KEYTRUDA (Page 5 of 21)

Merck Sharp & Dohme LLC 26 January 2023

5.2 Infusion-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. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].

5.3 Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone

In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling.

Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)].
Infusion-related reactions [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

Melanoma

Ipilimumab-Naive Melanoma

The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.

The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006.

Table 4: Selected * Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006
Adverse Reaction	KEYTRUDA10 mg/kg every 2 or 3 weeks		Ipilimumab
Adverse Reaction	n=555		n=256
	All Grades †(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Adverse reactions occurring at same or higher incidence than in the ipilimumab arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. § Includes skin hypopigmentation
General
Fatigue	28	0.9	28	3.1
Skin and Subcutaneous Tissue
Rash ‡	24	0.2	23	1.2
Vitiligo §	13	0	2	0
Musculoskeletal and Connective Tissue
Arthralgia	18	0.4	10	1.2
Back pain	12	0.9	7	0.8
Respiratory, Thoracic and Mediastinal
Cough	17	0	7	0.4
Dyspnea	11	0.9	7	0.8
Metabolism and Nutrition
Decreased appetite	16	0.5	14	0.8
Nervous System
Headache	14	0.2	14	0.8

Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%).

Table 5: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006
Laboratory Test †	KEYTRUDA10 mg/kg every 2 or 3 weeks		Ipilimumab
	All Grades ‡%	Grades 3-4%	All Grades%	Grades 3-4%
* Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm † Each 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. ‡ Graded per NCI CTCAE v4.0
Chemistry
Hyperglycemia	45	4.2	45	3.8
Hypertriglyceridemia	43	2.6	31	1.1
Hyponatremia	28	4.6	26	7
Increased AST	27	2.6	25	2.5
Hypercholesterolemia	20	1.2	13	0
Hematology
Anemia	35	3.8	33	4.0
Lymphopenia	33	7	25	6

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4).

Ipilimumab-Refractory Melanoma

The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator’s choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months.

The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis.

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002.

Table 6: Selected * Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002
Adverse Reaction	KEYTRUDA2 mg/kg or 10 mg/kg every 3 weeks		Chemotherapy †
Adverse Reaction	n=357		n=171
	All Grades ‡(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Adverse reactions occurring at same or higher incidence than in chemotherapy arm † Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin ‡ Graded per NCI CTCAE v4.0 § Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic
Skin and Subcutaneous Tissue
Pruritus	28	0	8	0
Rash §	24	0.6	8	0
Gastrointestinal
Constipation	22	0.3	20	2.3
Diarrhea	20	0.8	20	2.3
Abdominal pain	13	1.7	8	1.2
Respiratory, Thoracic and Mediastinal
Cough	18	0	16	0
General
Pyrexia	14	0.3	9	0.6
Asthenia	10	2.0	9	1.8
Musculoskeletal and Connective Tissue
Arthralgia	14	0.6	10	1.2

Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Table 7: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002
Laboratory Test †	KEYTRUDA2 mg/kg or 10 mg/kg every 3 weeks		Chemotherapy
	All Grades ‡%	Grades 3-4%	All Grades%	Grades 3-4%
* Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. † Each 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. ‡ Graded per NCI CTCAE v4.0
Chemistry
Hyperglycemia	49	6	44	6
Hypoalbuminemia	37	1.9	33	0.6
Hyponatremia	37	7	24	3.8
Hypertriglyceridemia	33	0	32	0.9
Increased alkaline phosphatase	26	3.1	18	1.9
Increased AST	24	2.2	16	0.6
Decreased bicarbonate	22	0.4	13	0
Hypocalcemia	21	0.3	18	1.9
Increased ALT	21	1.8	16	0.6

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

Among the 969 patients with stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Adjuvant Treatment of Stage III Resected Melanoma

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer.

The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes).

Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054.

Table 8: Selected * Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054
Adverse Reaction	KEYTRUDA200 mg every 3 weeksn=509		Placebon=502
Adverse Reaction	All Grades †(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Adverse reactions occurring at same or higher incidence than in placebo arm † Graded per NCI CTCAE v4.03
Gastrointestinal
Diarrhea	28	1.2	26	1.2
Nausea	17	0.2	15	0
Skin and Subcutaneous Tissue
Pruritus	19	0	12	0
Rash	13	0.2	9	0
Musculoskeletal and Connective Tissue
Arthralgia	16	1.2	14	0
Endocrine
Hypothyroidism	15	0	2.8	0
Hyperthyroidism	10	0.2	1.2	0
Respiratory, Thoracic and Mediastinal
Cough	14	0	11	0
General
Asthenia	11	0.2	8	0
Influenza like illness	11	0	8	0
Investigations
Weight loss	11	0	8	0

Table 9: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054
Laboratory Test †	KEYTRUDA200 mg every 3 weeks		Placebo
Laboratory Test †	All Grades ‡%	Grades 3-4%	All Grades%	Grades 3-4%
* Laboratory abnormalities occurring at same or higher incidence than placebo. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 503 to 507 patients) and placebo (range: 492 to 498 patients). ‡ Graded per NCI CTCAE v4.03
Chemistry
Increased ALT	27	2.4	16	0.2
Increased AST	24	1.8	15	0.4
Hematology
Lymphopenia	24	1	16	1.2

NSCLC

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The safety of KEYTRUDA in combination with pemetrexed and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Seventy-two percent of patients received carboplatin.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-189.

Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189
Adverse Reaction	KEYTRUDA 200 mg every 3 weeksPemetrexed Platinum Chemotherapyn=405		PlaceboPemetrexedPlatinum Chemotherapyn=202
	All Grades *(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Graded per NCI CTCAE v4.03 † Includes asthenia and fatigue ‡ Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
Gastrointestinal
Nausea	56	3.5	52	3.5
Constipation	35	1.0	32	0.5
Diarrhea	31	5	21	3.0
Vomiting	24	3.7	23	3.0
General
Fatigue †	56	12	58	6
Pyrexia	20	0.2	15	0
Metabolism and Nutrition
Decreased appetite	28	1.5	30	0.5
Skin and Subcutaneous Tissue
Rash ‡	25	2.0	17	2.5
Respiratory, Thoracic and Mediastinal
Cough	21	0	28	0
Dyspnea	21	3.7	26	5

Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189
Laboratory Test *	KEYTRUDA 200 mg every 3 weeksPemetrexed Platinum Chemotherapy		Placebo Pemetrexed Platinum Chemotherapy
	All Grades †%	Grades 3-4%	All Grades%	Grades 3-4%
* Each 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). † Graded per NCI CTCAE v4.03
Hematology
Anemia	85	17	81	18
Lymphopenia	64	22	64	25
Neutropenia	48	20	41	19
Thrombocytopenia	30	12	29	8
Chemistry
Hyperglycemia	63	9	60	7
Increased ALT	47	3.8	42	2.6
Increased AST	47	2.8	40	1.0
Hypoalbuminemia	39	2.8	39	1.1
Increased creatinine	37	4.2	25	1.0
Hyponatremia	32	7	23	6
Hypophosphatemia	30	10	28	14
Increased alkaline phosphatase	26	1.8	29	2.1
Hypocalcemia	24	2.8	17	0.5
Hyperkalemia	24	2.8	19	3.1
Hypokalemia	21	5	20	5

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The safety of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin.

The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases.

KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).

The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

Previously Untreated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator’s choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (stage IV), 13% had stage III disease (2% stage IIIA and 11% stage IIIB), and 5% had treated brain metastases at baseline.

KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).

Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042.

Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042
Adverse Reaction	KEYTRUDA200 mg every 3 weeksn=636		Chemotherapyn=615
Adverse Reaction	All Grades *(%)	Grades 3-5(%)	All Grades(%)	Grades 3-5(%)
* Graded per NCI CTCAE v4.03 † Includes fatigue and asthenia ‡ Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
General
Fatigue †	25	3.1	33	3.9
Pyrexia	10	0.3	8	0
Metabolism and Nutrition
Decreased appetite	17	1.7	21	1.5
Respiratory, Thoracic and Mediastinal
Dyspnea	17	2.0	11	0.8
Cough	16	0.2	11	0.3
Skin and Subcutaneous Tissue
Rash ‡	15	1.3	8	0.2
Gastrointestinal
Constipation	12	0	21	0.2
Diarrhea	12	0.8	12	0.5
Nausea	12	0.5	32	1.1
Endocrine
Hypothyroidism	12	0.2	1.5	0
Infections
Pneumonia	12	7	9	6
Investigations
Weight loss	10	0.9	7	0.2

Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042
Laboratory Test *	KEYTRUDA200 mg every 3 weeks		Chemotherapy
Laboratory Test *	All Grades †%	Grades 3-4%	All Grades%	Grades 3-4%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173. † Graded per NCI CTCAE v4.03
Chemistry
Hyperglycemia	52	4.7	51	5
Increased ALT	33	4.8	34	2.9
Hypoalbuminemia	33	2.2	29	1.0
Increased AST	31	3.6	32	1.7
Hyponatremia	31	9	32	8
Increased alkaline phosphatase	29	2.3	29	0.3
Hypocalcemia	25	2.5	19	0.7
Hyperkalemia	23	3.0	20	2.2
Increased prothrombin INR	21	2.0	15	2.9
Hematology
Anemia	43	4.4	79	19
Lymphopenia	30	7	41	13

Previously Treated NSCLC

The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m² every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010.

Table 14: Selected * Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010
Adverse Reaction	KEYTRUDA2 or 10 mg/kg every 3 weeksn=682		Docetaxel75 mg/m² every 3 weeksn=309
	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)
* Adverse reactions occurring at same or higher incidence than in docetaxel arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic
Metabolism and Nutrition
Decreased appetite	25	1.5	23	2.6
Respiratory, Thoracic and Mediastinal
Dyspnea	23	3.7	20	2.6
Cough	19	0.6	14	0
Gastrointestinal
Nausea	20	1.3	18	0.6
Constipation	15	0.6	12	0.6
Vomiting	13	0.9	10	0.6
Skin and Subcutaneous Tissue
Rash ‡	17	0.4	8	0
Pruritus	11	0	3	0.3
Musculoskeletal and Connective Tissue
Arthralgia	11	1.0	9	0.3
Back pain	11	1.5	8	0.3

Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Table 15: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010
Laboratory Test †	KEYTRUDA2 or 10 mg/kg every 3 weeks		Docetaxel75 mg/m² every 3 weeks
	All Grades ‡%	Grades 3-4%	All Grades ‡%	Grades 3-4%
* Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. † Each 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). ‡ Graded per NCI CTCAE v4.0
Chemistry
Hyponatremia	32	8	27	2.9
Increased alkaline phosphatase	28	3.0	16	0.7
Increased AST	26	1.6	12	0.7
Increased ALT	22	2.7	9	0.4

Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

Adjuvant Treatment of Resected NSCLC

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected stage IB (T2a ≥4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.2)]. A total of 1161 patients received KEYTRUDA 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents or had a history of interstitial lung disease or pneumonitis.

The median duration of exposure to KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months.

The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.

HNSCC

First-line treatment of metastatic or unresectable, recurrent HNSCC

The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.3)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.

The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin.

KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).

KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).

Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048.

Table 16: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048
	KEYTRUDA 200 mg every 3 weeks		KEYTRUDA 200 mg every 3 weeks Platinum FU		Cetuximab Platinum FU
Adverse Reaction	n=300		n=276		n=287
	All Grades *(%)	Grades 3-4(%)	All Grades *(%)	Grades 3-4(%)	All Grades *(%)	Grades 3-4(%)
* Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis § Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis ¶ Includes cough, productive cough # Includes dyspnea, exertional dyspnea Þ Includes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal ß Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia à Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia
General
Fatigue †	33	4	49	11	48	8
Pyrexia	13	0.7	16	0.7	12	0
Mucosal inflammation	4.3	1.3	31	10	28	5
Gastrointestinal
Constipation	20	0.3	37	0	33	1.4
Nausea	17	0	51	6	51	6
Diarrhea ‡	16	0.7	29	3.3	35	3.1
Vomiting	11	0.3	32	3.6	28	2.8
Dysphagia	8	2.3	12	2.9	10	2.1
Stomatitis	3	0	26	8	28	3.5
Skin
Rash §	20	2.3	17	0.7	70	8
Pruritus	11	0	8	0	10	0.3
Respiratory, Thoracic and Mediastinal
Cough ¶	18	0.3	22	0	15	0
Dyspnea #	14	2.0	10	1.8	8	1.0
Endocrine
Hypothyroidism	18	0	15	0	6	0
Metabolism and Nutrition
Decreased appetite	15	1.0	29	4.7	30	3.5
Weight loss	15	2	16	2.9	21	1.4
Infections
Pneumonia Þ	12	7	19	11	13	6
Nervous System
Headache	12	0.3	11	0.7	8	0.3
Dizziness	5	0.3	10	0.4	13	0.3
Peripheral sensory neuropathy ß	1	0	14	1.1	7	1
Musculoskeletal
Myalgia à	12	1.0	13	0.4	11	0.3
Neck pain	6	0.7	10	1.1	7	0.7
Psychiatric
Insomnia	7	0.7	10	0	8	0

Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048
	KEYTRUDA 200 mg every 3 weeks		KEYTRUDA 200 mg every 3 weeks Platinum FU		Cetuximab Platinum FU
Laboratory Test *	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 235 to 266 patients), KEYTRUDA (range: 241 to 288 patients), cetuximab/chemotherapy (range: 249 to 282 patients). † Graded per NCI CTCAE v4.0
Hematology
Lymphopenia	54	25	69	35	74	45
Anemia	52	7	89	28	78	19
Thrombocytopenia	12	3.8	73	18	76	18
Neutropenia	7	1.4	67	35	71	42
Chemistry
Hyperglycemia	47	3.8	55	6	66	4.7
Hyponatremia	46	17	56	20	59	20
Hypoalbuminemia	44	3.2	47	4.0	49	1.1
Increased AST	28	3.1	24	2.0	37	3.6
Increased ALT	25	2.1	22	1.6	38	1.8
Increased alkaline phosphatase	25	2.1	27	1.2	33	1.1
Hypercalcemia	22	4.6	16	4.3	13	2.6
Hypocalcemia	22	1.1	32	4	58	7
Hyperkalemia	21	2.8	27	4.3	29	4.3
Hypophosphatemia	20	5	35	12	48	19
Hypokalemia	19	5	34	12	47	15
Increased creatinine	18	1.1	36	2.3	27	2.2
Hypomagnesemia	16	0.4	42	1.7	76	6

Previously treated recurrent or metastatic HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.3)] , the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012.

The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.1)].

Relapsed or Refractory cHL

KEYNOTE-204

The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.4)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/µL, platelet count ≥75,000/µL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment.

Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia.

Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy.

Table 18 summarizes adverse reactions in KEYNOTE-204.

Table 18: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204
Adverse Reaction	KEYTRUDA200 mg every 3 weeksN=148		Brentuximab Vedotin1.8 mg/kg every 3 weeksN=152
	All Grades *(%)	Grades 3- 4(%)	All Grades *(%)	Grades 3- 4†(%)
* Graded per NCI CTCAE v4.0 † Adverse reactions in BV arm were Grade 3 only. ‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection § Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity ¶ Includes diarrhea, gastroenteritis, colitis, enterocolitis # Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper Þ Includes fatigue, asthenia ß Includes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular‚ rash maculo-papular, rash papular, rash pruritic, toxic skin eruption à Includes cough, productive cough è Includes pneumonitis, interstitial lung disease ð Includes dyspnea, dyspnea exertional, wheezing ø Includes dysesthesia, hypoesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy ý Includes headache, migraine, tension headache
Infections
Upper respiratory tract infection ‡	41	1.4	24	0
Urinary tract infection	11	0	3	0.7
Musculoskeletal and Connective Tissue
Musculoskeletal pain §	32	0	29	1.3
Gastrointestinal
Diarrhea ¶	22	2.7	17	1.3
Nausea	14	0	24	0.7
Vomiting	14	1.4	20	0
Abdominal pain #	11	0.7	13	1.3
General
Pyrexia	20	0.7	13	0.7
Fatigue Þ	20	0	22	0.7
Skin and Subcutaneous Tissue
Rash ß	20	0	19	0.7
Pruritus	18	0	12	0
Respiratory, Thoracic and Mediastinal
Cough à	20	0.7	14	0.7
Pneumonitis è	11	5	3	1.3
Dyspnea ð	11	0.7	7	0.7
Endocrine
Hypothyroidism	19	0	3	0
Nervous System
Peripheral neuropathy ø	11	0.7	43	7
Headache ý	11	0	11	0

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare.

Table 19 summarizes laboratory abnormalities in KEYNOTE-204.

Table 19: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204
Laboratory Abnormality *	KEYTRUDA200 mg every 3 weeks		Brentuximab Vedotin1.8 mg/kg every 3 weeks
	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148 patients) and BV (range: 146 to 152 patients); hypomagnesemia: KEYTRUDA n=53 and BV n=50. † Graded per NCI CTCAE v4.0
Chemistry
Hyperglycemia	46	4.1	36	2.0
Increased AST	39	5	41	3.9
Increased ALT	34	6	45	5
Hypophosphatemia	31	5	18	2.7
Increased creatinine	28	3.4	14	2.6
Hypomagnesemia	25	0	12	0
Hyponatremia	24	4.1	20	3.3
Hypocalcemia	22	2.0	16	0
Increased alkaline phosphatase	21	2.1	22	2.6
Hyperbilirubinemia	16	2.0	9	1.3
Hypoalbuminemia	16	0.7	19	0.7
Hyperkalemia	15	1.4	8	0
Hematology
Lymphopenia	35	9	32	13
Thrombocytopenia	34	10	26	5
Neutropenia	28	8	43	17
Anemia	24	5	33	8

KEYNOTE-087

Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.4)] , the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.

Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087
Adverse Reaction	KEYTRUDA200 mg every 3 weeksN=210
	All Grades *(%)	Grade 3(%)
* Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes cough, productive cough § Includes dyspnea, dyspnea exertional, wheezing ¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrheic dermatitis, dermatitis psoriasiform ß Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy
General
Fatigue †	26	1.0
Pyrexia	24	1.0
Respiratory, Thoracic and Mediastinal
Cough ‡	24	0.5
Dyspnea §	11	1.0
Musculoskeletal and Connective Tissue
Musculoskeletal pain ¶	21	1.0
Arthralgia	10	0.5
Gastrointestinal
Diarrhea #	20	1.4
Vomiting	15	0
Nausea	13	0
Skin and Subcutaneous Tissue
Rash Þ	20	0.5
Pruritus	11	0
Endocrine
Hypothyroidism	14	0.5
Infections
Upper respiratory tract infection	13	0
Nervous System
Headache	11	0.5
Peripheral neuropathy ß	10	0

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).

Table 21: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087
Laboratory Abnormality *	KEYTRUDA200 mg every 3 weeks
	All Grades †(%)	Grades 3-4(%)
* Each 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) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT
Chemistry
Hypertransaminasemia ‡	34	2
Increased alkaline phosphatase	17	0
Increased creatinine	15	0.5
Hematology
Anemia	30	6
Thrombocytopenia	27	4
Neutropenia	24	7

Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).

PMBCL

Among the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients 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. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170.

Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170
Adverse Reaction	KEYTRUDA200 mg every 3 weeksN=53
	All Grades *(%)	Grades 3-4(%)
* Graded per NCI CTCAE v4.0 † Includes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain ‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection § Includes fatigue, asthenia ¶ Includes allergic cough, cough, productive cough # Includes diarrhea, gastroenteritis Þ Includes abdominal pain, abdominal pain upper ß Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia
Musculoskeletal and Connective Tissue
Musculoskeletal pain †	30	0
Infections
Upper respiratory tract infection ‡	28	0
General
Pyrexia	28	0
Fatigue §	23	2
Respiratory, Thoracic and Mediastinal
Cough ¶	26	2
Dyspnea	21	11
Gastrointestinal
Diarrhea #	13	2
Abdominal pain Þ	13	0
Nausea	11	0
Cardiac
Arrhythmia ß	11	4
Nervous System
Headache	11	0

Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).

Table 23: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170
Laboratory Abnormality *	KEYTRUDA200 mg every 3 weeks
	All Grades †(%)	Grades 3-4(%)
* Each 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) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT
Hematology
Anemia	47	0
Leukopenia	35	9
Lymphopenia	32	18
Neutropenia	30	11
Chemistry
Hyperglycemia	38	4
Hypophosphatemia	29	10
Hypertransaminasemia ‡	27	4
Hypoglycemia	19	0
Increased alkaline phosphatase	17	0
Increased creatinine	17	0
Hypocalcemia	15	4
Hypokalemia	15	4

Urothelial Carcinoma

Platinum Ineligible Patients with Urothelial Carcinoma

The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. 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 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.

The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months).

KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent.

Table 24 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052.

Table 24: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-052
Adverse Reaction	KEYTRUDA200 mg every 3 weeksN=370
	All Grades *(%)	Grades 3–4(%)
* Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain § Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements ¶ Includes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper # Includes 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 Þ Includes 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 ß Includes edema peripheral, peripheral swelling
General
Fatigue †	38	6
Pyrexia	11	0.5
Weight loss	10	0
Musculoskeletal and Connective Tissue
Musculoskeletal pain ‡	24	4.9
Arthralgia	10	1.1
Metabolism and Nutrition
Decreased appetite	22	1.6
Hyponatremia	10	4.1
Gastrointestinal
Constipation	21	1.1
Diarrhea §	20	2.4
Nausea	18	1.1
Abdominal pain ¶	18	2.7
Elevated LFTs #	13	3.5
Vomiting	12	0
Skin and Subcutaneous Tissue
Rash Þ	21	0.5
Pruritus	19	0.3
Edema peripheral ß	14	1.1
Infections
Urinary tract infection	19	9
Blood and Lymphatic System
Anemia	17	7
Respiratory, Thoracic, and Mediastinal
Cough	14	0
Dyspnea	11	0.5
Renal and Urinary
Increased blood creatinine	11	1.1
Hematuria	13	3.0

Previously Treated Urothelial Carcinoma

The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator’s choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.6)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible.

The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.

KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045.

Table 25: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-045
Adverse Reaction	KEYTRUDA200 mg every 3 weeks		Chemotherapy *
Adverse Reaction	n=266		n=255
	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)
* Chemotherapy: paclitaxel, docetaxel, or vinflunine † Graded per NCI CTCAE v4.0 ‡ Includes asthenia, fatigue, malaise, lethargy § Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain ¶ Includes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes cough, productive cough ß Includes dyspnea, dyspnea exertional, wheezing à Includes blood urine present, hematuria, chromaturia
General
Fatigue ‡	38	4.5	56	11
Pyrexia	14	0.8	13	1.2
Musculoskeletal and Connective Tissue
Musculoskeletal pain §	32	3.0	27	2.0
Skin and Subcutaneous Tissue
Pruritus	23	0	6	0.4
Rash ¶	20	0.4	13	0.4
Gastrointestinal
Nausea	21	1.1	29	1.6
Constipation	19	1.1	32	3.1
Diarrhea #	18	2.3	19	1.6
Vomiting	15	0.4	13	0.4
Abdominal pain	13	1.1	13	2.7
Infections
Urinary tract infection	15	4.9	14	4.3
Metabolism and Nutrition
Decreased appetite	21	3.8	21	1.2
Respiratory, Thoracic and Mediastinal
Cough Þ	15	0.4	9	0
Dyspnea ß	14	1.9	12	1.2
Renal and Urinary
Hematuria à	12	2.3	8	1.6

Table 26: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045
Laboratory Test *	KEYTRUDA200 mg every 3 weeks		Chemotherapy
	All Grades †%	Grades 3-4%	All Grades †%	Grades 3-4%
* Each 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. † Graded per NCI CTCAE v4.0
Chemistry
Hyperglycemia	52	8	60	7
Anemia	52	13	68	18
Lymphopenia	45	15	53	25
Hypoalbuminemia	43	1.7	50	3.8
Hyponatremia	37	9	47	13
Increased alkaline phosphatase	37	7	33	4.9
Increased creatinine	35	4.4	28	2.9
Hypophosphatemia	29	8	34	14
Increased AST	28	4.1	20	2.5
Hyperkalemia	28	0.8	27	6
Hypocalcemia	26	1.6	34	2.1

BCG-unresponsive High-risk NMIBC

The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression.

The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months).

KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057.

Table 27: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-057
Adverse Reaction	KEYTRUDA200 mg every 3 weeksN=148
Adverse Reaction	All Grades *(%)	Grades 3–4(%)
* Graded per NCI CTCAE v4.03 † Includes asthenia, fatigue, malaise ‡ Includes edema peripheral, peripheral swelling § Includes diarrhea, gastroenteritis, colitis ¶ Includes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis # Includes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain Þ Includes cough, productive cough
General
Fatigue †	29	0.7
Peripheral edema ‡	11	0
Gastrointestinal
Diarrhea §	24	2.0
Nausea	13	0
Constipation	12	0
Skin and Subcutaneous Tissue
Rash ¶	24	0.7
Pruritus	19	0.7
Musculoskeletal and Connective Tissue
Musculoskeletal pain #	19	0
Arthralgia	14	1.4
Renal and Urinary
Hematuria	19	1.4
Respiratory, Thoracic, and Mediastinal
Cough Þ	19	0
Infections
Urinary tract infection	12	2.0
Nasopharyngitis	10	0
Endocrine
Hypothyroidism	11	0

Table 28: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057
Laboratory Test *	KEYTRUDA200 mg every 3 weeks
Laboratory Test *	All Grades †(%)	Grades 3-4(%)
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 124 to 147 patients) † Graded per NCI CTCAE v4.03
Chemistry
Hyperglycemia	59	8
Increased ALT	25	3.4
Hyponatremia	24	7
Hypophosphatemia	24	6
Hypoalbuminemia	24	2.1
Hyperkalemia	23	1.4
Hypocalcemia	22	0.7
Increased AST	20	3.4
Increased creatinine	20	0.7
Hematology
Anemia	35	1.4
Lymphopenia	29	1.6

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

Among the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.8)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Gastric Cancer

The safety analysis of Study KEYNOTE-811 included 217 patients with HER2-positive gastric cancer who received KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients who received placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.9)].

The median duration of exposure to KEYTRUDA was 5.8 months (range: 1 day to 17.7 months).

The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1.

KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%).

In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%), and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for increased ALT (34% vs 29%), and increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

Esophageal Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction

The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.10)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU.

The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm.

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590.

Table 29: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-590
Adverse Reaction	KEYTRUDA200 mg every 3 weeksCisplatin FUn=370		PlaceboCisplatinFUn=370
Adverse Reaction	All Grades *(%)	Grades 3-4†(%)	All Grades *(%)	Grades 3-4†(%)
* Graded per NCI CTCAE v4.03 † One fatal event of diarrhea was reported in each arm. ‡ Includes asthenia, fatigue
Gastrointestinal
Nausea	67	7	63	7
Constipation	40	0	40	0
Diarrhea	36	4.1	33	3
Vomiting	34	7	32	5
Stomatitis	27	6	26	3.8
General
Fatigue ‡	57	12	46	9
Metabolism and Nutrition
Decreased appetite	44	4.1	38	5
Investigations
Weight loss	24	3.0	24	5

Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving KEYTRUDA in KEYNOTE-590
Laboratory Test *	KEYTRUDA200 mg every 3 weeksCisplatin FU		Chemotherapy(Cisplatin and FU)
Laboratory Test *	All Grades †%	Grades 3-4%	All Grades †%	Grades 3-4%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 345 to 365 patients) and placebo/cisplatin/FU (range: 330 to 358 patients) † Graded per NCI CTCAE v4.03
Hematology
Anemia	83	21	86	24
Neutropenia	74	43	71	41
Leukopenia	72	21	73	17
Lymphopenia	55	22	53	18
Thrombocytopenia	43	5	46	8
Chemistry
Hyperglycemia	56	7	55	6
Hyponatremia	53	19	54	19
Hypoalbuminemia	52	2.8	52	2.3
Increased creatinine	45	2.5	42	2.5
Hypocalcemia	44	3.9	38	2
Hypophosphatemia	37	9	31	10
Hypokalemia	30	12	34	15
Increased alkaline phosphatase	29	1.9	29	1.7
Hyperkalemia	28	3.6	27	2.6
Increased AST	25	4.4	22	2.8
Increased ALT	23	3.6	18	1.7

Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer

Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.10)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

Cervical Cancer

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.11)]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks.

The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months).

Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.

Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%).

KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%).

Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

Table 31 and Table 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826.

Table 31: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826
Adverse Reaction	KEYTRUDA200 mg every 3 weeksand chemotherapy * with or without bevacizumabn=307		Placeboand chemotherapy * with or without bevacizumabn=309
Adverse Reaction	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)
* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Graded per NCI CTCAE v4.0 ‡ Includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia § Includes rash, rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular ¶ Includes fatigue, asthenia
Nervous System
Peripheral neuropathy ‡	58	4.2	57	6
Skin and Subcutaneous Tissue
Alopecia	56	0	58	0
Rash §	22	3.6	15	0.3
General
Fatigue ¶	47	7	46	6
Gastrointestinal
Nausea	40	2	44	1.6
Diarrhea	36	2	30	2.6
Constipation	28	0.3	33	1
Vomiting	26	2.6	27	1.9
Musculoskeletal and Connective Tissue
Arthralgia	27	0.7	26	1.3
Vascular
Hypertension	24	9	23	11
Infections
Urinary tract infection	24	9	26	8

Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826
Laboratory Test *	KEYTRUDA200 mg every 3 weeksand chemotherapy † with or without bevacizumabn=307		Placeboand chemotherapy † with or without bevacizumabn=309
Laboratory Test *	All Grades ‡(%)	Grades 3-4(%)	All Grades ‡(%)	Grades 3-4(%)
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA plus chemotherapy (range: 297 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients) † Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) ‡ Graded per NCI CTCAE v4.0
Hematology
Anemia	80	35	77	33
Leukopenia	76	27	69	19
Neutropenia	66	39	58	31
Lymphopenia	61	33	56	33
Thrombocytopenia	57	19	53	15
Chemistry
Hyperglycemia	51	4.7	46	2.3
Hypoalbuminemia	46	1.3	38	5
Hyponatremia	40	14	38	11
Increased ALT	40	7	38	6
Increased AST	40	6	36	3.0
Increased alkaline phosphatase	38	3.4	40	2.3
Hypocalcemia	37	4.0	31	5
Increased creatinine	34	5	32	6
Hypokalemia	29	7	26	7
Hyperkalemia	23	3.7	27	4.7
Hypercalcemia	21	1.0	20	1.3

Previously Treated Recurrent or Metastatic Cervical Cancer

Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.11)] , the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158.

Table 33: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158
Adverse Reaction	KEYTRUDA200 mg every 3 weeksN=98
	All Grades *(%)	Grades 3–4(%)
* Graded per NCI CTCAE v4.0 † Includes asthenia, fatigue, lethargy, malaise ‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache § Includes edema peripheral, peripheral swelling ¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity # Includes colitis, diarrhea, gastroenteritis Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper ß Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage à Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis è 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 ð Includes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular
General
Fatigue †	43	5
Pain ‡	22	2.0
Pyrexia	19	1.0
Edema peripheral §	15	2.0
Musculoskeletal and Connective Tissue
Musculoskeletal pain ¶	27	5
Gastrointestinal
Diarrhea #	23	2.0
Abdominal pain Þ	22	3.1
Nausea	19	0
Vomiting	19	1.0
Constipation	14	0
Metabolism and Nutrition
Decreased appetite	21	0
Vascular
Hemorrhage ß	19	5
Infections
UTI à	18	6
Infection (except UTI)è	16	4.1
Skin and Subcutaneous Tissue
Rash ð	17	2.0
Endocrine
Hypothyroidism	11	0
Nervous System
Headache	11	2.0
Respiratory, Thoracic and Mediastinal
Dyspnea	10	1.0

Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158
Laboratory Test *	KEYTRUDA200 mg every 3 weeks
	All Grades †(%)	Grades 3-4(%)
* Each 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) † Graded per NCI CTCAE v4.0
Hematology
Anemia	54	24
Lymphopenia	47	9
Chemistry
Hypoalbuminemia	44	5
Increased alkaline phosphatase	42	2.6
Hyponatremia	38	13
Hyperglycemia	38	1.3
Increased AST	34	3.9
Increased creatinine	32	5
Hypocalcemia	27	0
Increased ALT	21	3.9
Hypokalemia	20	6

Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (14% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4).

HCC

Among the 104 patients with HCC who received KEYTRUDA in KEYNOTE-224 [see Clinical Studies (14.12)] , the median duration of exposure to KEYTRUDA was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

MCC

Among the 50 patients with MCC enrolled in KEYNOTE-017 [see Clinical Studies (14.13)] , the median duration of exposure to KEYTRUDA was 6.6 months (range 1 day to 23.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

RCC

In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426)

The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.14)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren’s syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months).

The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80.

Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).

Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).

The most common adverse reactions (≥20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426.

Table 35: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426
Adverse Reaction	KEYTRUDA 200 mg every 3 weeks and Axitinibn=429		Sunitinibn=425
Adverse Reaction	All Grades *(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Graded per NCI CTCAE v4.03 † Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic ‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension § Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased ¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash
Gastrointestinal
Diarrhea †	56	11	45	5
Nausea	28	0.9	32	0.9
Constipation	21	0	15	0.2
General
Fatigue/Asthenia	52	5	51	10
Vascular
Hypertension ‡	48	24	48	20
Hepatobiliary
Hepatotoxicity §	39	20	25	4.9
Endocrine
Hypothyroidism	35	0.2	32	0.2
Metabolism and Nutrition
Decreased appetite	30	2.8	29	0.7
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	28	5	40	3.8
Stomatitis/Mucosal inflammation	27	1.6	41	4
Rash ¶	25	1.4	21	0.7
Respiratory, Thoracic and Mediastinal
Dysphonia	25	0.2	3.3	0
Cough	21	0.2	14	0.5

Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426
Laboratory Test *	KEYTRUDA 200 mg every 3 weeks and Axitinib		Sunitinib
Laboratory Test *	All Grades †%	Grades 3-4%	All Grades%	Grades 3-4%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients). † Graded per NCI CTCAE v4.03 ‡ Corrected for albumin § Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.
Chemistry
Hyperglycemia	62	9	54	3.2
Increased ALT	60	20	44	5
Increased AST	57	13	56	5
Increased creatinine	43	4.3	40	2.4
Hyponatremia	35	8	29	8
Hyperkalemia	34	6	22	1.7
Hypoalbuminemia	32	0.5	34	1.7
Hypercalcemia	27	0.7	15	1.9
Hypophosphatemia	26	6	49	17
Increased alkaline phosphatase	26	1.7	30	2.7
Hypocalcemia ‡	22	0.2	29	0.7
Blood bilirubin increased	22	2.1	21	1.9
Activated partial thromboplastin time prolonged §	22	1.2	14	0
Hematology
Lymphopenia	33	11	46	8
Anemia	29	2.1	65	8
Thrombocytopenia	27	1.4	78	14

In combination with lenvatinib in the first-line treatment of advanced RCC (KEYNOTE-581)

The safety of KEYTRUDA was evaluated in KEYNOTE-581 [see Clinical Studies (14.14)]. Patients received KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of KEYTRUDA and lenvatinib was 17 months (range: 0.1 to 39).

Fatal adverse reactions occurred in 4.3% of patients treated with KEYTRUDA in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.

Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).

Permanent discontinuation of either of KEYTRUDA, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving KEYTRUDA in combination with lenvatinib; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions of KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with lenvatinib. KEYTRUDA was interrupted in 55% of patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of KEYTRUDA were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%).

Fifteen percent (15%) of patients treated with KEYTRUDA in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581.

Table 37: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581
Adverse Reaction	KEYTRUDA200 mg every 3 weekswith LenvatinibN=352		Sunitinib 50 mgN=340
Adverse Reaction	All Grades(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Includes asthenia, fatigue, lethargy, malaise † Includes diarrhea, gastroenteritis ‡ Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, stomatitis § Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain ¶ Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw # Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism Þ Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure ß Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage à Includes decreased appetite, early satiety è Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular ð Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema ø Includes hemoglobinuria, nephrotic syndrome, proteinuria ý Includes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic £ Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gamma-glutamyltransferase increased
General
Fatigue *	63	9	56	8
Gastrointestinal
Diarrhea †	62	10	50	6
Stomatitis ‡	43	2	43	2
Nausea	36	3	33	1
Abdominal pain §	27	2	18	1
Vomiting	26	3	20	1
Constipation	25	1	19	0
Musculoskeletal and Connective Tissue
Musculoskeletal disorders ¶	58	4	41	3
Endocrine
Hypothyroidism #	57	1	32	0
Vascular
Hypertension Þ	56	29	43	20
Hemorrhagic events ß	27	5	26	4
Metabolism
Decreased appetite à	41	4	31	1
Skin and Subcutaneous Tissue
Rash è	37	5	17	1
Palmar-plantar erythrodysesthesia syndrome ð	29	4	38	4
Investigations
Weight loss	30	8	9	0.3
Respiratory, Thoracic and Mediastinal
Dysphonia	30	0	4	0
Renal and Urinary
Proteinuria ø	30	8	13	3
Acute kidney injury ý	21	5	16	2
Hepatobiliary
Hepatotoxicity £	25	9	21	5
Nervous System
Headache	23	1	16	1

Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDA with lenvatinib were myocardial infarction (3%) and angina pectoris (1%).

Table 38: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581
Laboratory Test *	KEYTRUDA200 mg every 3 weekswith Lenvatinib		Sunitinib 50 mg
Laboratory Test *	All Grades %†	Grade 3-4%†	All Grades%†	Grade 3-4%†
* With at least one Grade increase from baseline † Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients).
Chemistry
Hypertriglyceridemia	80	15	71	15
Hypercholesterolemia	64	5	43	1
Increased lipase	61	34	59	28
Increased creatinine	61	5	61	2
Increased amylase	59	17	41	9
Increased AST	58	7	57	3
Hyperglycemia	55	7	48	3
Increased ALT	52	7	49	4
Hyperkalemia	44	9	28	6
Hypoglycemia	44	2	27	1
Hyponatremia	41	12	28	9
Decreased albumin	34	0.3	22	0
Increased alkaline phosphatase	32	4	32	1
Hypocalcemia	30	2	22	1
Hypophosphatemia	29	7	50	8
Hypomagnesemia	25	2	15	3
Increased creatine phosphokinase	24	6	36	5
Hypermagnesemia	23	2	22	3
Hypercalcemia	21	1	11	1
Hematology
Lymphopenia	54	9	66	15
Thrombocytopenia	39	2	73	13
Anemia	38	3	66	8
Leukopenia	34	1	77	8
Neutropenia	31	4	72	16

Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3).

Adjuvant treatment of RCC

The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.14)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia.

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).

Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 39 and 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564.

Table 39: Selected * Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-564
Adverse Reaction	KEYTRUDA200 mg every 3 weeksn=488		Placebon=496
Adverse Reaction	All Grades †(%)	Grades 3-4(%)	All Grades(%)	Grades 3-4(%)
* Adverse reactions occurring at same or higher incidence than in placebo arm † Graded per NCI CTCAE v4.0 ‡ Includes arthralgia, back pain, myalgia, arthritis, pain in extremity, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort § Includes asthenia, fatigue ¶ Includes rash, rash maculo-papular, rash papular, skin exfoliation, lichen planus, rash erythematous, eczema, rash macular, dermatitis acneiform, dermatitis, rash pruritic, Stevens-Johnson Syndrome, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome # Includes diarrhea, colitis, enterocolitis, frequent bowel movements, enteritis Þ Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort, gastrointestinal pain ß Includes upper-airway cough syndrome, productive cough, cough à Includes tension headache, headache, sinus headache, migraine with aura è Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, transaminases increased, gamma-glutamyltransferase increased, bilirubin conjugated increased ð Includes acute kidney injury, blood creatinine increased, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic
Musculoskeletal and Connective Tissue
Musculoskeletal pain ‡	41	1.2	36	0.6
General
Fatigue §	40	1.2	31	0.2
Skin and Subcutaneous Tissue
Rash ¶	30	1.4	15	0.4
Pruritus	23	0.2	13	0
Gastrointestinal
Diarrhea #	27	2.7	23	0.2
Nausea	16	0.4	10	0
Abdominal pain Þ	11	0.4	13	0.2
Endocrine
Hypothyroidism	21	0.2	3.6	0
Hyperthyroidism	12	0.2	0.2	0
Respiratory, Thoracic and Mediastinal
Cough ß	17	0	12	0
Nervous System
Headache à	15	0.2	13	0
Hepatobiliary
Hepatotoxicity è	14	3.7	7	0.6
Renal and Urinary
Acute kidney injury ð	13	1.2	10	0.2

Table 40: Selected * Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-564
Laboratory Test †	KEYTRUDA200 mg every 3 weeks		Placebo
Laboratory Test †	All Grades ‡%	Grades 3-4%	All Grades%	Grades 3-4%
* Laboratory abnormalities occurring at same or higher incidence than placebo † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: KEYTRUDA n=228 and placebo n=254. ‡ Graded per NCI CTCAE v4.03
Chemistry
Increased glucose	48	8	45	4.5
Increased creatinine	40	1.1	28	0.2
Increased INR	27	0.9	20	0.8
Hyponatremia	21	3.3	13	1.9
Increased ALT	20	3.8	11	0.2
Hematology
Anemia	28	0.5	20	0.4

Endometrial Carcinoma

In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H.

The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.15)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325).

For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months).

Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.

Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%).

Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).

Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%).

Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775.

Table 41: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-775
	Endometrial Carcinoma (pMMR or not MSI-H)
Adverse Reaction	KEYTRUDA200 mg every 3 weeksand Lenvatinibn=342		Doxorubicin orPaclitaxeln=325
	All Grades *(%)	Grades 3-4(%)	All Grades *(%)	Grades 3-4(%)
* Graded per NCI CTCAE v4.03 † Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, secondary hypothyroidism ‡ Includes hypertension, blood pressure increased, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, blood pressure fluctuation § Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, melena, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, vessel puncture site bruise ¶ Includes fatigue, asthenia, malaise, lethargy # Includes diarrhea, gastroenteritis Þ Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration ß Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, epigastric discomfort à Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw è Includes decreased appetite, early satiety ð Includes proteinuria, protein urine present, hemoglobinuria ø Includes urinary tract infection, cystitis, pyelonephritis ý Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema £ Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, application site rash
Endocrine
Hypothyroidism †	67	0.9	0.9	0
Vascular
Hypertension ‡	67	39	6	2.5
Hemorrhagic events §	25	2.6	15	0.9
General
Fatigue ¶	58	11	54	6
Gastrointestinal
Diarrhea #	55	8	20	2.8
Nausea	49	2.9	47	1.5
Vomiting	37	2.3	21	2.2
Stomatitis Þ	35	2.6	26	1.2
Abdominal pain ß	34	2.6	21	1.2
Constipation	27	0	25	0.6
Musculoskeletal and Connective Tissue
Musculoskeletal disorders à	53	5	27	0.6
Metabolism
Decreased appetite è	44	7	21	0
Investigations
Weight loss	34	10	6	0.3
Renal and Urinary
Proteinuria ð	29	6	3.4	0.3
Infections
Urinary tract infection ø	31	5	13	1.2
Nervous System
Headache	26	0.6	9	0.3
Respiratory, Thoracic and Mediastinal
Dysphonia	22	0	0.6	0
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia ý	23	2.9	0.9	0
Rash £	20	2.3	4.9	0

Table 42: Laboratory Abnormalities Worsened from Baseline * Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775
	Endometrial Carcinoma (pMMR or not MSI-H)
Laboratory Test †	KEYTRUDA200 mg every 3 weeksand Lenvatinib		Doxorubicin orPaclitaxel
	All Grades ‡%	Grades 3-4%	All Grades ‡%	Grades 3-4%
* With at least one grade increase from baseline † Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). ‡ Graded per NCI CTCAE v4.03
Chemistry
Hypertriglyceridemia	70	6	45	1.7
Hypoalbuminemia	60	2.7	42	1.6
Increased aspartate aminotransferase	58	9	23	1.6
Hyperglycemia	58	8	45	4.4
Hypomagnesemia	53	6	32	3.8
Increased alanine aminotransferase	55	9	21	1.2
Hypercholesteremia	53	3.2	23	0.7
Hyponatremia	46	15	28	7
Increased alkaline phosphatase	43	4.7	18	0.9
Hypocalcemia	40	4.7	21	1.9
Increased lipase	36	14	13	3.9
Increased creatinine	35	4.7	18	1.9
Hypokalemia	34	10	24	5
Hypophosphatemia	26	8	17	3.2
Increased amylase	25	7	8	1
Hyperkalemia	23	2.4	12	1.2
Increased creatine kinase	19	3.7	7	0
Increased bilirubin	18	3.6	6	1.6
Hematology
Lymphopenia	50	16	65	20
Thrombocytopenia	50	8	30	4.7
Anemia	49	8	84	14
Leukopenia	43	3.5	83	43
Neutropenia	31	6	76	58

As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma

Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.15)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent.

TMB-H Cancer

The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.16)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

cSCC

Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.17)] , the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).

TNBC

Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC

The safety of KEYTRUDA in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC.

A total of 778 patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.18)].

The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).

Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction.

Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).

Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522.

Table 43: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522
Adverse Reaction	KEYTRUDA200 mg every 3 weekswith chemotherapy */KEYTRUDAn=778		Placebowith chemotherapy */Placebon=389
Adverse Reaction	All Grades †(%)	Grades 3-4(%)	All Grades †(%)	Grades 3-4(%)
* Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide † Graded per NCI CTCAE v4.0 ‡ Includes asthenia, fatigue § Includes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oral mucosal eruption, oral pain, stomatitis, tongue blistering, tongue ulceration ¶ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness # Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, incision site rash, injection site rash, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash rubelliform, skin exfoliation, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash Þ Includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy ß Includes cough, productive cough, upper-airway cough syndrome
General
Fatigue ‡	70	8	66	3.9
Pyrexia	28	1.3	19	0.3
Gastrointestinal
Nausea	67	3.7	66	1.8
Constipation	42	0	39	0.3
Diarrhea	41	3.2	34	1.8
Stomatitis §	34	2.7	29	1
Vomiting	31	2.7	28	1.5
Abdominal pain ¶	24	0.5	23	0.8
Skin and Subcutaneous Tissue
Alopecia	61	0	58	0
Rash #	52	5	41	0.5
Nervous System
Peripheral neuropathy Þ	41	3.3	42	2.3
Headache	30	0.5	29	1
Musculoskeletal and Connective Tissue
Arthralgia	29	0.5	31	0.3
Myalgia	20	0.5	19	0
Respiratory, Thoracic and Mediastinal
Cough ß	26	0.1	24	0
Metabolism and Nutrition
Decreased appetite	23	0.9	17	0.3
Psychiatric
Insomnia	21	0.5	19	0

Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522
Laboratory Test *	KEYTRUDA200 mg every 3 weekswith chemotherapy †/KEYTRUDA		Placebowith chemotherapy †/Placebo
Laboratory Test *	All Grades ‡%	Grades 3-4%	All Grades ‡%	Grades 3-4%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA in combination with chemotherapy followed by KEYTRUDA as a single agent (range: 759 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 378 to 389 patients). † Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide ‡ Graded per NCI CTCAE v4.0
Hematology
Anemia	97	22	96	19
Leukopenia	93	41	91	32
Neutropenia	88	62	89	62
Lymphopenia	80	28	74	22
Thrombocytopenia	58	11	57	9
Chemistry
Increased ALT	71	9	69	4.6
Increased AST	66	6	58	1.8
Hyperglycemia	65	5	62	2.8
Increased alkaline phosphatase	41	1	37	0.8
Hyponatremia	38	9	28	6
Hypoalbuminemia	36	1.2	30	1.5
Hypocalcemia	32	3.2	29	4.4
Hypokalemia	32	6	24	2.8
Hypophosphatemia	23	6	18	4.5
Hypercalcemia	21	3	24	3.4

Locally Recurrent Unresectable or Metastatic TNBC

The safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.18)]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.

The median duration of exposure to KEYTRUDA was 5.7 months (range: 1 day to 33.0 months).

Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%).

Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. Serious adverse reactions in ≥2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).

KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%).

Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355.

Table 45: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355
Adverse Reaction	KEYTRUDA200 mg every 3 weekswith chemotherapyn=596		Placebo every 3 weekswith chemotherapyn=281
Adverse Reaction	All Grades *(%)	Grades 3-4(%)	All Grades *(%)	Grades 3-4(%)
* Graded per NCI CTCAE v4.03 † Includes fatigue and asthenia ‡ Includes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash, rash erythematous, eyelid rash § Includes cough, productive cough, upper-airway cough syndrome ¶ Includes headache, migraine, tension headache
General
Fatigue †	48	5	49	4.3
Gastrointestinal
Nausea	44	1.7	47	1.8
Diarrhea	28	1.8	23	1.8
Constipation	28	0.5	27	0.4
Vomiting	26	2.7	22	3.2
Skin and Subcutaneous Tissue
Alopecia	34	0.8	35	1.1
Rash ‡	26	2	16	0
Respiratory, Thoracic and Mediastinal
Cough §	23	0	20	0.4
Metabolism and Nutrition
Decreased appetite	21	0.8	14	0.4
Nervous System
Headache ¶	20	0.7	23	0.7

Table 46: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355
Laboratory Test *	KEYTRUDA 200 mg every 3 weekswith chemotherapy		Placebo every 3 weekswith chemotherapy
Laboratory Test *	All Grades †%	Grades 3-4%	All Grades †%	Grades 3-4%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients). † Graded per NCI CTCAE v4.03
Hematology
Anemia	90	20	85	19
Leukopenia	85	39	86	39
Neutropenia	76	49	77	52
Lymphopenia	70	26	70	19
Thrombocytopenia	54	19	53	21
Chemistry
Increased ALT	60	11	58	8
Increased AST	57	9	55	6
Hyperglycemia	52	4.4	51	2.2
Hypoalbuminemia	37	2.2	32	2.2
Increased alkaline phosphatase	35	3.9	39	2.2
Hypocalcemia	29	3.3	27	1.8
Hyponatremia	28	5	26	6
Hypophosphatemia	21	7	18	4.8
Hypokalemia	20	4.4	18	4.0

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KEYTRUDA (Page 5 of 21)

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5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone

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