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 [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)]. Immune-mediated pneumonitis [see Warnings and Precautions (5.1)]. Immune-mediated colitis [see Warnings and Precautions (5.2)].. Immune-mediated hepatitis [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 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, and peripheral neuropathy. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. KEYTRUDA as 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, and peripheral neuropathy. (6.1). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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, these data reflect exposure to KEYTRUDA as single agent in non-randomized, open-label, multi-cohort trial (KEYNOTE-012), which enrolled 192 patients with HNSCC and in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087), which enrolled 241 patients with cHL; in combination with chemotherapy in randomized, active-controlled trial (KEYNOTE-189), which enrolled 405 patients with nonsquamous NSCLC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of mg/kg intravenously every weeks, 10 mg/kg intravenously every weeks, 10 mg/kg intravenously every weeks, or 200 mg intravenously every weeks. Among the 2799 patients, 41% were exposed for months or more and 21% were exposed for 12 months or more.The data described in this section were obtained in six randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-045, KEYNOTE-189, and KEYNOTE-407) and eight non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, and KEYNOTE-017). In these trials, KEYTRUDA was administered at mg/kg every weeks, 200 mg every weeks, or 10 mg/kg every or weeks.. Melanoma. Ipilimumab-Naive MelanomaThe 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 multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every weeks (n=278) or KEYTRUDA 10 mg/kg every weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab mg/kg every weeks for doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, medical condition that required systemic corticosteroids or other immunosuppressive medication; history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis or C, were ineligible.The median duration of exposure was 5.6 months (range: 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 or 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 years), 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 BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).In KEYNOTE-006, the adverse reaction profile was similar for the every week and every week schedule, therefore summary safety results are provided in 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 and summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.Table 2: 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 ReactionKEYTRUDA10 mg/kg every or weeksIpilimumabn=555n=256All GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)All Grades(%)Grade 3-4(%)General Fatigue280.9283.1Skin and Subcutaneous Tissue RashIncludes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. 240.2231.2 VitiligoIncludes skin hypopigmentation 13020Musculoskeletal and Connective Tissue Arthralgia180.4101.2 Back pain120.970.8Respiratory, Thoracic and Mediastinal Cough17070.4 Dyspnea110.970.8Metabolism and Nutrition Decreased appetite160.5140.8Nervous System Headache140.2140.8Other clinically important adverse reactions occurring in >=10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).Table 3: 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. KEYTRUDA10 mg/kg every or weeksIpilimumabAll GradesGraded per NCI CTCAE v4.0 %Grades 3-4%All Grades%Grades 3-4%Chemistry Hyperglycemia454.2453.8 Hypertriglyceridemia432.6311.1 Hyponatremia284.6267 Increased AST272.6252.5 Hypercholesterolemia201.2130Hematology Anemia353.8334.0 Lymphopenia337256Other 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 MelanomaThe safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA mg/kg (n=178) or 10 mg/kg (n=179) every weeks or investigators 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 toxicity or Grade 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; history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis or C, were ineligible.The median duration of exposure to KEYTRUDA mg/kg every weeks was 3.7 months (range: day to 16.6 months) and to KEYTRUDA 10 mg/kg every weeks was 4.8 months (range: day to 16.8 months). In the KEYTRUDA 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 years), 61% male, 98% White, 41% with an elevated LDH value at baseline, 83% with M1c stage disease, 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% BRAF inhibitor), and 15% with history of brain metastasis.In KEYNOTE-002, the adverse reaction profile was similar for the mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in 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 and summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.Table 4: 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 ReactionKEYTRUDA2 mg/kg or 10 mg/kg every weeksChemotherapyChemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin n=357n=171All GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)All Grades(%)Grade 3-4(%)General Pyrexia140.390.6 Asthenia102.091.8Skin and Subcutaneous Tissue Pruritus28080 RashIncludes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic 240.680Gastrointestinal Constipation220.3202.3 Diarrhea200.8202.3 Abdominal pain131.781.2Respiratory, Thoracic and Mediastinal Cough180160Musculoskeletal and Connective Tissue Arthralgia140.6101.2Other 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 5: 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. KEYTRUDA2 mg/kg or 10 mg/kg every weeksChemotherapyAll GradesGraded per NCI CTCAE v4.0 %Grades 3-4%All Grades%Grades 3-4%Chemistry Hyperglycemia496446 Hypoalbuminemia371.9330.6 Hyponatremia377243.8 Hypertriglyceridemia330320.9 Increased alkaline phosphatase263.1181.9 Increased AST242.2160.6 Decreased bicarbonate220.4130 Hypocalcemia 210.3181.9 Increased ALT211.8160.6Other 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).. NSCLC. First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapyThe safety of KEYTRUDA in combination with pemetrexed and investigators choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, 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)]. total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every weeks for cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every weeks for cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within years of treatment; 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 weeks was 7.2 months (range: 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 years 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 and summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189.Table 6: Adverse Reactions Occurring in >=20% of Patients in KEYNOTE-189 Adverse ReactionKEYTRUDA Pemetrexed Platinum Chemotherapyn=405PlaceboPemetrexedPlatinum Chemotherapyn=202All GradesGraded per NCI CTCAE v4.03 (%)Grade 3-4(%)All Grades(%)Grade 3-4(%)Gastrointestinal Nausea563.5523.5 Constipation351.0320.5 Diarrhea315213.0 Vomiting243.7233.0General FatigueIncludes asthenia and fatigue 5612586 Pyrexia200.2150Metabolism and Nutrition Decreased appetite281.5300.5Skin and Subcutaneous Tissue RashIncludes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 252.0172.5Respiratory, Thoracic and Mediastinal Cough210280 Dyspnea213.7265Table 7: 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 Pemetrexed Platinum ChemotherapyPlacebo Pemetrexed Platinum ChemotherapyAll GradesGraded per NCI CTCAE v4.03 %Grades 3-4%All Grades%Grades 3-4%Chemistry Hyperglycemia639607 Increased ALT 473.8422.6 Increased AST472.8401.0 Hypoalbuminemia392.8391.1 Increased creatinine 374.2251.0 Hyponatremia327236 Hypophosphatemia30102814 Increased alkaline phosphatase 261.8292.1 Hypocalcemia242.8170.5 Hyperkalemia242.8193.1 Hypokalemia215205Hematology Anemia85178118 Lymphopenia64226425 Neutropenia48204119 Thrombocytopenia3012298. First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or nab-paclitaxel chemotherapyThe safety of KEYTRUDA in combination with carboplatin and investigators choice of either paclitaxel or nab-paclitaxel was investigated in KEYNOTE-407, 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 years of treatment; 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 months (range: day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for >=6 months. total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received nab-paclitaxel 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 Treated NSCLCThe safety of KEYTRUDA was investigated in KEYNOTE-010, 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)]. total of 991 patients received KEYTRUDA mg/kg (n=339) or 10 mg/kg (n=343) every weeks or docetaxel (n=309) at 75 mg/m2 every 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 mg/kg every weeks was 3.5 months (range: day to 22.4 months) and to KEYTRUDA 10 mg/kg every weeks was 3.5 months (range day to 20.8 months). The data described below reflect exposure to KEYTRUDA 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 years or older, 61% male, 72% white and 21% Asian, 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 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in 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 and summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-407.Table 8: 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 ReactionKEYTRUDA2 or 10 mg/kg every weeksn=682Docetaxel75 mg/m2 every weeksn=309All GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)All Grades (%)Grade 3-4(%)Metabolism and Nutrition Decreased appetite251.5232.6Gastrointestinal Nausea201.3180.6 Constipation150.6120.6 Vomiting130.9100.6Respiratory, Thoracic and Mediastinal Dyspnea233.7202.6 Cough190.6140Musculoskeletal and Connective Tissue Arthralgia111.090.3 Back pain111.580.3Skin and Subcutaneous Tissue RashIncludes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic 170.480 Pruritus11030.3Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).Table 9: 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). KEYTRUDA2 or 10 mg/kg every weeksDocetaxel75 mg/m2 every weeksAll GradesGraded per NCI CTCAE v4.0 %Grades 3-4%All Grades %Grades 3-4%Chemistry Hyponatremia328272.9 Alkaline phosphatase increased283.0160.7 Increased AST261.6120.7 Increased ALT222.790.4Other 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).. HNSCCAmong the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.3)], the median duration of exposure to KEYTRUDA was 3.3 months (range: day to 27.9 months). Patients with autoimmune disease or medical condition that required immunosuppression were ineligible for KEYNOTE-012.The median age of patients was 60 years (range: 20 to 84), 35% were age 65 years or older, 83% were male, 77% were White, 15% were Asian, and 5% were 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 (30%) or (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 weeks or 200 mg every weeks); therefore, summary safety results are provided in 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 patients with melanoma or NSCLC, 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)].. cHLAmong the 210 patients with cHL enrolled in KEYNOTE-087 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 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 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-087.Table 10: Adverse Reactions in >=10% of Patients with cHL in KEYNOTE-087 Adverse ReactionKEYTRUDA200 mg every weeksN=210All GradesGraded per NCI CTCAE v4.0 (%)Grade 3(%)General FatigueIncludes fatigue, asthenia 261.0 Pyrexia241.0Respiratory, Thoracic and Mediastinal CoughIncludes cough, productive cough 240.5 DyspneaIncludes dyspnea, dyspnea exertional, wheezing 111.0Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 211.0 Arthralgia100.5Gastrointestinal DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 201.4 Vomiting150 Nausea130Skin 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 200.5 Pruritus110Endocrine Hypothyroidism140.5Infections and Infestations Upper respiratory tract infection130Nervous System Headache110.5 Peripheral neuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 100Other 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 11: 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) KEYTRUDA200 mg every weeksAll GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)Chemistry HypertransaminasemiaIncludes elevation of AST or ALT 342 Increased alkaline phosphatase170 Increased creatinine150.5Hematology Anemia306 Thrombocytopenia274 Neutropenia247Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).. PMBCLAmong the 53 patients with PMBCL treated in KEYNOTE-170 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 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 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-170.Table 12: Adverse Reactions in >=10% of Patients with PMBCL in KEYNOTE-170 Adverse ReactionKEYTRUDA200 mg every weeksN=53All GradesGraded per NCI CTCAE v4.0 (%)Grade 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 300Infections and Infestations Upper respiratory tract infectionIncludes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection 280General Pyrexia280 FatigueIncludes fatigue, asthenia 232Respiratory, Thoracic and Mediastinal CoughIncludes allergic cough, cough, productive cough 262 Dyspnea2111Gastrointestinal DiarrheaIncludes diarrhea, gastroenteritis 132 Abdominal pain Includes abdominal pain, abdominal pain upper 130 Nausea110Cardiac Arrhythmia Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia 114Nervous System Headache110Other 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 13: 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) KEYTRUDA200 mg every weeksAll GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)Chemistry Hyperglycemia384 Hypophosphatemia2910 HypertransaminasemiaIncludes elevation of AST or ALT 274 Hypoglycemia190 Increased alkaline phosphatase170 Increased creatinine170 Hypocalcemia154 Hypokalemia154Hematology Anemia470 Leukopenia359 Lymphopenia3218 Neutropenia3011. Urothelial Carcinoma. Cisplatin Ineligible Patients with Urothelial Carcinoma The safety of KEYTRUDA was investigated in KEYNOTE-052, 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 (14.6)]. Patients received KEYTRUDA 200 mg every weeks until unacceptable toxicity or either radiographic or clinical disease progression.The median duration of exposure to KEYTRUDA was 2.8 months (range: 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 14 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.Table 14: Adverse Reactions Occurring in >=10% of Patients Receiving KEYTRUDA in KEYNOTE-052Adverse ReactionKEYTRUDA200 mg every weeksN=370All GradesGraded per NCI CTCAE v4.0 (%)Grades - 4(%)Blood and Lymphatic SystemAnemia177GastrointestinalConstipation211.1DiarrheaIncludes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements 202.4Nausea181.1Abdominal painIncludes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper 182.7Elevated 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 133.5Vomiting120GeneralFatigueIncludes fatigue, asthenia 386Pyrexia110.5Weight decreased100Infections and InfestationsUrinary tract infection199Metabolism and NutritionDecreased appetite221.6Hyponatremia104.1Musculoskeletal and Connective TissueMusculoskeletal painIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain 244.9Arthralgia101.1Renal and UrinaryIncreased blood creatinine111.1Hematuria 133.0Respiratory, Thoracic, and MediastinalCough140Dyspnea 110.5Skin and Subcutaneous TissueRashIncludes 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 210.5Pruritus 190.3Edema peripheral141.1. Previously Treated Urothelial CarcinomaThe 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 multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every weeks or investigators choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.6)]. Patients with autoimmune disease or medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible.The median duration of exposure was 3.5 months (range: day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 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 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.Table 15: Adverse Reactions Occurring in >=10% of Patients Receiving KEYTRUDA in KEYNOTE-045 Adverse ReactionKEYTRUDA200 mg every weeksChemotherapyChemotherapy: paclitaxel, docetaxel, or vinflunine n=266n=255All GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)All Grades (%)Grade 3-4(%)Gastrointestinal Nausea211.1291.6 Constipation191.1323.1 DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 182.3191.6 Vomiting150.4130.4 Abdominal pain131.1132.7General FatigueIncludes asthenia, fatigue, malaise lethargy 384.55611 Pyrexia140.8131.2Infections and Infestations Urinary tract infection154.9144.3Metabolism and Nutrition Decreased appetite213.8211.2Musculoskeletal and Connective Tissue Musculoskeletal painIncludes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain 323.0272.0Renal and Urinary HematuriaIncludes blood urine present, hematuria, chromaturia 122.381.6Respiratory, Thoracic and Mediastinal CoughIncludes cough, productive cough 150.490 DyspneaIncludes dyspnea, dyspnea exertional, wheezing 141.9121.2Skin and Subcutaneous Tissue Pruritus23060.4 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, seborrhoeic keratosis, lichenoid keratosis 200.4130.4Table 16: 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. KEYTRUDA200 mg every weeksChemotherapyAll GradesGraded per NCI CTCAE v4.0 %Grades 3-4%All Grades %Grades 3-4%Chemistry Hyperglycemia528607 Anemia52136818 Lymphopenia45155325 Hypoalbuminemia431.7503.8 Hyponatremia3794713 Increased alkaline phosphatase377334.9 Increased creatinine354.4282.9 Hypophosphatemia2983414 Increased AST284.1202.5 Hyperkalemia280.8276 Hypocalcemia261.6342.1. Gastric CancerAmong the 259 patients with gastric cancer enrolled in KEYNOTE-059 [see Clinical Studies (14.8)], the median duration of exposure to KEYTRUDA was 2.1 months (range: day to 21.4 months). Patients with autoimmune disease or 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 patients with melanoma or NSCLC.. Cervical CancerAmong the 98 patients with cervical cancer enrolled in Cohort of KEYNOTE-158 [see Clinical Studies (14.9)], the median duration of exposure to KEYTRUDA was 2.9 months (range: day to 22.1 months). Patients with autoimmune disease or 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 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.Table 17: Adverse Reactions Occurring in >=10% of Patients with Cervical Cancer in KEYNOTE-158 Adverse ReactionKEYTRUDA200 mg every weeksN=98All GradesGraded per NCI CTCAE v4.0 (%)Grades - 4(%)General FatigueIncludes asthenia, fatigue, lethargy, malaise 435 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 222.0 Pyrexia191.0 Edema peripheralIncludes edema peripheral, peripheral swelling 152.0Musculoskeletal and Connective Tissue Musculoskeletal painIncludes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity 275Gastrointestinal DiarrheaIncludes colitis, diarrhea, gastroenteritis 232.0 Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper 223.1 Nausea190 Vomiting191.0 Constipation140Metabolism and Nutrition Decreased appetite210Vascular HemorrhageIncludes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage 195Infections and Infestations UTIIncludes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis 186 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 164.1Skin and Subcutaneous Tissue RashIncludes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular 172.0Endocrine Hypothyroidism110Nervous System Headache112.0Respiratory, Thoracic and Mediastinal Dyspnea101.0Table 18: 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) KEYTRUDA200 mg every weeksAll GradesGraded per NCI CTCAE v4.0 (%)Grade 3-4(%)Chemistry Hypoalbuminemia445 Increased alkaline phosphatase422.6 Hyponatremia3813 Hyperglycemia381.3 Increased aspartate aminotransferase343.9 Increased creatinine325 Hypocalcemia270 Increased alanine aminotransferase213.9 Hypokalemia206Hematology Anemia5424 Lymphopenia479Other 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).. HCCAmong the 104 patients with HCC who received KEYTRUDA in KEYNOTE-224, the median duration of exposure to KEYTRUDA was 4.2 months (range: day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC, 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 higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).. MCCAmong the 50 patients with MCC enrolled in KEYNOTE-017, the median duration of exposure to KEYTRUDA was 6.6 months (range day to 23.6 months). Patients with autoimmune disease or medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in patients with melanoma or NSCLC. Laboratory abnormalities (Grades 3-4) that occurred at higher incidence were elevated AST (11%) and hyperglycemia (19%).. 6.2Immunogenicity. 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, subset analysis was performed in the patients with concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at dose of mg/kg every weeks, 200 mg every weeks, or 10 mg/kg every or 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. 14.1Melanoma. Ipilimumab-Naive MelanomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at dose of 10 mg/kg every weeks or 10 mg/kg every weeks intravenously until disease progression or unacceptable toxicity or to ipilimumab mg/kg every weeks intravenously for 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 decline in performance status, or was confirmed at to weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (>=1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis or hepatitis infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors [RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ]). Additional efficacy outcome measures were overall response rate (ORR) and response duration.The study population characteristics were: median age of 62 years (range: 18 to 89 years), 60% male, 98% White, 66% had no prior systemic therapy for metastatic disease, 69% ECOG PS of 0, 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay, 65% had M1c stage disease, 68% with normal LDH, 36% with reported BRAF mutation-positive melanoma, and 9% with history of brain metastases. Among patients with BRAF mutation-positive melanoma, 139 (46%) were previously treated with BRAF inhibitor.The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 19 and Figure 1.Table 19: Efficacy Results in KEYNOTE-006EndpointKEYTRUDA10 mg/kg every weeksn=277KEYTRUDA10 mg/kg every weeksn=279Ipilimumab3 mg/kg every weeksn=278OS Deaths (%)92 (33%)85 (30%)112 (40%) Hazard ratioHazard ratio (KEYTRUDA compared to ipilimumab) based on the stratified Cox proportional hazard model (95% CI) 0.69 (0.52, 0.90)0.63 (0.47, 0.83)--- p-Value (stratified log-rank)0.004<0.001---PFS by BICR Events (%)157 (57%)157 (56%)188 (68%) Median in months (95% CI)4.1 (2.9, 6.9)5.5 (3.4, 6.9)2.8 (2.8, 2.9) Hazard ratio (95% CI)0.58 (0.47, 0.72)0.58 (0.46, 0.72)--- p-Value (stratified log-rank)<0.001<0.001---Best overall response by BICR ORR (95% CI)33% (27, 39)34% (28, 40)12% (8, 16) Complete response rate6%5%1% Partial response rate27%29%10%Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006based on the final analysis with an additional follow-up of months (total of 383 deaths as pre-specified in the protocol) Figure 1. Ipilimumab-Refractory MelanomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-002 (NCT01704287), multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of KEYTRUDA in blinded fashion or investigators choice chemotherapy. The treatment arms consisted of KEYTRUDA mg/kg or 10 mg/kg intravenously every weeks or investigators choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every weeks (26%), temozolomide 200 mg/m2 orally once daily for days every 28 days (25%), carboplatin AUC intravenously plus paclitaxel 225 mg/m2 intravenously every weeks for four cycles then carboplatin AUC of plus paclitaxel 175 mg/m2 every weeks (25%), paclitaxel 175 mg/m2 intravenously every weeks (16%), or carboplatin AUC or intravenously every weeks (8%). Randomization was stratified by ECOG performance status (0 vs. 1), LDH levels (normal vs. elevated [>=110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received KEYTRUDA until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with decline in performance status, or was confirmed at to weeks with repeat imaging; withdrawal of consent; or physicians decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. The major efficacy outcomes were progression-free survival (PFS) as assessed by BICR per RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, and overall survival (OS). Additional efficacy outcome measures were confirmed overall response rate (ORR) as assessed by BICR per RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, and duration of response.The study population characteristics were: median age was 62 years (range: 15 to 89 years), with 43% age 65 or older; 61% male; 98% White; and ECOG performance score was (55%) and (45%). Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease.The study demonstrated statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared to control arm. There was no statistically significant difference between KEYTRUDA mg/kg and chemotherapy or between KEYTRUDA 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive KEYTRUDA. Among the 38 patients randomized to KEYTRUDA mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 20.Table 20: Efficacy Results in KEYNOTE-002EndpointKEYTRUDA2 mg/kg every weeksKEYTRUDA10 mg/kg every weeksChemotherapyn=180n=181n=179+ With additional follow-up of 18 months after the PFS analysis Not statistically significant compared to multiplicity adjusted significance level of 0.01PFS Number of Events, (%)129 (72%)126 (70%)155 (87%) Progression, (%)105 (58%)107 (59%)134 (75%) Death, (%)24 (13%)19 (10%)21 (12%) Median in months (95% CI)2.9 (2.8, 3.8)2.9 (2.8, 4.7)2.7 (2.5, 2.8) p-Value (stratified log-rank)<0.001<0.001--- Hazard ratioHazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model (95% CI) 0.57 (0.45, 0.73)0.50 (0.39, 0.64)---OS Deaths (%)123 (68%)117 (65%)128 (72%) Hazard ratio (95% CI)0.86 (0.67, 1.10)0.74 (0.57, 0.96)--- p-Value (stratified log-rank)0.1170.011 --- Median in months (95% CI)13.4 (11.0, 16.4)14.7 (11.3, 19.5)11.0 (8.9, 13.8)Objective Response Rate ORR (95% CI)21% (15, 28)25% (19, 32)4% (2, 9) Complete response rate2%3%0% Partial response rate19%23%4%Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002. Figure 2. 14.2Non-Small Cell Lung Cancer. First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapyThe efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), randomized, multicenter, double-blind, active-controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within years of treatment; medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS >=1%). Patients were randomized (2:1) to one of the following treatment arms:KEYTRUDA 200 mg, pemetrexed 500 mg/m2, and investigators choice of cisplatin 75 mg/m2 or carboplatin AUC mg/mL/min intravenously on Day of each 21-day cycle for cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.Placebo, pemetrexed 500 mg/m2, and investigators choice of cisplatin 75 mg/m2 or carboplatin AUC mg/mL/min intravenously on Day of each 21-day cycle for cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every weeks.Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow maximum of 10 target lesions and maximum of target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator.Patients randomized to placebo and chemotherapy were offered KEYTRUDA as single agent at the time of disease progression.Assessment of tumor status was performed at Week 6, Week 12, and then every weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ.The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.The trial demonstrated statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 21 and Figure summarize the efficacy results for KEYNOTE-189.Table 21: Efficacy Results in KEYNOTE-189EndpointKEYTRUDAPemetrexedPlatinum Chemotherapyn=410PlaceboPemetrexed Platinum Chemotherapyn=206NR not reachedOS Number (%) of patients with event127 (31%)108 (52%) Median in months (95% CI)NR(NR, NR)11.3(8.7, 15.1) Hazard ratioBased on the stratified Cox proportional hazard model (95% CI)0.49 (0.38, 0.64) p-ValueBased on stratified log-rank test. <0.0001PFS Number of patients with event (%)244 (60%)166 (81%) Median in months (95% CI)8.8 (7.6, 9.2)4.9 (4.7, 5.5) Hazard ratio (95% CI)0.52 (0.43, 0.64) p-Value <0.0001Objective Response Rate ORRResponse: Best objective response as confirmed complete response or partial response (95% CI)48% (43, 53)19% (14, 25) Complete response0.5%0.5% Partial response47%18% p-ValueBased on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status <0.0001Duration of Response Median in months (range)11.2 (1.1+, 18.0+)7.8 (2.1+, 16.4+)Figure 3: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189. KEYTRUDA 200 mg, pemetrexed 500 mg/m2, and investigators choice of cisplatin 75 mg/m2 or carboplatin AUC mg/mL/min intravenously on Day of each 21-day cycle for cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.. Placebo, pemetrexed 500 mg/m2, and investigators choice of cisplatin 75 mg/m2 or carboplatin AUC mg/mL/min intravenously on Day of each 21-day cycle for cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every weeks.. Figure 3. First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or nab-paclitaxel chemotherapyThe efficacy of KEYTRUDA in combination with carboplatin and investigators choice of either paclitaxel or nab-paclitaxel was investigated in KEYNOTE-407 (NCT02775435), randomized, multi-center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within years of treatment; medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 status (TPS <1% [negative] vs. TPS >=1%), choice of paclitaxel or nab-paclitaxel, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion.KEYTRUDA 200 mg and carboplatin AUC mg/mL/min on Day of each 21-day cycle for cycles, and paclitaxel 200 mg/m2 on Day of each 21-day cycle for cycles or nab-paclitaxel 100 mg/m2 on Days 1, and 15 of each 21-day cycle for cycles, followed by KEYTRUDA 200 mg every weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.Placebo and carboplatin AUC mg/mL/min on Day of each 21-day cycle for cycles and paclitaxel 200 mg/m2 on Day of each 21-day cycle for cycles or nab-paclitaxel 100 mg/m2 on Days 1, and 15 of each 21-day cycle for cycles, followed by placebo every weeks. Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow maximum of 10 target lesions and maximum of target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as single agent at the time of disease progression.Assessment of tumor status was performed every weeks through Week 18, every weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, and OS. An additional efficacy outcome measure was DOR as assessed by BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ.The study population characteristics were: median age of 65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; 71% ECOG performance status of 1; and 8% with history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel.The trial demonstrated statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or nab-paclitaxel chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or nab-paclitaxel chemotherapy. Table 22 and Figure summarize the efficacy results for KEYNOTE-407.Table 22: Efficacy Results in KEYNOTE-407EndpointKEYTRUDA Carboplatin Paclitaxel/Nab-paclitaxeln=278Placebo Carboplatin Paclitaxel/Nab-paclitaxeln=281NE not estimableOS Number of events (%)85 (31%)120 (43%) Median in months (95% CI)15.9 (13.2, NE)11.3 (9.5, 14.8) Hazard ratioBased on the stratified Cox proportional hazard model (95% CI) 0.64 (0.49, 0.85) p-ValueBased on stratified log-rank test 0.0017PFS Number of events (%)152 (55%)197 (70%) Median in months (95% CI)6.4 (6.2, 8.3)4.8 (4.3, 5.7) Hazard ratio (95% CI) 0.56 (0.45, 0.70) p-Value <0.0001n=101n=103Objective Response RateORR primary analysis and DOR analysis were conducted with the first 204 patients enrolled. ORR (95% CI)58% (48, 68)35% (26, 45) Difference (95% CI)23.6% (9.9, 36.4) p-ValueBased on stratified Miettinen-Nurminen test 0.0008Duration of Response Median duration of response in months (range)7.2 (2.4, 12.4+)4.9 (2.0, 12.4+)Figure 4: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407. KEYTRUDA 200 mg and carboplatin AUC mg/mL/min on Day of each 21-day cycle for cycles, and paclitaxel 200 mg/m2 on Day of each 21-day cycle for cycles or nab-paclitaxel 100 mg/m2 on Days 1, and 15 of each 21-day cycle for cycles, followed by KEYTRUDA 200 mg every weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.. Placebo and carboplatin AUC mg/mL/min on Day of each 21-day cycle for cycles and paclitaxel 200 mg/m2 on Day of each 21-day cycle for cycles or nab-paclitaxel 100 mg/m2 on Days 1, and 15 of each 21-day cycle for cycles, followed by placebo every weeks. Figure 4. First-line treatment of metastatic NSCLC as single agentKEYNOTE-024 (NCT02142738) was randomized, multicenter, open-label, active-controlled trial in 305 patients with metastatic NSCLC, whose tumors had high PD-L1 expression [tumor proportion score (TPS) of 50% or greater] by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit, and had not received prior systemic treatment for metastatic NSCLC. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within years of treatment; medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG performance status (0 vs. 1), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every weeks or investigators choice of any of the following platinum-containing chemotherapy regimens:Pemetrexed 500 mg/m2 every weeks and carboplatin AUC to mg/mL/min every weeks on Day for to cycles followed by optional pemetrexed 500 mg/m2 every weeks for patients with nonsquamous histologies;Pemetrexed 500 mg/m2 every weeks and cisplatin 75 mg/m2 every weeks on Day for to cycles followed by optional pemetrexed 500 mg/m2 every weeks for patients with nonsquamous histologies;Gemcitabine 1250 mg/m2 on days and and cisplatin 75 mg/m2 every weeks on Day for to cycles;Gemcitabine 1250 mg/m2 on Days and and carboplatin AUC to mg/mL/min every weeks on Day for to cycles;Paclitaxel 200 mg/m2 every weeks and carboplatin AUC to mg/mL/min every weeks on Day for to cycles followed by optional pemetrexed maintenance (for nonsquamous histologies).Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow maximum of 10 target lesions and maximum of target lesions per organ)-defined progression of disease as determined by an independent radiology committee, unacceptable toxicity, or for up to 24 months. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression.Assessment of tumor status was performed every weeks. The main efficacy outcome measure was PFS as assessed by blinded independent central radiologists (BICR) review according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by the BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ.The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% white and 15% Asian; 65% ECOG performance status of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression.The trial demonstrated statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared with chemotherapy. Additionally, pre-specified interim OS analysis at 108 events (64% of the events needed for final analysis) also demonstrated statistically significant improvement of OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 23 and Figure summarize the efficacy results for KEYNOTE-024.Table 23: Efficacy Results in KEYNOTE-024EndpointKEYTRUDA200 mg every weeksChemotherapyn=154n=151NR not reachedPFS Number (%) of patients with event73 (47%)116 (77%) Median in months (95% CI)10.3 (6.7, NR)6.0 (4.2, 6.2) Hazard ratioBased on the stratified Cox proportional hazard model for the interim analysis (95% CI)0.50 (0.37, 0.68) p-Value (stratified log-rank)<0.001OS Number (%) of patients with event44 (29%)64 (42%) Median in months (95% CI)Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. 30.0(18.3, NR)14.2(9.8, 19.0) Hazard ratio (95% CI) 0.60 (0.41, 0.89) p-Value (stratified log-rank)0.005p-Value is compared with 0.0118 of the allocated alpha for the interim analysis Objective Response Rate ORR (95% CI)45% (37, 53)28% (21, 36) Complete response rate4%1% Partial response rate41%27% p-Value (Miettinen-Nurminen)0.001 Median duration of response in months (range)NR(1.9+, 14.5+)6.3(2.1+, 12.6+)Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024Based on the protocol specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. Pemetrexed 500 mg/m2 every weeks and carboplatin AUC to mg/mL/min every weeks on Day for to cycles followed by optional pemetrexed 500 mg/m2 every weeks for patients with nonsquamous histologies;. Pemetrexed 500 mg/m2 every weeks and cisplatin 75 mg/m2 every weeks on Day for to cycles followed by optional pemetrexed 500 mg/m2 every weeks for patients with nonsquamous histologies;. Gemcitabine 1250 mg/m2 on days and and cisplatin 75 mg/m2 every weeks on Day for to cycles;. Gemcitabine 1250 mg/m2 on Days and and carboplatin AUC to mg/mL/min every weeks on Day for to cycles;. Paclitaxel 200 mg/m2 every weeks and carboplatin AUC to mg/mL/min every weeks on Day for to cycles followed by optional pemetrexed maintenance (for nonsquamous histologies).. Figure 5. Previously treated NSCLCThe efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit. Patients with autoimmune disease; medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS >=50% vs. PD-L1 expression TPS=1-49%), ECOG performance scale (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA mg/kg intravenously every weeks, KEYTRUDA 10 mg/kg intravenously every weeks or docetaxel intravenously 75 mg/m2 every weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with decline in performance status, or confirmation of progression at to weeks with repeat imaging or for up to 24 months without disease progression.Assessment of tumor status was performed every weeks. The main efficacy outcome measures were OS and PFS as assessed by the BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ in the subgroup of patients with TPS >=50% and the overall population with TPS >=1%. Additional efficacy outcome measures were ORR and response duration in the subgroup of patients with TPS >=50% and the overall population with TPS >=1%.The study population characteristics were: median age 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG performance status 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease.Tables 24 and 25 and Figure summarize efficacy results in the subgroup with TPS >=50% population and in all patients, respectively.Table 24: Efficacy Results of the Subgroup of Patients with TPS >=50% in KEYNOTE-010EndpointKEYTRUDA2 mg/kg every weeksn=139KEYTRUDA10 mg/kg every weeksn=151Docetaxel75 mg/m2 every weeksn=152NR not reachedOS Deaths (%)58 (42%)60 (40%)86 (57%) Median in months (95% CI)14.9 (10.4, NR)17.3 (11.8, NR)8.2 (6.4, 10.7) Hazard ratioHazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model (95% CI) 0.54 (0.38, 0.77)0.50 (0.36, 0.70)--- p-Value (stratified log-rank)<0.001<0.001---PFS Events (%)89 (64%)97 (64%)118 (78%) Median in months (95% CI)5.2 (4.0, 6.5)5.2 (4.1, 8.1)4.1 (3.6, 4.3) Hazard ratio (95% CI) 0.58 (0.43, 0.77)0.59 (0.45, 0.78)--- p-Value (stratified log-rank)<0.001<0.001---Objective Response Rate ORRAll responses were partial responses (95% CI)30% (23, 39)29% (22, 37)8% (4, 13) p-Value (Miettinen-Nurminen)<0.001<0.001--- Median duration of response in months (range)NR(0.7+, 16.8+)NR(2.1+, 17.8+)8.1(2.1+, 8.8+)Table 25: Efficacy Results of All Randomized Patients (TPS >=1%) in KEYNOTE-010EndpointKEYTRUDA2 mg/kg every weeksn=344KEYTRUDA10 mg/kg every weeksn=346Docetaxel75 mg/m2 every weeksn=343NR not reachedOS Deaths (%)172 (50%)156 (45%)193 (56%) Median in months (95% CI)10.4 (9.4, 11.9)12.7 (10.0, 17.3)8.5 (7.5, 9.8) Hazard ratioHazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model (95% CI) 0.71 (0.58, 0.88)0.61 (0.49, 0.75)--- p-Value (stratified log-rank)<0.001<0.001---PFS Events (%)266 (77%)255 (74%)257 (75%) Median in months (95% CI)3.9 (3.1, 4.1)4.0 (2.6, 4.3)4.0 (3.1, 4.2) Hazard ratio (95% CI) 0.88 (0.73, 1.04)0.79 (0.66, 0.94)--- p-Value (stratified log-rank)0.0680.005---Objective Response Rate ORRAll responses were partial responses (95% CI)18% (14, 23)19% (15, 23)9% (7, 13) p-Value (Miettinen-Nurminen)<0.001<0.001--- Median duration of response in months (range)NR(0.7+, 20.1+)NR(2.1+, 17.8+)6.2(1.4+, 8.8+)Figure 6: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS >=1%). Figure 6. 14.3Head and Neck Squamous Cell Cancer. The efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), multicenter, non-randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS >=2 were ineligible.Patients received KEYTRUDA 10 mg/kg every weeks (n=53) or 200 mg every weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with decline in performance status, or was confirmed at least weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to additional year. Assessment of tumor status was performed every weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, as assessed by blinded independent central review, and duration of response.The study population characteristics were median age 60 years (32% age 65 or older); 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2.The ORR was 16% (95% CI: 11, 22) with complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median duration of response had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of months or longer. The ORR and duration of response were similar irrespective of dosage regimen (10 mg/kg every weeks or 200 mg every weeks) or HPV status.. 14.4Classical Hodgkin Lymphoma. The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), multicenter, non-randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past years (or 5 years but with symptoms of GVHD), active autoimmune disease, medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 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, CRR, and duration of response) were assessed by blinded independent central review 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; 49% had an ECOG performance status (PS) of and 51% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was (range: 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 26.Table 26: Efficacy Results in KEYNOTE-087EndpointKEYTRUDA200 mg every weeksn=210Median follow-up time of 9.4 months Objective Response Rate ORR (95% CI)69% (62, 75) Complete response22% Partial response47%Response Duration Median in months (range)11.1 (0.0+, 11.1) Based on patients (n=145) with response by independent review 14.5Primary Mediastinal Large B-Cell Lymphoma. The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), 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 years (or >5 years but with symptoms of GVHD), active autoimmune disease, medical condition that required immunosuppression, or an active infection requiring systemic therapy. The patients were treated with KEYTRUDA 200 mg intravenously every 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 blinded independent central review according to the 2007 revised IWG criteria. The efficacy outcome measures were overall response rate (ORR) and duration of response.The study population characteristics were: median age 33 years (range: 20 to 61 years), 43% male; 92% White; 43% had an ECOG performance status (PS) of and 57% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was (range 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 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 27.Table 27: Efficacy Results in KEYNOTE-170EndpointKEYTRUDA200 mg every weeksn=53Median follow-up time of 9.7 months NR not reachedObjective Response Rate ORR (95% CI)45% (32, 60) Complete response11% Partial response34%Response Duration Median in months (range)NR (1.1+, 19.2+)Based on patients (n=24) with response by independent review 14.6Urothelial Carcinoma. Cisplatin Ineligible Patients with Urothelial CarcinomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), 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 medical condition that required immunosuppression.Patients received KEYTRUDA 200 mg every 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 decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at weeks after the first dose, then every weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ as assessed by independent radiology review, and duration of response.The study population characteristics were: median age was 74 years, 77% were male, and 89% were White. Eighty-seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had primary tumor in the lower tract, and 19% of patients had 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 performance status of 2, 9% with ECOG and baseline creatinine clearance of <60 mL/min, and 9% with other reasons (Class III heart failure, Grade or greater peripheral neuropathy, and Grade or greater hearing loss). Ninety percent of patients were treatment naive, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.Among the 370 patients, 30% (n 110) had tumors that expressed PD-L1 with combined positive score (CPS) of >= 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 73 years, 68% male, and 87% White. Eighty-two percent had M1 disease, and 18% had M0 disease. Eighty-one percent had primary tumor in the lower tract, and 18% of patients had 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 performance status of 2, 10% with ECOG and baseline creatinine clearance of <60 mL/min, and 8% with other reasons (Class III heart failure, Grade or greater peripheral neuropathy, and Grade or greater hearing loss). Ninety percent of patients were treatment naive, 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 28.Table 28: Efficacy Results in KEYNOTE-052EndpointKEYTRUDA200 mg every weeksAll Subjectsn=370PD-L1 CPS <10n=260Includes subjects with unknown PD-L1 status PD-L1 CPS >=10n=110+Denotes ongoingNR not reachedObjective Response Rate ORR (95% CI)29% (24, 34)21% (16, 26)47% (38, 57) Complete response rate7%3%15% Partial response rate22%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 CarcinomaKEYNOTE-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 third arm of monotherapy with KEYTRUDA to compare to platinum-based chemotherapy alone. The independent Data Monitoring Committee (iDMC) for the study conducted 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 CarcinomaThe efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), 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 medical condition that required immunosuppression.Patients were randomized to receive either KEYTRUDA 200 mg every weeks (n=270) or investigators choice of any of the following chemotherapy regimens all given intravenously every 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 decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at weeks after randomization, then every 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 maximum of 10 target lesions and maximum of target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, and duration of response.The study population characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG status of and 56% ECOG performance status 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 primary tumor in the lower tract and 14% had 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 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 29 and Figure summarize the efficacy results for KEYNOTE-045.Table 29: Efficacy Results in KEYNOTE-045KEYTRUDA200 mg every weeksChemotherapyn=270n=272+Denotes ongoingNR not reachedOS 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) 0.004PFS 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)0.833Objective Response Rate ORR (95% CI)21% (16, 27)11% (8, 16) Complete response rate7%3% Partial response rate14%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 7: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045. Figure 7. 14.7Microsatellite 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 medical condition that required immunosuppression were ineligible across the five trials. Patients received either KEYTRUDA 200 mg every weeks or KEYTRUDA 10 mg/kg every weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with decline in performance status. maximum of 24 months of treatment with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity across these trials, the major efficacy outcome measures were ORR as assessed by blinded independent central radiologists (BICR) review according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, and duration of response.Table 30: MSI-H TrialsStudyDesign and Patient PopulationNumber of PatientsMSI-H/dMMR TestingDosagePrior TherapyCRC colorectal cancerPCR polymerase chain reactionIHC immunohistochemistryKEYNOTE-016NCT01876511prospective, investigator-initiated6 sitespatients with CRC and other tumors 28 CRC30 non-CRClocal PCR or IHC 10 mg/kg every weeksCRC: >= prior regimensNon-CRC: >=1 prior regimenKEYNOTE-164NCT02460198prospective international multi-center CRC61local PCR or IHC200 mg every weeksPrior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb KEYNOTE-012NCT01848834retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer central PCR10 mg/kg every weeks>=1 prior regimenKEYNOTE-028NCT02054806retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC5central PCR10 mg/kg every weeks>=1 prior regimenKEYNOTE-158NCT02628067prospective international multi-center enrollment of patients with MSI-H/dMMR non-CRCretrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts19 local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts)200 mg every weeks>=1 prior regimenTotal149A 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 55 years (36% age 65 or older); 56% male; 77% White, 19% Asian, 2% Black; and ECOG PS (36%) or (64%). 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 total of 415 patients using 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 31 and 32.Table 31: Efficacy Results for Patients with MSI-H/dMMR CancerEndpointKEYTRUDAn=149NR not reachedObjective Response Rate ORR (95% CI)39.6% (31.7, 47.9) Complete response rate7.4% Partial response rate32.2%Response duration Median in months (range)NR (1.6+, 22.7+) with duration >=6 months78%Table 32: Response by Tumor TypeObjective response rateDOR rangeNn (%)95% CI(months)CR complete responsePR partial responseSD stable diseasePD progressive diseaseNE not evaluableCRC9032 (36%)(26%, 46%)(1.6+, 22.7+)Non-CRC5927 (46%)(33%, 59%)(1.9+, 22.1+) Endometrial cancer145 (36%)(13%, 65%)(4.2+, 17.3+) Biliary cancer113 (27%)(6%, 61%)(11.6+, 19.6+) Gastric or GE junction cancer95 (56%)(21%, 86%)(5.8+, 22.1+) Pancreatic cancer65 (83%)(36%, 100%)(2.6+, 9.2+) Small intestinal cancer83 (38%)(9%, 76%)(1.9+, 9.1+) Breast cancer2PR, PR(7.6, 15.9) Prostate cancer2PR, SD9.8+ Bladder cancer1NE Esophageal cancer1PR18.2+ Sarcoma1PD Thyroid cancer1NE Retroperitoneal adenocarcinoma1PR7.5+ Small cell lung cancer1CR8.9+ Renal cell cancer1PD. prospective, investigator-initiated. sites. patients with CRC and other tumors CRC: >= prior regimens. Non-CRC: >=1 prior regimen. prospective international multi-center CRC. retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC. 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. 14.8Gastric Cancer. The efficacy of KEYTRUDA was investigated in KEYNOTE-059 (NCT02335411), multicenter, non-randomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least prior systemic treatments for advanced disease. Previous treatment must have included 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 medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible.Patients received KEYTRUDA 200 mg every weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with decline in performance status, or was confirmed at least weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every to weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, as assessed by blinded independent central review, and duration of response.Among the 259 patients, 55% (n 143) had tumors that expressed PD-L1 with combined positive score (CPS) of >= 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 64 years (47% age 65 or older); 77% male; 82% White, 11% Asian; and ECOG PS of (43%) and (57%). 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 complete response and 11.9% had partial response. Among the 19 responding patients, the duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of months or longer and patients (26%) having responses of 12 months or longer.Among the 259 patients enrolled in KEYNOTE-059, (3%) had tumors that were determined to be MSI-H. An objective response was observed in patients, including complete response. The duration of response ranged from 5.3+ to 14.1+ months.. 14.9Cervical Cancer. The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or medical condition that required immunosuppression.Patients received KEYTRUDA 200 mg intravenously every 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 decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 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 maximum of 10 target lesions and maximum of target lesions per organ, as assessed by blinded independent central review, and duration of response.Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with CPS >= and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. The baseline characteristics of these 77 patients were: median age was 45 years (range: 27 to 75 years); 81% were White, 14% Asian, 3% Black; ECOG PS was (32%) or (68%); 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; 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 33 for patients with PD-L1 expression (CPS >=1).Efficacy results are summarized in Table 33.Table 33: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS >=1) in KEYNOTE-158Endpointn=77Median follow-up time of 11.7 months (range 0.6 to 22.7 months) +Denotes ongoingNR not reachedObjective Response Rate ORR (95% CI)14.3% (7.4, 24.1) Complete response rate2.6% Partial response rate11.7%Response duration Median in months (range)NR (4.1, 18.6+)Based on patients (n=11) with response by independent review with duration >=6 months91%. 14.10Hepatocellular Carcinoma. The efficacy of KEYTRUDA was investigated in KEYNOTE-224 (NCT02702414), 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 liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, 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 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least weeks from the initial scan showing progression), or completion of 24 months of KEYTRUDA. Assessment of tumor status was performed every weeks. The major efficacy outcome measures were ORR and duration of response according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ, as assessed by blinded independent central review committee (BICR).The study population characteristics were: median age 68 years (67% age 65 or older); 83% male; 81% White; 14% Asian; ECOG PS of (61%) or (39%). 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 patients (9%) who were seropositive for both HBV and HCV. For these 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 34.Table 34: Efficacy Results in KEYNOTE-224EndpointKEYTRUDA200 mg every weeksn=104BICR-Assessed Objective Response Rate (RECIST v1.1Modified to follow maximum of 10 target lesions and maximum of target lesions per organ) ORR (95% CI)Based on patients (n=18) with confirmed response by independent review. 17% (11, 26) Complete response rate1% Partial response rate16%BICR-Assessed Response Duration with duration >=6 months89% with duration >=12 months56%. 14.11Merkel Cell Carcinoma. The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), 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 medical condition that required immunosuppression were ineligible.Patients received KEYTRUDA mg/kg every weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with decline in performance status, or was confirmed at least 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 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and duration of response as assessed by BICR per RECIST v1.1.The study population characteristics were: median age was 71 years (range: 46 to 91 years), with 80% age 65 or older; 68% male; 90% White; and ECOG performance score was (48%) and (52%). 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 35.Table 35: Efficacy Results in KEYNOTE-017EndpointKEYTRUDA2 mg/kg every weeksn=50Objective Response Rate ORR (95% CI)56% (41, 70) Complete response (CR) rate (95% CI)24% (13, 38) Partial response (PR) 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, (%)27 (96%) Patients with duration >=12 months, (%)15 (54%).

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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 infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least month after discontinuation of pembrolizumab.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

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 cells, inhibits 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 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 dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or mg/kg every weeks in patients with melanoma or NSCLC.. 12.3 Pharmacokinetics. The pharmacokinetics (PK) of pembrolizumab was characterized using population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of to 10 mg/kg every weeks, to 10 mg/kg every weeks, or 200 mg every 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 to 10 mg/kg every weeks.. DistributionThe geometric mean value (CV%) for volume of distribution at steady state is 6.0 (20%).. EliminationPembrolizumab 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 PopulationsThe 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 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 mg/kg every weeks in pediatric patients (2 to 17 years) are comparable to those of adults at the same dose.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Pembrolizumab is programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is 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) for injection is sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. Each mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.KEYTRUDA (pembrolizumab) injection is sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in mL of solution. Each 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Melanoma: 200 mg every weeks. (2.2)NSCLC: 200 mg every weeks. (2.3)HNSCC: 200 mg every weeks. (2.4)cHL or PMBCL: 200 mg every weeks for adults; mg/kg (up to 200 mg) every weeks for pediatrics. (2.5, 2.6)Urothelial Carcinoma: 200 mg every weeks. (2.7)MSI-H Cancer: 200 mg every weeks for adults and mg/kg (up to 200 mg) every weeks for pediatrics. (2.8)Gastric Cancer: 200 mg every weeks. (2.9)Cervical Cancer: 200 mg every weeks. (2.10)HCC: 200 mg every weeks. (2.11)MCC: 200 mg every weeks for adults; mg/kg (up to 200 mg) every weeks for pediatrics. (2.12)Administer KEYTRUDA as an intravenous infusion over 30 minutes.. Melanoma: 200 mg every weeks. (2.2). NSCLC: 200 mg every weeks. (2.3). HNSCC: 200 mg every weeks. (2.4). cHL or PMBCL: 200 mg every weeks for adults; mg/kg (up to 200 mg) every weeks for pediatrics. (2.5, 2.6). Urothelial Carcinoma: 200 mg every weeks. (2.7). MSI-H Cancer: 200 mg every weeks for adults and mg/kg (up to 200 mg) every weeks for pediatrics. (2.8). Gastric Cancer: 200 mg every weeks. (2.9). Cervical Cancer: 200 mg every weeks. (2.10). HCC: 200 mg every weeks. (2.11). MCC: 200 mg every weeks for adults; mg/kg (up to 200 mg) every weeks for pediatrics. (2.12). 2.1Patient Selection for NSCLC, Urothelial Carcinoma, Gastric Cancer, or Cervical Cancer. Select patients for treatment with KEYTRUDA as single agent based on the presence of positive PD-L1 expression in:metastatic NSCLC [see Clinical Studies (14.2)]. metastatic urothelial carcinoma [see Clinical Studies (14.6)]. metastatic gastric cancer [see Clinical Studies (14.8)]. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining tumor biopsy for PD-L1 testing. recurrent or metastatic cervical cancer [see Clinical Studies (14.9)]. Information on FDA-approved tests for the detection of PD-L1 expression for these indications is available at: http://www.fda.gov/CompanionDiagnostics.. metastatic NSCLC [see Clinical Studies (14.2)]. metastatic urothelial carcinoma [see Clinical Studies (14.6)]. metastatic gastric cancer [see Clinical Studies (14.8)]. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining tumor biopsy for PD-L1 testing. recurrent or metastatic cervical cancer [see Clinical Studies (14.9)]. 2.2Recommended Dosage for Melanoma. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity.. 2.3Recommended Dosage for NSCLC. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.. 2.4Recommended Dosage for HNSCC. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.. 2.5Recommended Dosage for cHL. The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.The recommended dose of KEYTRUDA in pediatric patients is mg/kg (up to maximum of 200 mg), administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.. 2.6Recommended Dosage for PMBCL. The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.The recommended dose of KEYTRUDA in pediatric patients is mg/kg (up to maximum of 200 mg), administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.. 2.7Recommended Dosage for Urothelial Carcinoma. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.. 2.8Recommended Dosage for MSI-H Cancer. The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The recommended dose of KEYTRUDA in pediatric patients is mg/kg (up to maximum of 200 mg), administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. 2.9Recommended Dosage for Gastric Cancer. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. 2.10Recommended Dosage for Cervical Cancer. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. 2.11 Recommended Dosage for HCC. The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.. 2.12 Recommended Dosage for MCC. The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The recommended dose of KEYTRUDA in pediatric patients is mg/kg (up to maximum of 200 mg), administered as an intravenous infusion over 30 minutes every weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.. 2.13Dose Modifications. No dose reductions of KEYTRUDA are recommended. Withhold or discontinue KEYTRUDA to manage adverse reactions as described in Table 1.Table 1: Recommended Dose Modifications for Adverse Reactions [see Warnings and Precautions (5.1-5.9)]Adverse ReactionSeverityToxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4) Dose Modification for KEYTRUDAImmune-mediated pneumonitisGrade 2WithholdResume in patients with complete or partial resolution (Grades to 1) after corticosteroid taper. Grades or or recurrent Grade 2Permanently discontinueImmune-mediated colitisGrades or 3Withhold Grade 4Permanently discontinueImmune-mediated hepatitis in patients with HCCAspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to times upper limit of normal (ULN) if baseline less than times ULN;AST or ALT greater than times baseline if baseline greater than or equal to times ULNTotal bilirubin greater than 2.0 mg/dL if baseline less than 1.5 mg/dL; orTotal bilirubin greater than 3.0 mg/dL, regardless of baseline levelsWithholdResume 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 points;Gastrointestinal bleeding suggestive of portal hypertension; orNew onset of clinically detectable ascites; or encephalopathyPermanently discontinueImmune-mediated hepatitis in patients without HCCAST or ALT greater than but no more than times the ULN or total bilirubin greater than 1.5 but no more than times the ULNWithhold In patients without liver metastases, AST or ALT greater than times ULN or total bilirubin greater than times ULNIn patients with liver metastasis and Grade AST or ALT at baseline, with an increase in AST or ALT of 50% or more relative to baseline that persists for at least weekPermanently discontinueImmune-mediated endocrinopathiesGrades or 4Withhold until clinically stableImmune-mediated nephritisGrade 2Withhold Grades or 4Permanently discontinueImmune-mediated skin adverse reactionsGrade or suspected Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN)WithholdGrade or confirmed SJS or TENPermanently discontinueHematologic toxicity in patients with cHL or PMBCLGrade 4Withhold until resolution to Grades or 1Other immune-mediated adverse reactionsGrades or based on the severity and type of reactionWithhold Grade based on the severity and type of reaction or Grade 4Permanently discontinueRecurrent immune-mediated adverse reactionsRecurrent Grade pneumonitisRecurrent Grades or 4Permanently discontinueInability to taper corticosteroidRequirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks after last dose of KEYTRUDAPermanently discontinuePersistent Grade or adverse reaction (excluding endocrinopathy)Grades or adverse reactions lasting 12 weeks or longer after last dose of KEYTRUDAPermanently discontinueInfusion-related reactionsGrades or 2Interrupt or slow the rate of infusionGrades or 4Permanently discontinue. 2.14Preparation and Administration. Reconstitution of KEYTRUDA for Injection (Lyophilized Powder)Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).Slowly swirl the vial. Allow up to minutes for the bubbles to clear. Do not shake the vial.. Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).. Slowly swirl the vial. Allow up to minutes for the bubbles to clear. Do not shake the vial.. Preparation for Intravenous InfusionVisually 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) or reconstituted lyophilized powder 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. The final concentration of the diluted solution should be between mg/mL to 10 mg/mL.Discard any unused portion left in the vial.. 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) or reconstituted lyophilized powder 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. The final concentration of the diluted solution should be between mg/mL to 10 mg/mL.. Discard any unused portion left in the vial.. Storage of Reconstituted and Diluted SolutionsThe product does not contain preservative.Store the reconstituted and diluted solution from the KEYTRUDA 50 mg vial either:At room temperature for no more than hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion.Under refrigeration at 2C to 8C (36F to 46F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:At room temperature for no more than 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 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.Discard after hours at room temperature or after 24 hours under refrigeration.Do not freeze.. At room temperature for no more than hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion.. Under refrigeration at 2C to 8C (36F to 46F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.. At room temperature for no more than 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 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.. AdministrationAdminister diluted solution intravenously over 30 minutes through an intravenous line containing sterile, non-pyrogenic, low-protein binding 0.2 micron to micron in-line or add-on filter.Do not co-administer other drugs through the same infusion line.. Administer diluted solution intravenously over 30 minutes through an intravenous line containing sterile, non-pyrogenic, low-protein binding 0.2 micron to micron in-line or add-on filter.. Do not co-administer other drugs through the same infusion line.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: 50 mg white to off-white lyophilized powder in single-dose vial for reconstitution Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in single-dose vial. For injection: 50 mg white to off-white lyophilized powder in single-dose vial for reconstitution Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in single-dose vial. For injection: 50 mg lyophilized powder in single-dose vial for reconstitution (3)Injection: 100 mg/4 mL (25 mg/mL) solution in single-dose vial (3). For injection: 50 mg lyophilized powder in single-dose vial for reconstitution (3). Injection: 100 mg/4 mL (25 mg/mL) solution in single-dose vial (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)]. ContraceptionKEYTRUDA can cause fetal harm when administered to 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 months following the final dose.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. KEYTRUDA for injection (white to off-white lyophilized powder): carton containing one 50 mg single-dose vial (NDC 0006-3029-02).. Store vials under refrigeration at 2C to 8C (36F to 46F).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)Store vials under refrigeration at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. KEYTRUDA is programmed death receptor-1 (PD-1)-blocking antibody indicated: Melanomafor the treatment of patients with unresectable or metastatic melanoma. (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 nab-paclitaxel, as first-line treatment of patients with metastatic squamous NSCLC. (1.2)as single agent for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) >=50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. (1.2) as 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)Head and Neck Squamous Cell Cancer (HNSCC)for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.1 (1.3)Classical Hodgkin Lymphoma (cHL)for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after or more prior lines of therapy.1 (1.4)Primary Mediastinal Large B-Cell Lymphoma (PMBCL)for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after or more prior lines of therapy.1 (1.5)Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.Urothelial Carcinomafor 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 (1.6)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. (1.6)Microsatellite Instability-High Cancerfor the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficientsolid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options,1 orcolorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.1 (1.7) Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. (1.7)Gastric Cancerfor 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 two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.1 (1.8)Cervical Cancerfor 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.1 (1.9)Hepatocellular Carcinoma (HCC)for the treatment of patients with HCC who have been previously treated with sorafenib.1 (1.10)Merkel Cell Carcinoma (MCC)for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.1 (1.11)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.. for the treatment of patients with unresectable or metastatic melanoma. (1.1). 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 nab-paclitaxel, as first-line treatment of patients with metastatic squamous NSCLC. (1.2). as single agent for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) >=50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. (1.2) as 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). for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.1 (1.3). for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after or more prior lines of therapy.1 (1.4). for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after or more prior lines of therapy.1 (1.5). Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.. 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 (1.6). 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. (1.6). for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficientsolid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options,1 orcolorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.1 (1.7) 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 fluoropyrimidine, oxaliplatin, and irinotecan.1 (1.7) Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. (1.7). 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 two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.1 (1.8). 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.1 (1.9). for the treatment of patients with HCC who have been previously treated with sorafenib.1 (1.10). for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.1 (1.11). 1.1Melanoma. KEYTRUDA(R) (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma.. 1.2Non-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 nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.KEYTRUDA, as single agent, is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) >=50%] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.KEYTRUDA, as 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.. 1.3Head and Neck Squamous Cell Cancer. KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.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 the confirmatory trials.. 1.4Classical Hodgkin Lymphoma. KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 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 (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. 1.5Primary 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 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 confirmatory trials. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. 1.6Urothelial 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 [Combined Positive Score (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 (14.6)]. 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 [see Clinical Studies (14.6)]. 1.7Microsatellite 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 solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, orcolorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.7)]. 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.. 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 fluoropyrimidine, oxaliplatin, and irinotecan.. 1.8Gastric 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 [Combined Positive Score (CPS) >=1] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after two 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 (14.8)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. 1.9Cervical 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 (14.9)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. 1.10Hepatocellular 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 (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. 1.11 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 (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Immune-Mediated Adverse ReactionsInform 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)].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 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 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)]. 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)].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 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 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)]. 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)].. 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 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 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)]. 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 ReactionsAdvise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.8)] 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 HSCTAdvise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.9)]. Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.9)]. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of 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 months after the last dose [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)].. Advise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of 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 months after the last dose [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)].. LactationAdvise women not to breastfeed during treatment with KEYTRUDA and for months after the final dose [see Use in Specific Populations (8.2)].. Advise women not to breastfeed during treatment with KEYTRUDA and for months after the final dose [see Use in Specific Populations (8.2)].. Laboratory TestsAdvise 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)].. 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)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 months after the final dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on cells, inhibits 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 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.

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 infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least month after discontinuation of pembrolizumab.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 50 mg Vial Carton. NDC 0006-3029-02Keytruda(R)(pembrolizumab)for Injection50 mg vialFor Intravenous Infusion OnlyDispense the enclosed Medication Guide to each patient.Sterile lyophilized powder must be reconstituted with Sterile Water forInjection, USP. Reconstituted solution requires further dilution priorto administration.Rx onlySingle-dose vial. Discard unused portion.. PRINCIPAL DISPLAY PANEL 50 mg Vial Carton.

PEDIATRIC USE SECTION.

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 (14,4, 14.5, 14.7), Clinical Pharmacology (12.3)].There is limited experience with KEYTRUDA in pediatric patients. In trial (NCT02332668), 40 pediatric patients (16 children ages years to less than 12 years and 24 adolescents ages 12 years to 18 years) with various cancers, including unapproved usages were administered KEYTRUDA mg/kg every weeks. Patients received KEYTRUDA for median of doses (range: 1-17 doses), with 34 patients (85%) receiving KEYTRUDA for doses or more.The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at 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 mg/kg every weeks.The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or mg/kg every weeks in patients with melanoma or NSCLC.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics (PK) of pembrolizumab was characterized using population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of to 10 mg/kg every weeks, to 10 mg/kg every weeks, or 200 mg every 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 to 10 mg/kg every weeks.. DistributionThe geometric mean value (CV%) for volume of distribution at steady state is 6.0 (20%).. EliminationPembrolizumab 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 PopulationsThe 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 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 mg/kg every weeks in pediatric patients (2 to 17 years) are comparable to those of adults at the same dose.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, KEYTRUDA can cause fetal harm when administered to 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 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 DataAnimal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. literature-based asessment of the effects of the PD-1 pathway on reproduction demonstrated that 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.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)12/2018Dosage and Administration (2)12/2018Warnings and Precautions (5) 08/2018.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEKEYTRUDA(R) (key-true-duh)(pembrolizumab)for injectionKEYTRUDA(R) (key-true-duh)(pembrolizumab)injectionThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: December 2018What is the most important information should know about KEYTRUDAKEYTRUDA is 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 breathchest painnew 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 usualstools that are black, tarry, sticky, or have blood or mucus severe stomach-area (abdomen) pain or tenderness Liver problems (hepatitis). Signs and symptoms of hepatitis may include: yellowing of your skin or the whites of your eyesnausea or vomitingpain on the right side of your stomach area (abdomen)dark urinefeeling less hungry than usualbleeding 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 beatweight loss or weight gainincreased sweatingfeeling more hungry or thirstyurinating more often than usualhair lossfeeling coldconstipationyour voice gets deepermuscle achesdizziness or faintingheadaches 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: rashitchingblisters, peeling or skin sorespainful 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 eyesightsevere or persistent muscle or joint painssevere muscle weaknesslow 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 shakingshortness of breath or wheezingitching or rashflushingdizzinessfeverfeeling like passing out Rejection of 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 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 KEYTRUDAKEYTRUDA is prescription medicine used to treat: kind of skin cancer called melanoma that has spread or cannot be removed by surgery (advanced melanoma).a kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used with the chemotherapy medicines pemetrexed and platinum as your first treatment when your lung cancer:has spread (advanced NSCLC), and is 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 nab-paclitaxel as your first treatment when your lung cancer:has spread (advanced NSCLC), and is type called squamous. KEYTRUDA may be used alone when your lung cancer:has spread (advanced NSCLC) and, tests positive for PD-L1 and, as your first treatment if you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal EGFR or ALK gene, or you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, 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. kind of cancer called head and neck squamous cell cancer (HNSCC) that:has returned or spread and you have received chemotherapy that contains platinum and it did not work or is no longer working. kind of cancer called classical Hodgkin lymphoma (cHL) in adults and children when:you have tried treatment and it did not work or your cHL has returned after you received or more types of treatment. kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when:you have tried treatment and it did not work or your PMBCL has returned after you received or more types of treatment. kind of bladder and urinary tract cancer called urothelial carcinoma. 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 medicine called cisplatin, and your tumor tests positive for PD-L1, or you are not able to receive medicine called cisplatin or carboplatin, or you have received chemotherapy that contains platinum, and it did not work or is no longer working. kind of cancer that is shown by laboratory test to be microsatellite instability-high (MSI-H) or 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). 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 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 HER2/neu-targeted medicine and it did not work or is no longer working. 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. 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. What should tell my doctor before receiving KEYTRUDABefore you receive KEYTRUDA, tell your doctor if you:have immune system problems such as Crohns disease, ulcerative colitis, or lupushave received an organ transplant, such as kidney or liverhave received or plan to receive stem cell transplant that uses donor stem cells (allogeneic)have lung or breathing problemshave liver problemshave any other medical problemsare pregnant or plan to become pregnant KEYTRUDA can harm your unborn baby. Females who are able to become pregnant: Your doctor will give you pregnancy test before you start treatment with KEYTRUDA.You should use an effective method of birth control during and for at least 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 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 list of them to show your doctor and pharmacist when you get new medicine.How will receive KEYTRUDAYour doctor will give you KEYTRUDA into your vein through an intravenous (IV) line over 30 minutes.KEYTRUDA is usually given every 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 KEYTRUDAKEYTRUDA can cause serious side effects. See What is the most important information should know about KEYTRUDACommon 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, and inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs.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 KEYTRUDAMedicines are sometimes prescribed for purposes other than those listed in 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 KEYTRUDAActive ingredient: pembrolizumabInactive ingredients:KEYTRUDA for injection: L-histidine, polysorbate 80, and sucrose. May contain hydrochloric acid/sodium hydroxide.KEYTRUDA injection: L-histidine, polysorbate 80, sucrose, and Water for Injection, USP.Manufactured by: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USAFor KEYTRUDA for injection, at:MSD International GmbH, County Cork, IrelandFor KEYTRUDA injection, at:MSD Ireland (Carlow), County Carlow, IrelandU.S. License No. 0002For patent information: www.merck.com/product/patent/home.htmlCopyright (C) 2014-2018 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved. usmg-mk3475-iv-1812r020. shortness of breath. chest pain. new or worse cough. 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. 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. feeling less hungry than usual. bleeding or bruising more easily than normal. 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. dizziness or fainting. headaches that will not go away or unusual headache. change in the amount or color of your urine. rash. itching. blisters, peeling or skin sores. painful sores or ulcers in your mouth or in your nose, throat, or genital area. 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). chills or shaking. shortness of breath or wheezing. itching or rash. flushing. dizziness. fever. feeling like passing out. kind of skin cancer called melanoma that has spread or cannot be removed by surgery (advanced melanoma).. kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used with the chemotherapy medicines pemetrexed and platinum as your first treatment when your lung cancer:has spread (advanced NSCLC), and is 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 nab-paclitaxel as your first treatment when your lung cancer:has spread (advanced NSCLC), and is type called squamous. KEYTRUDA may be used alone when your lung cancer:has spread (advanced NSCLC) and, tests positive for PD-L1 and, as your first treatment if you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal EGFR or ALK gene, or you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and if your tumor has an abnormal EGFR or ALK gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working. KEYTRUDA may be used with the chemotherapy medicines pemetrexed and platinum as your first treatment when your lung cancer:has spread (advanced NSCLC), and is type called nonsquamous, and your tumor does not have an abnormal EGFR or ALK gene. has spread (advanced NSCLC), and is 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 nab-paclitaxel as your first treatment when your lung cancer:has spread (advanced NSCLC), and is type called squamous. has spread (advanced NSCLC), and is type called squamous.. KEYTRUDA may be used alone when your lung cancer:has spread (advanced NSCLC) and, tests positive for PD-L1 and, as your first treatment if you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal EGFR or ALK gene, or you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, 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. has spread (advanced NSCLC) and, tests positive for PD-L1 and, as your first treatment if you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal EGFR or ALK gene, or you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, 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. as your first treatment if you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal EGFR or ALK gene,. you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, 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.. kind of cancer called head and neck squamous cell cancer (HNSCC) that:has returned or spread and you have received chemotherapy that contains platinum and it did not work or is no longer working. has returned or spread and you have received chemotherapy that contains platinum and it did not work or is no longer working.. kind of cancer called classical Hodgkin lymphoma (cHL) in adults and children when:you have tried treatment and it did not work or your cHL has returned after you received or more types of treatment. you have tried treatment and it did not work or your cHL has returned after you received or more types of treatment.. kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when:you have tried treatment and it did not work or your PMBCL has returned after you received or more types of treatment. you have tried treatment and it did not work or your PMBCL has returned after you received or more types of treatment.. kind of bladder and urinary tract cancer called urothelial carcinoma. 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 medicine called cisplatin, and your tumor tests positive for PD-L1, or you are not able to receive medicine called cisplatin or carboplatin, or you have received chemotherapy that contains platinum, and it did not work or is no longer working. has spread or cannot be removed by surgery (advanced urothelial cancer) and,. you are not able to receive chemotherapy that contains medicine called cisplatin, and your tumor tests positive for PD-L1, or you are not able to receive medicine called cisplatin or carboplatin, or you have received chemotherapy that contains platinum, and it did not work or is no longer working.. kind of cancer that is shown by laboratory test to be microsatellite instability-high (MSI-H) or 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). 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.. 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 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 HER2/neu-targeted medicine and it did not work or is no longer working. has returned or spread (advanced gastric cancer), and you have received 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 HER2/neu-targeted medicine and it did not work or is no longer working.. 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. 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.. kind of liver cancer called hepatocellular carcinoma, after you have received the medicine sorafenib.. 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.. have immune system problems such as Crohns disease, ulcerative colitis, or lupus. have received an organ transplant, such as kidney or liver. have received or plan to receive 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 pregnancy test before you start treatment with KEYTRUDA.You should use an effective method of birth control during and for at least 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. KEYTRUDA can harm your unborn baby. Your doctor will give you pregnancy test before you start treatment with KEYTRUDA.. You should use an effective method of birth control during and for at least 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 months after your final dose of KEYTRUDA. It is not known if KEYTRUDA passes into your breast milk.. Do not breastfeed during treatment with KEYTRUDA and for months after your final dose of KEYTRUDA.. Your doctor will give you KEYTRUDA into your vein through an intravenous (IV) line over 30 minutes.. KEYTRUDA is usually given every 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.

SPL UNCLASSIFIED SECTION.

1.1Melanoma. KEYTRUDA(R) (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma.

STORAGE AND HANDLING SECTION.

Store vials under refrigeration at 2C to 8C (36F to 46F).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)Store vials under refrigeration at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, KEYTRUDA can cause fetal harm when administered to 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 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 DataAnimal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. literature-based asessment of the effects of the PD-1 pathway on reproduction demonstrated that 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 SummaryThere 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 months after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)]. ContraceptionKEYTRUDA can cause fetal harm when administered to 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 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 (14,4, 14.5, 14.7), Clinical Pharmacology (12.3)].There is limited experience with KEYTRUDA in pediatric patients. In trial (NCT02332668), 40 pediatric patients (16 children ages years to less than 12 years and 24 adolescents ages 12 years to 18 years) with various cancers, including unapproved usages were administered KEYTRUDA mg/kg every weeks. Patients received KEYTRUDA for median of doses (range: 1-17 doses), with 34 patients (85%) receiving KEYTRUDA for doses or more.The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at 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 mg/kg every 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.

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: Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue. (5.3)Immune-mediated endocrinopathies (5.4): 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 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 history of allogeneic HSCT, consider the benefit of treatment with KEYTRUDA versus the risk of GVHD. Treatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibody in combination with 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 fetus and to use effective method of contraception. (5.11, 8.1, 8.3). 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: Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue. (5.3). Immune-mediated endocrinopathies (5.4): 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 diabetes mellitus: Monitor for hyperglycemia. Withhold KEYTRUDA in cases of severe hyperglycemia. 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 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 history of allogeneic HSCT, consider the benefit of treatment with KEYTRUDA versus the risk of GVHD. 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 history of allogeneic HSCT, consider the benefit of treatment with KEYTRUDA versus the risk of GVHD.. Treatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibody in combination with 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 fetus and to use effective method of contraception. (5.11, 8.1, 8.3). 5.1Immune-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 to mg/kg/day prednisone or equivalent followed by taper) for Grade 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 (2.13) and Adverse Reactions (6.1)]. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade (0.8%), Grade (1.3%), Grade (0.9%), Grade (0.3%), and Grade (0.1%) pneumonitis. The median time to onset was 3.3 months (range: days to 19.3 months), and the median duration was 1.5 months (range: 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 median duration of days (range: day to 10.1 months) followed by corticosteroid taper. Pneumonitis occurred more frequently in patients with 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.. 5.2Immune-Mediated Colitis. KEYTRUDA can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of to mg/kg/day prednisone or equivalent followed by taper) for Grade 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 (2.13) and Adverse Reactions (6.1)]. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade (0.4%), Grade (1.1%), and Grade (<0.1%) colitis. The median time to onset was 3.5 months (range: 10 days to 16.2 months), and the median duration was 1.3 months (range: day to 8.7+ months). Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of the 33 requiring high-dose corticosteroids for median duration of days (range: day to 5.3 months) followed by corticosteroid taper. Colitis led to discontinuation of KEYTRUDA in 15 (0.5%) patients. Colitis resolved in 41 (85%) of the 48 patients.. 5.3Immune-Mediated Hepatitis. KEYTRUDA can cause immune-mediated hepatitis. Monitor patients for changes in liver function. Administer corticosteroids (initial dose of 0.5 to mg/kg/day [for Grade hepatitis] and to mg/kg/day [for Grade or greater hepatitis] prednisone or equivalent followed by taper) and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA [see Dosage and Administration (2.13) and Adverse Reactions (6.1)]. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade (0.1%), Grade (0.4%), and Grade (<0.1%) hepatitis. The median time to onset was 1.3 months (range: days to 21.4 months), and the median duration was 1.8 months (range: days to 20.9+ months). Thirteen (68%) of the 19 patients received systemic corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for median duration of days (range: to 26 days) followed by corticosteroid taper. Hepatitis led to discontinuation of KEYTRUDA in (0.2%) patients. Hepatitis resolved in 15 (79%) of the 19 patients.. 5.4Immune-Mediated Endocrinopathies. HypophysitisKEYTRUDA can cause hypophysitis. Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). 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 (2.13) and Adverse Reactions (6.1)]. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade (0.2%), Grade (0.3%), and Grade (<0.1%) hypophysitis. The median time to onset was 3.7 months (range: 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 of the 16 receiving high-dose corticosteroids. Hypophysitis led to discontinuation of KEYTRUDA in (0.1%) patients. Hypophysitis resolved in (41%) of the 17 patients.. Thyroid DisordersKEYTRUDA 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 (2.13) and Adverse Reactions (6.1)]. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade (0.8%) and Grade (0.1%) hyperthyroidism. The median time to onset was 1.4 months (range: day to 21.9 months), and the median duration was 2.1 months (range: days to 15.0+ months). Hyperthyroidism led to discontinuation of KEYTRUDA in (<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 (6.2%) and Grade (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: day to 18.9 months), and the median duration was not reached (range: days to 27.7+ months). Hypothyroidism led to discontinuation of KEYTRUDA in (<0.1%) patient. Hypothyroidism resolved in 48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients receiving KEYTRUDA, including Grade (0.5%) hypothyroidism. Of these 28 patients, 15 had no prior history of hypothyroidism.Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months).. Type Diabetes mellitusKEYTRUDA can cause type diabetes mellitus, including diabetic ketoacidosis, which have been reported in (0.2%) of 2799 patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type diabetes and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia [see Dosage and Administration (2.13) and Adverse Reactions (6.1)].. 5.5Immune-Mediated Nephritis and Renal Dysfunction. KEYTRUDA can cause immune-mediated nephritis. Monitor patients for changes in renal function. Administer corticosteroids (initial dose of to mg/kg/day prednisone or equivalent followed by taper) for Grade 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 (2.13) and Adverse Reactions (6.1)]. Nephritis occurred in (0.3%) of 2799 patients receiving KEYTRUDA, including Grade (0.1%), Grade (0.1%), and Grade (<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 patients received systemic corticosteroids, with of the receiving high-dose corticosteroids for median duration of 15 days (range: days to 4.0 months) followed by corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in (0.1%) patients. Nephritis resolved in (56%) of the patients. Nephritis occurred in 1.7% of 405 patients receiving KEYTRUDA in combination with pemetrexed and platinum in the KEYNOTE-189 study, including Grade (1%) and Grade (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 patients received systemic corticosteroids, with all receiving high-dose corticosteroids for median duration of days (range: to 17 days) followed by corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in (1.2%) patients. Nephritis resolved in (29%) of the patients.. 5.6Immune-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 (2.13)]. 5.7Other 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 or less, initiate corticosteroid taper and continue to taper over at least 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 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction [see Dosage and Administration (2.13) 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-Barre 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.. 5.8Infusion-Related Reactions. KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in (0.2%) of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.13)].. 5.9Complications of Allogeneic HSCT Allogeneic HSCT after treatment with KEYTRUDAImmune-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, patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 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 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 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 KEYTRUDAIn patients with 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 history of allogeneic HSCT.. 5.10Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to Thalidomide Analogue and Dexamethasone. In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to thalidomide analogue plus dexamethasone, use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibody in combination with thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.. 5.11Embryo-Fetal Toxicity. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].

POSTMARKETING EXPERIENCE SECTION.

6.3Postmarketing Experience. The following adverse reactions have been identified during postapproval use of KEYTRUDA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary: sclerosing cholangitis.

IMMUNOGENICITY.

12.6 Immunogenicity. The observed incidence of anti-drug antibody (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described in this section with the incidence of ADA in other studies, including those of KEYTRUDA or of other pembrolizumab products.Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, subset analysis was performed in the patients with concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at dose of mg/kg every weeks, 200 mg every weeks, or 10 mg/kg every or 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.