n=82 OS Number (%) of patients with event 68 (80%) 72 (88%) Median in months (95% CI) 10.3 (7.0, 13.5) 6.7 (4.8, 8.6) Hazard ratioBased on the Cox regression model stratified by geographic region (Asia vs. ex-Asia) (95% CI) 0.64 (0.46, 0.90) PFS Number (%) of patients with event 76 (89%) 76 (93%) Median in months (95% CI) 3.2 (2.1, 4.4) 2.3 (2.1, 3.4) Hazard ratio (95% CI) 0.66 (0.48, 0.92) Objective Response Rate ORR (95% CI) 22 (14, 33) 7 (3, 15) Number (%) of complete responses 4 (5) 1 (1) Number (%) of partial responses 15 (18) 5 (6) Median duration of response in months (range) 9.3 (2.1+, 18.8+) 7.7 (4.3, 16.8+) Figure 12: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS 10) KEYNOTE-180 The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, non-randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS 10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease. The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer. 14.11 Cervical Cancer The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). Efficacy results are summarized in Table 53 for patients with PD-L1 expression (CPS 1). Table 53: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS 1) in KEYNOTE-158 Endpoint KEYTRUDA 200 mg every 3 weeks n=77Median follow-up time of 11.7 months (range 0.6 to 22.7 months) + Denotes ongoing NR = not reached Objective Response Rate ORR (95% CI) 14.3% (7.4, 24.1) Complete response rate 2.6% Partial response rate 11.7% Duration of Response Median in months (range) NR (4.1, 18.6+)Based on patients (n=11) with a response by independent review % with duration 6 months 91% 14.12 Hepatocellular Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-224 (NCT02702414), a single-arm, multicenter trial in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib; had measurable disease; and Child-Pugh class A liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of KEYTRUDA. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. The study population characteristics were: median age of 68 years, 67% age 65 or older; 83% male; 81% White and 14% Asian; and 61% ECOG PS of 0 and 39% ECOG PS of 1. Child-Pugh class and score were A5 for 72%, A6 for 22%, B7 for 5%, and B8 for 1% of patients. Twenty-one percent of the patients were HBV seropositive and 25% HCV seropositive. There were 9 patients (9%) who were seropositive for both HBV and HCV. For these 9 patients, all of the HBV cases and three of the HCV cases were inactive. Sixty-four percent (64%) of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both. Thirty-eight percent (38%) of patients had alpha-fetoprotein (AFP) levels 400 mcg/L. All patients received prior sorafenib; of whom 20% were unable to tolerate sorafenib. No patient received more than one prior systemic therapy (sorafenib). Efficacy results are summarized in Table 54. Table 54: Efficacy Results in KEYNOTE-224 Endpoint KEYTRUDA 200 mg every 3 weeks n=104 BICR-Assessed Objective Response Rate (RECIST v1.1) ORR (95% CI)Based on patients (n=18) with a confirmed response by independent review 17% (11, 26) Complete response rate 1% Partial response rate 16% BICR-Assessed Duration of Response % with duration 6 months 89% % with duration 12 months 56% 14.13 Merkel Cell Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1. The study population characteristics were: median age of 71 years (range: 46 to 91), 80% age 65 or older; 68% male; 90% White; and 48% ECOG PS of 0 and 52% ECOG PS of 1. Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy. Efficacy results are summarized in Table 55. Table 55: Efficacy Results in KEYNOTE-017 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=50 Objective Response Rate ORR (95% CI) 56% (41, 70) Complete response rate (95% CI) 24% (13, 38) Partial response rate (95% CI) 32% (20, 47) Duration of Response Range in monthsThe median duration of response was not reached. 5.9-34.5+ Patients with duration 6 months, n (%) 27 (96%) Patients with duration 12 months, n (%) 15 (54%) 14.14 Renal Cell Carcinoma The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus "Rest of the World"). Patients were randomized (1:1) to one of the following treatment arms: KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity. Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks. Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter. The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. Table 56 and Figure 13 summarize the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months). Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status. Table 56: Efficacy Results in KEYNOTE-426 Endpoint KEYTRUDA 200 mg every 3 weeks and Axitinib Sunitinib n=432 n=429 NR = not reached OS Number of patients with event (%) 59 (14%) 97 (23%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.53 (0.38, 0.74) p-ValueBased on stratified log-rank test <0.0001p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis). 12-month OS rate 90% (86, 92) 78% (74, 82) PFS Number of patients with event (%) 183 (42%) 213 (50%) Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5) Hazard ratio (95% CI) 0.69 (0.56, 0.84) p-Value 0.0001p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis). ORR Overall confirmed response rate (95% CI) 59% (54, 64) 36% (31, 40) Complete response rate 6% 2% Partial response rate 53% 34% p-ValueBased on Miettinen and Nurminen method stratified by IMDC risk group and geographic region <0.0001 Figure 13: Kaplan-Meier Curve for Overall Survival in KEYNOTE-426 14.15 Endometrial Carcinoma The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-146 (NCT02501096), a single-arm, multicenter, open-label, multi-cohort trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator. The major efficacy outcome measures were ORR and DoR as assessed by BICR using RECIST 1.1. Administration of KEYTRUDA and lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA dosing was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 6 weeks until week 24, followed by every 9 weeks thereafter. Among the 108 patients, 87% (n=94) had tumors that were not MSI-H or dMMR, 10% (n=11) had tumors that were MSI-H or dMMR, and in 3% (n=3) the status was not known. Tumor MSI status was determined using a polymerase chain reaction (PCR) test. Tumor MMR status was determined using an IHC test. The baseline characteristics of the 94 patients with tumors that were not MSI-H or dMMR were: median age of 66 years, 62% age 65 or older; 86% White, 6% Black, 4% Asian, and 3% other races; and ECOG PS of 0 (52%) or 1 (48%). All 94 of these patients received prior systemic therapy for endometrial carcinoma: 51% had one, 38% had two, and 11% had three or more prior systemic therapies. Efficacy results are summarized in Table 57. Table 57: Efficacy Results in KEYNOTE-146 Endpoint KEYTRUDA 200 mg every 3 weeks with lenvatinib n=94Median follow-up time of 18.7 months + Denotes ongoing NR = not reached Objective Response Rate ORR (95% CI) 38.3% (29, 49) Complete response rate 10.6% Partial response rate 27.7% Response duration Median in months (range) NR (1.2+, 33.1+)Based on patients (n=36) with a response by independent review % with duration 6 months 69% 14.16 Adult Indications: Additional Dosing Regimen of 400 mg Every 6 Weeks The efficacy and safety of KEYTRUDA using a dosage of 400 mg every 6 weeks for all approved adult indications was primarily based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma [see Clinical Pharmacology (12.2)].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated: Melanoma for the treatment of patients with unresectable or metastatic melanoma. (1.1) for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. (1.1) Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. (1.2) in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. (1.2) as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) 1%] as determined by an FDA-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 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. (1.2, 2.1) Small Cell Lung Cancer (SCLC) for the treatment of patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.1 (1.3) Head and Neck Squamous Cell Cancer (HNSCC) in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. (1.4) as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test. (1.4, 2.1) as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. (1.4) Classical Hodgkin Lymphoma (cHL) for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after 3 or more prior lines of therapy.1 (1.5) Primary Mediastinal Large B-Cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy.1 (1.6) Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Carcinoma for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.1 (1.7, 2.1) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.7) for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. (1.7) Microsatellite Instability-High Cancer for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options,1 or colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1 (1.8) Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. (1.8) Gastric Cancer for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.1 (1.9, 2.1) Esophageal Cancer for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 [Combined Positive Score (CPS) 10] as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. (1.10, 2.1) Cervical Cancer for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test.1 (1.11, 2.1) Hepatocellular Carcinoma (HCC) for the treatment of patients with HCC who have been previously treated with sorafenib.1 (1.12) Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.1 (1.13) Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of patients with advanced RCC. (1.14) Endometrial Carcinoma in combination with lenvatinib, for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.1 (1.15) Adult Indications: Additional Dosing Regimen of 400 mg Every 6 Weeks for use at an additional recommended dosage of 400 mg every 6 weeks for all approved adult indications.2 (1.16, 2.2) 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. 2 This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.1 Melanoma KEYTRUDA (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. 1.2 Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) 1%] as determined by an FDA-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, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-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. 1.3 Small Cell Lung Cancer KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1.4 Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. 1.5 Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.6 Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. 1.7 Urothelial Carcinoma KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test [see Dosage and Administration (2.1)], or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14.7)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. 1.8 Microsatellite Instability-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.8)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. 1.9 Gastric Cancer KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.9)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.10 Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression after one or more prior lines of systemic therapy. 1.11 Cervical Cancer KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.12 Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.12)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.13 Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.13)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.14 Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). 1.15 Endometrial Carcinoma KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.15)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.16 Adult Indications: Additional Dosing Regimen of 400 mg Every 6 Weeks KEYTRUDA is indicated for use at an additional recommended dosage of 400 mg every 6 weeks for all approved adult indications [see Indications and Usage (1.1-1.15) and Dosage and Administration (2.2)]. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety [see Clinical Pharmacology (12.2) and Clinical Studies (14.16)]. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) SCLC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) Urothelial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) MSI-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) HCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) RCC: 200 mg every 3 weeks or 400 mg every 6 weeks with axitinib 5 mg orally twice daily. (2.2) Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks with lenvatinib 20 mg orally once daily for tumors that are not MSI-H or dMMR. (2.2) Administer KEYTRUDA as an intravenous infusion over 30 minutes. 2.1 Patient Selection for NSCLC, HNSCC, Urothelial Carcinoma, Gastric Cancer, Esophageal Cancer, or Cervical Cancer Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in: stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.2)]. metastatic NSCLC [see Clinical Studies (14.2)]. first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.4)]. metastatic urothelial carcinoma [see Clinical Studies (14.7)]. metastatic gastric cancer [see Clinical Studies (14.9)]. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing. metastatic esophageal cancer [see Clinical Studies (14.10)]. recurrent or metastatic cervical cancer [see Clinical Studies (14.11)]. Information on FDA-approved tests for the detection of PD-L1 expression for these indications is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage Table 1: Recommended Dosage Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment Monotherapy Adult patients with unresectable or metastatic melanoma 200 mg every 3 weeks30 minute intravenous infusion or 400 mg every 6 weeks Until disease progression or unacceptable toxicity Adjuvant treatment of adult patients with melanoma 200 mg every 3 weeks or 400 mg every 6 weeks Until disease recurrence, unacceptable toxicity, or up to 12 months Adult patients with NSCLC, SCLC, HNSCC, cHL, PMBCL, locally advanced or metastatic Urothelial Carcinoma, MSI-H Cancer, Gastric Cancer, Esophageal Cancer, Cervical Cancer, HCC, or MCC 200 mg every 3 weeks or 400 mg every 6 weeks Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with high-risk BCG- unresponsive NMIBC 200 mg every 3 weeks or 400 mg every 6 weeks Until persistent or recurrent high-risk NMIBC, disease progression, unacceptable toxicity, or up to 24 months Pediatric patients with cHL, PMBCL, MSI-H Cancer, or MCC 2 mg/kg every 3 weeks (up to a maximum of 200 mg) Until disease progression, unacceptable toxicity, or up to 24 months Combination TherapyRefer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate. Adult patients with NSCLC or HNSCC 200 mg every 3 weeks or 400 mg every 6 weeks Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with RCC 200 mg every 3 weeks or 400 mg every 6 weeks Administer KEYTRUDA in combination with axitinib 5 mg orally twice daily.When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months Adult patients with Endometrial Carcinoma 200 mg every 3 weeks or 400 mg every 6 weeks Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months 2.3 Dose Modifications No dose reductions of KEYTRUDA are recommended. Withhold or discontinue KEYTRUDA to manage adverse reactions as described in Table 2. Table 2: Recommended Dose Modifications for Adverse Reactions [see Warnings and Precautions (5.1-5.9)] Adverse Reaction SeverityToxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4) Dose Modification for KEYTRUDA Immune-mediated pneumonitis Grade 2 WithholdResume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Grades 3 or 4 or recurrent Grade 2 Permanently discontinue Immune-mediated colitis Grades 2 or 3 Withhold Grade 4 Permanently discontinue Immune-mediated hepatitis in patients with HCC Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to 5 times upper limit of normal (ULN) if baseline less than 2 times ULN; AST or ALT greater than 3 times baseline if baseline greater than or equal to 2 times ULN Total bilirubin greater than 2.0 mg/dL if baseline less than 1.5 mg/dL; or Total bilirubin greater than 3.0 mg/dL, regardless of baseline levels WithholdResume in HCC patients when AST or ALT and total bilirubin recover to Grades 0-1 or to baseline. ALT or AST greater than 10 times ULN; or Child-Pugh score greater than or equal to 9 points; Gastrointestinal bleeding suggestive of portal hypertension; or New onset of clinically detectable ascites; or encephalopathy Permanently discontinue Immune-mediated hepatitis in patients without HCC AST or ALT greater than 3 but no more than 5 times the ULN or total bilirubin greater than 1.5 but no more than 3 times the ULN Withhold For liver enzyme elevations in RCC patients treated with combination therapy, see dosing guidelines following this table. In patients without liver metastases, AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN In patients with liver metastasis and Grade 2 AST or ALT at baseline, with an increase in AST or ALT of 50% or more relative to baseline that persists for at least 1 week Permanently discontinue Immune-mediated endocrinopathies Grades 3 or 4 Withhold until clinically stable Immune-mediated nephritis Grade 2 Withhold Grades 3 or 4 Permanently discontinue Immune-mediated skin adverse reactions Grade 3 or suspected Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN) Withhold Grade 4 or confirmed SJS or TEN Permanently discontinue Hematologic toxicity in patients with cHL or PMBCL Grade 4 Withhold until resolution to Grades 0 or 1 Other immune-mediated adverse reactions Grades 2 or 3 based on the severity and type of reaction Withhold Grade 3 based on the severity and type of reaction or Grade 4 Permanently discontinue Recurrent immune-mediated adverse reactions Recurrent Grade 2 pneumonitis Recurrent Grades 3 or 4 Permanently discontinue Inability to taper corticosteroid Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks after last dose of KEYTRUDA Permanently discontinue Persistent Grade 2 or 3 adverse reaction (excluding endocrinopathy) Grades 2 or 3 adverse reactions lasting 12 weeks or longer after last dose of KEYTRUDA Permanently discontinue Infusion-related reactions Grades 1 or 2 Interrupt or slow the rate of infusion Grades 3 or 4 Permanently discontinue In patients with RCC being treated with KEYTRUDA in combination with axitinib: If ALT or AST 3 times ULN but 3 times ULN with concurrent total bilirubin 2 times ULN, permanently discontinue both KEYTRUDA and axitinib and consider corticosteroid therapy. When administering KEYTRUDA in combination with lenvatinib for the treatment of endometrial carcinoma, interrupt one or both as appropriate. No dose reductions are recommended for KEYTRUDA. Withhold, dose reduce, or discontinue lenvatinib in accordance with the instructions in the lenvatinib prescribing information. 2.4 Preparation and Administration Preparation for Intravenous Infusion Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed. Dilute KEYTRUDA injection (solution) prior to intravenous administration. Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL. Discard any unused portion left in the vial. Storage of Diluted Solution The product does not contain a preservative. Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion. Under refrigeration at 2C to 8C (36F to 46F) for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake. Discard after 6 hours at room temperature or after 96 hours under refrigeration. Do not freeze. Administration Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. Do not co-administer other drugs through the same infusion line.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution): Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02) Carton containing two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04) Store vials under refrigeration at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake.

SPL UNCLASSIFIED SECTION.


Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA U.S. License No. 0002 For KEYTRUDA injection, at: MSD Ireland (Carlow) County Carlow, Ireland For patent information: www.merck.com/product/patent/home.html The trademarks depicted herein are owned by their respective companies. Copyright 2014-2020 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. uspi-mk3475-iv-2004r033

DESCRIPTION SECTION.


11 DESCRIPTION Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 12.2 Pharmacodynamics Based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data from an interim analysis of 41 patients with melanoma treated with pembrolizumab 400 mg every 6 weeks, there are no anticipated clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks. 12.3 Pharmacokinetics The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks. Distribution The geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%). Elimination Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t1/2) is 22 days (32%). Specific Populations The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR 15 mL/min/1.73 m2), mild hepatic impairment (total bilirubin upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or tumor burden. The impact of moderate or severe hepatic impairment on the pharmacokinetics of pembrolizumab is unknown. Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (2 to 17 years) are comparable to those of adults at the same dose.

SPL MEDGUIDE SECTION.


MEDICATION GUIDE KEYTRUDA (key-true-duh) (pembrolizumab) injection This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: April 2020 What is the most important information I should know about KEYTRUDA? KEYTRUDA is a medicine that may treat certain cancers by working with your immune system. KEYTRUDA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse: Lung problems (pneumonitis). Symptoms of pneumonitis may include: shortness of breath chest pain new or worse cough Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include: diarrhea or more bowel movements than usual stools that are black, tarry, sticky, or have blood or mucus severe stomach-area (abdomen) pain or tenderness Liver problems, including hepatitis. Signs and symptoms of liver problems may include: yellowing of your skin or the whites of your eyes nausea or vomiting pain on the right side of your stomach area (abdomen) dark urine bleeding or bruising more easily than normal Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include: rapid heart beat weight loss or weight gain increased sweating feeling more hungry or thirsty urinating more often than usual hair loss feeling cold constipation your voice gets deeper muscle aches feeling very weak dizziness or fainting headaches that will not go away or unusual headache Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include: change in the amount or color of your urine Skin problems. Signs of skin problems may include: rash itching blisters, peeling or skin sores painful sores or ulcers in your mouth or in your nose, throat, or genital area Problems in other organs. Signs and symptoms of these problems may include: changes in eyesight severe or persistent muscle or joint pains severe muscle weakness low red blood cells (anemia) swollen lymph nodes, rash or tender lumps on skin, cough, shortness of breath, vision changes, or eye pain (sarcoidosis) confusion, fever, muscle weakness, balance problems, nausea, vomiting, stiff neck, memory problems, or seizures (encephalitis) shortness of breath, irregular heartbeat, feeling tired, or chest pain (myocarditis) Infusion (IV) reactions that can sometimes be severe and life-threatening. Signs and symptoms of infusion reactions may include: chills or shaking shortness of breath or wheezing itching or rash flushing dizziness fever feeling like passing out Rejection of a transplanted organ. People who have had an organ transplant may have an increased risk of organ transplant rejection. Your doctor should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had. Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with KEYTRUDA. Your doctor will monitor you for the following signs and symptoms: skin rash, liver inflammation, stomach-area (abdominal) pain, and diarrhea. Getting medical treatment right away may help keep these problems from becoming more serious. Your doctor will check you for these problems during treatment with KEYTRUDA. Your doctor may treat you with corticosteroid or hormone replacement medicines. Your doctor may also need to delay or completely stop treatment with KEYTRUDA, if you have severe side effects. What is KEYTRUDA? KEYTRUDA is a prescription medicine used to treat: a kind of skin cancer called melanoma. KEYTRUDA may be used: when your melanoma has spread or cannot be removed by surgery (advanced melanoma), or to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery. a kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer: has spread (advanced NSCLC), and is a type called "nonsquamous", and your tumor does not have an abnormal "EGFR" or "ALK" gene. KEYTRUDA may be used with the chemotherapy medicines carboplatin and either paclitaxel or paclitaxel protein-bound as your first treatment when your lung cancer: has spread (advanced NSCLC), and is a type called "squamous". KEYTRUDA may be used alone as your first treatment when your lung cancer: has not spread outside your chest (stage III) and you cannot have surgery or chemotherapy with radiation or your NSCLC has spread to other areas of your body (advanced NSCLC), and your tumor tests positive for "PD-L1", and does not have an abnormal "EGFR" or "ALK" gene. KEYTRUDA may also be used alone when: you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and your tumor tests positive for "PD-L1", and if your tumor has an abnormal "EGFR" or "ALK" gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working. a kind of lung cancer called small cell lung cancer (SCLC). KEYTRUDA may be used when your lung cancer: has spread (advanced SCLC), and you have received 2 or more types of chemotherapy, including one that contains platinum, and it did not work or is no longer working. a kind of cancer called head and neck squamous cell cancer (HNSCC). KEYTRUDA may be used with the chemotherapy medicines fluorouracil and a platinum as your first treatment when your head and neck cancer has spread or returned and cannot be removed by surgery. KEYTRUDA may be used alone as your first treatment when your head and neck cancer: has spread or returned and cannot be removed by surgery, and your tumor tests positive for "PD-L1". KEYTRUDA may be used alone when your head and neck cancer: has spread or returned, and you have received chemotherapy that contains platinum and it did not work or is no longer working. a kind of cancer called classical Hodgkin lymphoma (cHL) in adults and children when: you have tried a treatment and it did not work or your cHL has returned after you received 3 or more types of treatment. a kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when: you have tried a treatment and it did not work or your PMBCL has returned after you received 2 or more types of treatment. a kind of bladder and urinary tract cancer called urothelial carcinoma. KEYTRUDA may be used when your cancer has not spread to nearby tissue in the bladder, but is at high-risk for spreading (high-risk non-muscle-invasive bladder cancer [NMIBC]) when: your tumor is a type called "carcinoma in situ" (CIS), and you have tried treatment with Bacillus Calmette-Guerin (BCG) and it did not work, and you are not able to or have decided not to have surgery to remove your bladder. KEYTRUDA may be used when your bladder or urinary tract cancer: has spread or cannot be removed by surgery (advanced urothelial cancer) and, you are not able to receive chemotherapy that contains a medicine called cisplatin, and your tumor tests positive for "PD-L1", or you are not able to receive a medicine called cisplatin or carboplatin, or you have received chemotherapy that contains platinum, and it did not work or is no longer working. a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. KEYTRUDA may be used in adults and children to treat: cancer that has spread or cannot be removed by surgery (advanced cancer), and has progressed following treatment, and you have no satisfactory treatment options, or you have colon or rectal cancer, and you have received chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan but it did not work or is no longer working. It is not known if KEYTRUDA is safe and effective in children with MSI-H cancers of the brain or spinal cord (central nervous system cancers). a kind of stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that tests positive for "PD-L1." KEYTRUDA may be used when your stomach cancer: has returned or spread (advanced gastric cancer), and you have received 2 or more types of chemotherapy including fluoropyrimidine and chemotherapy that contains platinum, and it did not work or is no longer working, and if your tumor has an abnormal "HER2/neu" gene, you also received a HER2/neu-targeted medicine and it did not work or is no longer working. a kind of cancer called squamous cell carcinoma of the esophagus. KEYTRUDA may be used when: your cancer has returned or spread (advanced esophageal cancer), and your tumor tests positive for "PD-L1" and you have received one or more types of treatment and it did not work or is no longer working. a kind of cancer called cervical cancer that tests positive for "PD-L1." KEYTRUDA may be used when your cervical cancer: has returned, or has spread or cannot be removed by surgery (advanced cervical cancer), and you have received chemotherapy, and it did not work or is no longer working. a kind of liver cancer called hepatocellular carcinoma, after you have received the medicine sorafenib. a kind of skin cancer called Merkel cell carcinoma (MCC) in adults and children. KEYTRUDA may be used to treat your skin cancer when it has spread or returned. a kind of kidney cancer called renal cell carcinoma (RCC). KEYTRUDA may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC). a kind of uterine cancer called endometrial carcinoma. KEYTRUDA may be used with the medicine lenvatinib: when your tumors are not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and you have received anti-cancer treatment, and it did not work or is no longer working, and your cancer cannot be removed by surgery or radiation (advanced endometrial carcinoma). What should I tell my doctor before receiving KEYTRUDA? Before you receive KEYTRUDA, tell your doctor if you: have immune system problems such as Crohn's disease, ulcerative colitis, or lupus have received an organ transplant, such as a kidney or liver have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) have lung or breathing problems have liver problems have any other medical problems are pregnant or plan to become pregnant KEYTRUDA can harm your unborn baby. Females who are able to become pregnant: Your doctor will give you a pregnancy test before you start treatment with KEYTRUDA. You should use an effective method of birth control during and for at least 4 months after the final dose of KEYTRUDA. Talk to your doctor about birth control methods that you can use during this time. Tell your doctor right away if you think you may be pregnant or if you become pregnant during treatment with KEYTRUDA. are breastfeeding or plan to breastfeed. It is not known if KEYTRUDA passes into your breast milk. Do not breastfeed during treatment with KEYTRUDA and for 4 months after your final dose of KEYTRUDA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How will I receive KEYTRUDA? Your doctor will give you KEYTRUDA into your vein through an intravenous (IV) line over 30 minutes. In adults, KEYTRUDA is usually given every 3 weeks or 6 weeks depending on the dose of KEYTRUDA that you are receiving. In children, KEYTRUDA is usually given every 3 weeks. Your doctor will decide how many treatments you need. Your doctor will do blood tests to check you for side effects. If you miss any appointments, call your doctor as soon as possible to reschedule your appointment. What are the possible side effects of KEYTRUDA? KEYTRUDA can cause serious side effects. See "What is the most important information I should know about KEYTRUDA?" Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, bones or joints and stomach-area (abdominal) pain, decreased appetite, itching, diarrhea, nausea, rash, fever, cough, shortness of breath, and constipation. Common side effects of KEYTRUDA when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, and mouth sores. Common side effects of KEYTRUDA when given with axitinib include: diarrhea, feeling tired or weak, high blood pressure, liver problems, low levels of thyroid hormone, decreased appetite, blisters or rash on the palms of your hands and soles of your feet, nausea, mouth sores or swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, hoarseness, rash, cough, and constipation. Common side effects of KEYTRUDA when given with lenvatinib include: feeling tired, high blood pressure, joint and muscle pain, diarrhea, decreased appetite, low levels of thyroid hormone, nausea, mouth sores, vomiting, weight loss, stomach-area (abdominal) pain, headache, constipation, urinary tract infection, hoarseness, bleeding, low magnesium level, blisters or rash on the palms of your hands and soles of your feet, shortness of breath, cough, and rash. In children, feeling tired, vomiting and stomach-area (abdominal) pain, and increased levels of liver enzymes and decreased levels of salt (sodium) in the blood are more common than in adults. These are not all the possible side effects of KEYTRUDA. For more information, ask your doctor or pharmacist. Tell your doctor if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of KEYTRUDA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about KEYTRUDA, talk with your doctor. You can ask your doctor or nurse for information about KEYTRUDA that is written for healthcare professionals. For more information, go to www.keytruda.com. What are the ingredients in KEYTRUDA? Active ingredient: pembrolizumab Inactive ingredients: KEYTRUDA injection: L-histidine, polysorbate 80, sucrose, and Water for Injection, USP. Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA For KEYTRUDA injection, at: MSD Ireland (Carlow), County Carlow, Ireland U.S. License No. 0002 For patent information: www.merck.com/product/patent/home.html Copyright 2014-2020 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. usmg-mk3475-iv-2004r030

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS None. None. (4)