Keytruda Qlex

Description for Keytruda Qlex

KEYTRUDA QLEX is a fixed-combination drug product containing pembrolizumab and berahyaluronidase alfa.

Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.

Berahyaluronidase alfa is an endoglycosidase used to enhance dispersion and permeation, which facilitates delivery of increased volume of pembrolizumab that is co-administered subcutaneously. It is produced by mammalian CHO (Chinese Hamster Ovary) cells containing a DNA plasmid encoding a variant of human hyaluronidase PH20. It is a glycosylated protein with an approximate molecular weight of 49 kDa under nonreducing, deglycosylated conditions.

KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph) injection is a sterile, preservativefree, clear to slightly opalescent, colorless to slightly yellow solution supplied in single-dose vials for subcutaneous administration.

KEYTRUDA QLEX is supplied as two different configurations:

• Each KEYTRUDA QLEX 2.4 mL single-dose vial contains 395 mg of pembrolizumab and 4,800 units of berahyaluronidase alfa, and histidine (0.7 mg), histidine hydrochloride monohydrate (4.1 mg), methionine (3.6 mg), polysorbate 80 (0.5 mg), sucrose (168 mg), and Water for Injection, USP. The pH is 5.3-5.9.
• Each KEYTRUDA QLEX 4.8 mL single-dose vial contains 790 mg of pembrolizumab and 9,600 units of berahyaluronidase alfa, and histidine (1.4 mg), histidine hydrochloride monohydrate (8.2 mg), methionine (7.2 mg), polysorbate 80 (1 mg), sucrose (336 mg), and Water for Injection, USP. The pH is 5.3-5.9.

ADVERSE REACTIONS

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

• Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)].
• Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.2)].

Clinical Trials Experience

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

The data described in the WARNINGS AND PRECAUTIONS reflect exposure to intravenous pembrolizumab as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA QLEX in combination with platinum doublet chemotherapy in a randomized, open-label, active-controlled trial (Study MK-3475A-D77), which enrolled 251 patients with NSCLC; intravenous pembrolizumab as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC; a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, patients were administered either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks or intravenous pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Among the 2799 patients who received intravenous pembrolizumab, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

The most common adverse reactions (≥ 20%) in patients who received KEYTRUDA QLEX in combination with chemotherapy were nausea (25%), fatigue (25%), and musculoskeletal pain (21%).

The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines.

The most common adverse reactions (≥ 20%) in patients who received intravenous pembrolizumab were:

• as a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.
• in combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism.
• in combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite.
• in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
• in combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury.
• in combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection.

Adverse Reactions in Patients with NSCLC Treated with KEYTRUDA QLEX

The safety of KEYTRUDA QLEX compared to intravenous pembrolizumab in patients with previously untreated, metastatic NSCLC with no EGFR, ALK or ROS1 genomic tumor aberrations was evaluated in Study MK-3475A-D77 [see Clinical Studies (14.1)]. A total of 377 patients received either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks in combination with platinum doublet chemotherapy (n=251) or intravenous pembrolizumab 400 mg every 6 weeks in combination with platinum doublet chemotherapy (n=126).

Among patients who received KEYTRUDA QLEX, 58% were exposed for 6 months or longer and 3.2% were exposed for greater than one year.

The median age of patients who received KEYTRUDA QLEX was 65 years (range: 39 to 87); 73% male, 63% White; 29% Asian, 4.8% multiple races, 2% Black or African American, 0.8% Alaska Native or American Indian; and 29% were of Hispanic or Latino ethnicity.

Serious adverse reactions occurred in 39% of patients who received KEYTRUDA QLEX in combination with chemotherapy. Serious adverse reactions in ≥ 1% of patients who received KEYTRUDA QLEX were pneumonia (10%), thrombocytopenia (4%), febrile neutropenia (4%), neutropenia (2.8%), musculoskeletal pain (2%), pneumonitis (2%), diarrhea (1.6%), rash (1.2%), respiratory failure (1.2%), and anemia (1.2%). Fatal adverse reactions occurred in 10% of patients who received KEYTRUDA QLEX in combination with chemotherapy including pneumonia (3.2%), neutropenic sepsis (2%), death not otherwise specified (1.6%), respiratory failure (1.2%), parotitis (0.4%), pneumonitis (0.4%), pneumothorax (0.4%), pulmonary embolism (0.4%), neutropenic colitis (0.4%), and seizure (0.4%).

Permanent discontinuation of KEYTRUDA QLEX due to an adverse reaction occurred in 16% of patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥ 2% of patients included pneumonia and pneumonitis.

Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase.

Tables 4 and 5 summarize the adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA QLEX in Study MK-3475A-D77.

Table 4: Adverse Reactions Occurring in ≥ 10% of Patients with Metastatic NSCLC
Receiving KEYTRUDA QLEX in Study MK-3475A-D77

Adverse Reaction	KEYTRUDA QLEX and Platinum Doublet Chemotherapy (n=251)		Intravenous Pembrolizumab and Platinum Doublet Chemotherapy (n=126)
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
Gastrointestinal
Nausea	25	1.2	25	0.8
Diarrhea†	16	2	14	0.8
Constipation	14	0	18	1.6
General
Fatigue‡	25	3.6	26	3.2
Musculoskeletal and Connective Tissue
Musculoskeletal pain§	21	2.4	30	2.4
Skin and Subcutaneous Tissue
Rash¶	18	2	19	0.8
Pruritus	12	0	13	0.8
Endocrine
Hypothyroidism	14	0	12	0
Infections
Pneumonia#	17	10	16	7
Nervous System
Peripheral neuropathyþ	11	0.4	14	0
Metabolism and Nutrition
Decreased appetite	11	0.8	21	2.4
Hyperglycemia	11	0.8	11	0.8
Respiratory, Thoracic and Mediastinal
Coughβ	10	0	11	0.8
*    Graded per NCI CTCAE V5.0 †    Includes diarrhea, colitis, and enterocolitis. ‡    Includes fatigue, asthenia. §    Includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, non-cardiac chest pain, and pain in extremity. ¶    Includes rash, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, eczema, erythema multiforme, immune-mediated dermatitis, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin exfoliation. #   Includes pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung abscess, pneumocystis jirovecii pneumonia, pneumonia bacterial, and pneumonia mycoplasmal. þ    Includes neuropathy peripheral, hypoaesthesia, neuralgia, paraesthesia, and peripheral sensory neuropathy. β    Includes cough, productive cough, and upper-airway cough syndrome.

Clinically relevant adverse reactions in < 10% of patients who received KEYTRUDA QLEX included local injection site reactions (2.4%).

Table 5: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients with
Metastatic NSCLC Receiving KEYTRUDA QLEX in Study MK-3475A-D77

Laboratory Test*	KEYTRUDA QLEX and Platinum Doublet Chemotherapy		Intravenous Pembrolizumab and Platinum Doublet Chemotherapy
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
Hematology
Anemia	80	22	86	26
Leukopenia	61	13	52	10
Neutropenia	58	28	49	19
Lymphopenia	55	22	54	18
Thrombocytopenia	43	11	41	6
Chemistry
Increased AST	43	2.5	38	3.2
Hypoalbuminemia	38	0.4	39	0
Increased ALT	37	2.1	36	0.8
Hyponatremia	35	4.1	42	7
Increased creatinine	33	4.5	38	6
Hypocalcemia	31	2.1	31	2.4
Increased alkaline phosphatase	29	0.4	34	0
Hypokalemia	21	5	24	6
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA QLEX plus platinum doublet chemotherapy (range: 240 to 246 patients) and intravenous pembrolizumab plus platinum doublet chemotherapy (range: 124 to 125 patients). †    Graded per NCI CTCAE V5.0

Adverse Reactions in Adult and Pediatric Patients Treated with Intravenous Pembrolizumab

The safety of KEYTRUDA QLEX for its approved indications [see Indications and Usage (1)] has been established in adequate and well-controlled studies of KEYTRUDA QLEX in combination with platinum doublet chemotherapy (Study MK-3475A-D77) and intravenous pembrolizumab, as a single agent or in combination therapy, across tumor types.

Below is a description of adverse reactions of intravenous pembrolizumab in these adequate and well-controlled studies.

Melanoma

Ipilimumab-Naive Melanoma

The safety of intravenous pembrolizumab for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, activecontrolled trial where patients were randomized (1:1:1) and received intravenous pembrolizumab 10 mg/kg every 2 weeks (n=278) or intravenous pembrolizumab 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.2)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

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

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

In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both intravenous pembrolizumab arms. Adverse reactions leading to permanent discontinuation of intravenous pembrolizumab occurred in 9% of patients. Adverse reactions leading to discontinuation of intravenous pembrolizumab in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 21% of patients; the most common (≥ 1%) was diarrhea (2.5%). Tables 6 and 7 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-006.

Table 6: Selected* Adverse Reactions Occurring in ≥ 10% of Patients
Receiving Intravenous Pembrolizumab in KEYNOTE-006

Adverse Reaction	Intravenous Pembrolizumab 10 mg/kg every 2 or 3 weeks n=555		Ipilimumab n=256
	All Grades† (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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
*    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 maculopapular, rash papular, rash pruritic, and exfoliative rash. §    Includes skin hypopigmentation

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

Table 7: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of
Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-006

Laboratory Test†	Intravenous Pembrolizumab 10 mg/kg every 2 or 3 weeks		Ipilimumab
	All Grades‡ %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	45	4.2	45	3.8
Hypertriglyceridemia	43	2.6	31	1.1
Hyponatremia	28	4.6	26	7
Increased AST	27	2.6	25	2.5
Hypercholesterolemia	20	1.2	13	0
Hematology
Anemia	35	3.8	33	4.0
Lymphopenia	33	7	25	6
*    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 onstudy laboratory measurement available: intravenous pembrolizumab (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: intravenous pembrolizumab n=429 and ipilimumab n=183; hypercholesterolemia: intravenous pembrolizumab n=484 and ipilimumab n=205. ‡    Graded per NCI CTCAE v4.0

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

Ipilimumab-Refractory Melanoma

The safety of intravenous pembrolizumab in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (intravenous pembrolizumab dose), randomized (1:1:1), active-controlled trial in which 528 patients received intravenous pembrolizumab 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator’s choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.2)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

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

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

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both intravenous pembrolizumab arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving intravenous pembrolizumab; the most common (≥ 1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 14% of patients; the most common (≥ 1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-002.

Table 8: Selected* Adverse Reactions Occurring in ≥ 10% of Patients Receiving
Intravenous Pembrolizumab in KEYNOTE-002

Adverse Reaction	Intravenous Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks n=357		Chemotherapy† n=171
	All Grades‡ (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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
*    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

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

Table 9: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of
Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-002

Laboratory Test†	Intravenous Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks		Chemotherapy
	All Grades‡ %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	49	6	44	6
Hypoalbuminemia	37	1.9	33	0.6
Hyponatremia	37	7	24	3.8
Hypertriglyceridemia	33	0	32	0.9
Increased alkaline phosphatase	26	3.1	18	1.9
Increased AST	24	2.2	16	0.6
Decreased bicarbonate	22	0.4	13	0
Hypocalcemia	21	0.3	18	1.9
Increased ALT	21	1.8	16	0.6
*    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: intravenous pembrolizumab (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: intravenous pembrolizumab n=247 and chemotherapy n=116; decreased bicarbonate: intravenous pembrolizumab n=263 and chemotherapy n=123. ‡    Graded per NCI CTCAE v4.0

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

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma

Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.2)] treated with intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent.

Adjuvant Treatment of Stage III Resected Melanoma

The safety of intravenous pembrolizumab as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of intravenous pembrolizumab by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.2)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received intravenous pembrolizumab for 6 months or longer.

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

Two patients treated with intravenous pembrolizumab died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving intravenous pembrolizumab. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving intravenous pembrolizumab; the most common (≥ 1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 19% of patients; the most common (≥ 1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-054.

Table 10: Selected* Adverse Reactions Occurring in ≥ 10% of Patients Receiving
Intravenous Pembrolizumab in KEYNOTE-054

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks n=509		Placebo n=502
	All Grades† (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Gastrointestinal
Diarrhea	28	1.2	26	1.2
Nausea	17	0.2	15	0
Skin and Subcutaneous Tissue
Pruritus	19	0	12	0
Rash	13	0.2	9	0
Musculoskeletal and Connective Tissue
Arthralgia	16	1.2	14	0
Endocrine
Hypothyroidism	15	0	2.8	0
Hyperthyroidism	10	0.2	1.2	0
Respiratory, Thoracic and Mediastinal
Cough	14	0	11	0
General
Asthenia	11	0.2	8	0
Influenza like illness	11	0	8	0
Investigations
Weight loss	11	0	8	0
*    Adverse reactions occurring at same or higher incidence than in placebo arm †    Graded per NCI CTCAE v4.03

Table 11: Selected* Laboratory Abnormalities Worsened from Baseline
Occurring in ≥ 20% of Melanoma Patients Receiving Intravenous
Pembrolizumab in KEYNOTE-054

Laboratory Test†	Intravenous Pembrolizumab 200 mg every 3 weeks		Placebo
	All Grades‡ %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
Increased ALT	25	2.4	15	0.2
Increased AST	22	1.8	14	0.4
Hematology
Lymphopenia	22	1	15	1.2
*    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: intravenous pembrolizumab (range: 502 to 505 patients) and placebo (range: 491 to 497 patients). ‡    Graded per NCI CTCAE v4.03

NSCLC

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

The safety of intravenous pembrolizumab in combination with pemetrexed and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.3)]. A total of 607 patients received intravenous pembrolizumab 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by intravenous pembrolizumab and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

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

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

Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥ 2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-189.

Table 12: Adverse Reactions Occurring in ≥ 20% of Patients in KEYNOTE-189

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=405		Placebo Pemetrexed Platinum Chemotherapy n=202
	All Grades* (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Gastrointestinal
Nausea	56	3.5	52	3.5
Constipation	35	1.0	32	0.5
Diarrhea	31	5	21	3.0
Vomiting	24	3.7	23	3.0
General
Fatigue†	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
*    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.

Table 13: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients in KEYNOTE-189

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy		Placebo Pemetrexed Platinum Chemotherapy
	All Grades† %	Grades 3-4 %	All Grades %	Grades 3-4 %
Hematology
Anemia	85	17	81	18
Lymphopenia	65	22	64	25
Neutropenia	50	21	41	19
Thrombocytopenia	30	12	29	8
Chemistry
Hyperglycemia	63	9	60	7
Increased ALT	47	3.8	42	2.6
Increased AST	47	2.8	40	1.0
Hypoalbuminemia	39	2.8	39	1.1
Increased creatinine	37	4.2	25	1.0
Hyponatremia	32	7	23	6
Hypophosphatemia	30	10	28	14
Increased alkaline phosphatase	26	1.8	29	2.1
Hypocalcemia	24	2.8	17	0.5
Hyperkalemia	24	2.8	19	3.1
Hypokalemia	21	5	20	5
*    Each test incidence is based on the number of patients who had both baseline and at least one onstudy laboratory measurement available: intravenous pembrolizumab /pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). †    Graded per NCI CTCAE v4.03

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

The safety of intravenous pembrolizumab in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, doubleblind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.3)]. Safety data are available for the first 203 patients who received intravenous pembrolizumab and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

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

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

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

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

Previously Untreated NSCLC

The safety of intravenous pembrolizumab was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.3)]. Patients received intravenous pembrolizumab 200 mg every 3 weeks (n=636) or investigator’s choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

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

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

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

Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-042.

Table 14: Adverse Reactions Occurring in ≥ 10% of Patients in KEYNOTE-042

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks n=636		Chemotherapy n=615
	All Grades* (%)	Grades 3-5 (%)	All Grades (%)	Grades 3-5 (%)
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
*    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.

Table 15: Laboratory Abnormalities Worsened from
Baseline in ≥ 20% of Patients in KEYNOTE-042

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks		Chemotherapy
	All Grades† %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	52	4.7	51	5
Increased ALT	33	4.8	34	2.9
Hypoalbuminemia	33	2.2	29	1.0
Increased AST	31	3.6	32	1.7
Hyponatremia	31	9	32	8
Increased alkaline phosphatase	29	2.3	29	0.3
Hypocalcemia	25	2.5	19	0.7
Hyperkalemia	23	3.0	20	2.2
Increased prothrombin INR	21	2.0	15	2.9
Hypophosphatemia	20	4.7	17	4.3
Hematology
Anemia	43	4.4	79	19
Lymphopenia	30	7	42	13
*    Each test incidence is based on the number of patients who had both baseline and at least one onstudy laboratory measurement available: intravenous pembrolizumab (range: 598 to 610 patients) and chemotherapy (range: 585 to 598 patients); increased prothrombin INR: intravenous pembrolizumab n=203 and chemotherapy n=173. †    Graded per NCI CTCAE v4.03

Previously Treated NSCLC

The safety of intravenous pembrolizumab was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.3)]. A total of 991 patients received intravenous pembrolizumab 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/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 intravenous pembrolizumab 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to intravenous pembrolizumab 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to intravenous pembrolizumab 2 mg/kg in 31% of patients exposed to intravenous pembrolizumab for ≥ 6 months. In the intravenous pembrolizumab 10 mg/kg arm, 34% of patients were exposed to intravenous pembrolizumab for ≥ 6 months.

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

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving. The most common adverse events resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.8%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 23% of patients; the most common (≥ 1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-010.

Table 16: Selected* Adverse Reactions Occurring in ≥ 10% of Patients Receiving
Intravenous Pembrolizumab in KEYNOTE-010

Adverse Reaction	Intravenous Pembrolizumab 2 or 10 mg/kg every 3 weeks n=682		Docetaxel 75 mg/m2 every 3 weeks n=309
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
Metabolism and Nutrition
Decreased appetite	25	1.5	23	2.6
Respiratory, Thoracic and Mediastinal
Dyspnea	23	3.7	20	2.6
Cough	19	0.6	14	0
Gastrointestinal
Nausea	20	1.3	18	0.6
Constipation	15	0.6	12	0.6
Vomiting	13	0.9	10	0.6
Skin and Subcutaneous Tissue
Rash‡	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
*    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

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

Table 17: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of
NSCLC Patients Receiving Intravenous Pembrolizumab in KEYNOTE-010

Laboratory Test†	Intravenous Pembrolizumab 2 or 10 mg/kg every 3 weeks		Docetaxel 75 mg/m2 every 3 weeks
	All Grades‡ %	Grades 3-4 %	All Grades‡ %	Grades 3-4 %
Chemistry
Hyponatremia	32	8	27	2.9
Increased alkaline phosphatase	28	3.0	16	0.7
Increased AST	26	1.6	12	0.7
Increased ALT	22	2.7	9	0.4
Hypocalcemia	20	0.9	20	1.8
*    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: intravenous pembrolizumab (range: 631 to 638 patients) and docetaxel (range: 271 to 277 patients). ‡    Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥ 20% of patients receiving intravenous pembrolizumab were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (32% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

Neoadjuvant and Adjuvant Treatment of Resectable NSCLC

The safety of intravenous pembrolizumab in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with intravenous pembrolizumab as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.3)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible.

The median duration of exposure to intravenous pembrolizumab 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino.

Adverse reactions occurring in patients with resectable NSCLC receiving intravenous pembrolizumab in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous pembrolizumab in combination with chemotherapy.

Neoadjuvant Phase of KEYNOTE-671

A total of 396 patients received at least 1 dose of intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.

Serious adverse reactions occurred in 34% of patients who received intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥ 2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).

Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥ 1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).

Of the 396 intravenous pembrolizumab-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. The most frequent (≥ 1%) adverse reactions that led to cancellation of surgery in the intravenous pembrolizumab arm was interstitial lung disease (1%).

Of the 325 intravenous pembrolizumab-treated patients who received surgery, 3.1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions.

Of the 325 intravenous pembrolizumab-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions.

Adjuvant Phase of KEYNOTE-671

A total of 290 patients in the intravenous pembrolizumab arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment.

Of the patients who received single agent intravenous pembrolizumab as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant intravenous pembrolizumab due to an adverse reaction occurred in 12% of patients; the most frequent (≥ 1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous pembrolizumab were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%).

Adjuvant Treatment of Resected NSCLC

The safety of intravenous pembrolizumab as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected Stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.3)]. A total of 1161 patients received intravenous pembrolizumab 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis.

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

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

Malignant Pleural Mesothelioma (MPM)

First-line treatment of unresectable advanced or metastatic MPM with pemetrexed and platinum chemotherapy

The safety of intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy (either carboplatin or cisplatin) was investigated in KEYNOTE-483, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with previously untreated, unresectable advanced or metastatic MPM [see Clinical Studies (14.4)]. A total of 473 patients received intravenous pembrolizumab 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by intravenous pembrolizumab (n=241), or pemetrexed and platinum chemotherapy every 3 weeks for up to 6 cycles (n=232). Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible.

The median duration of exposure to intravenous pembrolizumab 200 mg every 3 weeks was 6.9 months (range: 1 day to 25.2 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥ 6 months.

Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy.

HNSCC

First-line treatment of metastatic or unresectable, recurrent HNSCC

The safety of intravenous pembrolizumab, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.5)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received intravenous pembrolizumab 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by intravenous pembrolizumab, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.

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

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

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

Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-048.

Table 18: Adverse Reactions Occurring in ≥ 10% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-048

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks n=300		Intravenous Pembrolizumab 200 mg every 3 weeks Platinum FU n=276		Cetuximab Platinum FU n=287
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
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
Pneumoniaþ	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 neuropathyβ	1	0	14	1.1	7	1
Musculoskeletal
Myalgiaà	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
*    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 β    Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia à    Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

Table 19: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab in KEYNOTE-048

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks		Intravenous Pembrolizumab 200 mg every 3 weeks Platinum FU		Cetuximab Platinum FU
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
Hematology
Lymphopenia	54	25	70	35	75	46
Anemia	52	7	89	29	79	20
Thrombocytopenia	12	3.8	73	18	76	18
Neutropenia	8	1.4	68	37	73	43
Chemistry
Hyperglycemia	47	3.8	54	6	65	4.7
Hyponatremia	46	18	55	20	59	20
Hypoalbuminemia	44	3.5	46	3.9	49	1.1
Increased AST	28	3.1	25	1.9	37	3.6
Increased ALT	25	2.1	22	1.5	38	1.8
Increased alkaline phosphatase	25	2.1	26	1.1	33	1.1
Hypercalcemia	22	4.5	16	4.2	13	2.5
Hypocalcemia	22	1.0	32	3.8	58	6
Hyperkalemia	21	2.8	28	4.2	29	4.6
Hypophosphatemia	20	5	34	12	49	20
Hypokalemia	19	5	33	12	47	15
Increased creatinine	17	1.0	36	2.3	27	2.1
Hypomagnesemia	15	0.4	40	1.7	76	9
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/chemotherapy (range: 240 to 267 patients), intravenous pembrolizumab (range: 245 to 292 patients), cetuximab/chemotherapy (range: 249 to 282 patients). †    Graded per NCI CTCAE v4.0

Previously treated recurrent or metastatic HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.5)], the median duration of exposure to intravenous pembrolizumab 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.

Intravenous pembrolizumab was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. 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 intravenous pembrolizumab 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)].

Urothelial Cancer

Patients with urothelial cancer in combination with enfortumab vedotin

The safety of intravenous pembrolizumab in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.6)]. A total of 440 patients received intravenous pembrolizumab 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received intravenous pembrolizumab and enfortumab vedotin, the median duration of exposure to intravenous pembrolizumab was 8.5 months (range: 9 days to 28.5 months).

Fatal adverse reactions occurred in 3.9% of patients treated with intravenous pembrolizumab in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin. Serious adverse reactions in ≥ 2% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).

Permanent discontinuation of intravenous pembrolizumab occurred in 27% of patients. The most common adverse reactions (≥ 2%) resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis/ILD (4.8%) and rash (3.4%).

Dose interruptions of intravenous pembrolizumab occurred in 61% of patients. The most common adverse reactions (≥ 2%) resulting in interruption of intravenous pembrolizumab were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%).

Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39.

Table 20: Adverse Reactions ≥ 20% (All Grades) in Patients Treated with Intravenous
Pembrolizumab in Combination with Enfortumab Vedotin in KEYNOTE-A39

Adverse Reaction	Intravenous Pembrolizumab in combination with Enfortumab Vedotin n=440		Chemotherapy n=433
	All Grades* %	Grades 3-4 %	All Grades* %	Grades 3-4 %
Skin and subcutaneous tissue disorders
Rash†	68	15	15	0
Pruritus	41	1.1	7	0
Alopecia	35	0.5	8	0.2
General disorders and administration site conditions
Fatigue†	51	6	57	7
Nervous system disorders
Peripheral neuropathy†	67	8	14	0
Dysgeusia	21	0	9	0
Metabolism and nutrition disorders
Decreased appetite	33	1.8	26	1.8
Gastrointestinal disorders
Diarrhea	38	4.5	16	1.4
Nausea	26	1.6	41	2.8
Constipation	26	0	34	0.7
Investigations
Weight loss	33	3.6	9	0.2
Eye disorders
Dry eye†	24	0	2.1	0
Infections and infestations
Urinary tract infection	21	5	19	8
*    Graded per NCI CTCAE v4.03 †    Includes multiple terms

Clinically relevant adverse reactions (< 20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%).

Table 21: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of
Patients in KEYNOTE-A39

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks and Enfortumab Vedotin		Chemotherapy
	All Grades† %	Grades 3-4 %	All Grades† %	Grades 3-4 %
Chemistry
Increased aspartate aminotransferase	75	4.6	39	3.3
Increased creatinine	71	3.2	68	2.6
Hyperglycemia	66	14	54	4.7
Increased alanine aminotransferase	59	5	49	3.3
Hyponatremia	46	13	47	13
Hypophosphatemia	44	9	36	9
Hypoalbuminemia	39	1.8	35	0.5
Hypokalemia	26	5	16	3.1
Hyperkalemia	24	1.4	36	4.0
Hypercalcemia	21	1.2	14	0.2
Hematology
Lymphopenia	58	15	59	17
Anemia	53	7	89	33
Neutropenia	30	9	80	50
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 407 to 439 patients) †    Graded per NCI CTCAE v4.03

Cisplatin-ineligible patients with urothelial cancer in combination with enfortumab vedotin

The safety of intravenous pembrolizumab in combination with enfortumab vedotin was investigated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer and who are not eligible for cisplatin-based chemotherapy [see Clinical Studies (14.6)]. A total of 121 patients received intravenous pembrolizumab 200 mg on Day 1, and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle. The median duration of exposure to intravenous pembrolizumab was 6.9 months (range 1 day to 29.6 months).

Fatal adverse reactions occurred in 5% of patients treated with intravenous pembrolizumab in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%).

Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab and enfortumab vedotin. Serious adverse reactions in ≥ 2% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%).

Permanent discontinuation of intravenous pembrolizumab occurred in 32% of patients. The most common adverse reactions (≥ 2%) resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%).

Dose interruptions of intravenous pembrolizumab occurred in 69% of patients. The most common adverse reactions (≥ 2%) resulting in interruption of intravenous pembrolizumab were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), lipase increased (5%), acute kidney injury (3.3%), ALT increased (2.5%), and COVID-19 (2.5%).

Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-869.

Table 22: Adverse Reactions Occurring in ≥ 20% of Patients Treated with Intravenous
Pembrolizumab in Combination with Enfortumab Vedotin in KEYNOTE-869

Adverse Reaction	KEYTRUDA QLEX and Platinum Doublet Chemotherapy (n=251)
	All Grades* %	Grades 3-4 %
Skin and subcutaneous tissue disorders
Rash†	71	21
Alopecia	52	0
Pruritus	40	3.3
Dry skin	21	0.8
Nervous system disorders
Peripheral neuropathy‡	65	3.3
Dysgeusia	35	0
Dizziness	23	0
General disorders and administration site conditions
Fatigue	60	11
Peripheral edema	26	0
Investigations
Weight loss	48	5
Gastrointestinal disorders
Diarrhea	45	7
Nausea	36	0.8
Constipation	27	0
Metabolism and nutrition disorders
Decreased appetite	38	0.8
Infections and infestations
Urinary tract infection	30	12
Eye disorders
Dry eye	25	0
Musculoskeletal and connective tissue disorders
Arthralgia	23	1.7
*    Graded per NCI CTCAE v4.03 †    Includes: blister, conjunctivitis, dermatitis, dermatitis bullous, dermatitis exfoliative generalized, erythema, erythema multiforme, exfoliative rash, palmar-plantar erythrodysesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, skin exfoliation, and stomatitis ‡    Includes: dysesthesia, hypoesthesia, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and gait disturbance

Clinically relevant adverse reactions (< 20%) include vomiting (19.8%), fever (18%), hypothyroidism (11%), pneumonitis/ILD (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%).

Table 23: Selected Laboratory Abnormalities Worsened from
Baseline Occurring in ≥ 20% of Patients in KEYNOTE-869

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks and Enfortumab Vedotin
	All Grades† %	Grades 3-4 %
Chemistry
Hyperglycemia	74	13
Increased aspartate aminotransferase	73	9
Increased creatinine	69	3.3
Hyponatremia	60	19
Increased alanine aminotransferase	60	7
Increased lipase	59	32
Hypoalbuminemia	59	4.2
Hypophosphatemia	51	15
Hypokalemia	35	8
Increased potassium	27	1.7
Increased calcium	27	4.2
Hematology
Anemia	69	15
Lymphopenia	64	17
Neutropenia	32	12
*     Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 114 to 121 patients) †    Graded per NCI CTCAE v4.03

Platinum-Ineligible Patients with Urothelial Carcinoma

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.

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

Intravenous pembrolizumab 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 intravenous pembrolizumab experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of intravenous pembrolizumab 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 intravenous pembrolizumab in KEYNOTE-052.

Table 24: Adverse Reactions Occurring in ≥ 10% of Patients Receiving Intravenous Pembrolizumab
in KEYNOTE-052

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks N=370
	All Grades* (%)	Grades 3-4 (%)
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
Rashþ	21	0.5
Pruritus	19	0.3
Edema peripheralβ	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
*    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 β    Includes edema peripheral, peripheral swelling

Previously Treated Urothelial Carcinoma

The safety of intravenous pembrolizumab 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), activecontrolled trial in which 266 patients received intravenous pembrolizumab 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 intravenous pembrolizumab and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.

Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.9%). Adverse reactions leading to interruption of intravenous pembrolizumab 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 intravenous pembrolizumab-treated patients. The most frequent serious adverse reactions (≥ 2%) in intravenous pembrolizumab-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-045.

Table 25: Adverse Reactions Occurring in ≥ 10% of Patients Receiving Intravenous
Pembrolizumab in KEYNOTE-045

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks n=266		Chemotherapy n=255
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
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	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
Metabolism and Nutrition
Decreased appetite	21	3.8	21	1.2
Infections
Urinary tract infection	15	4.9	14	4.3
Respiratory, Thoracic and Mediastinal
Coughþ	15	0.4	9	0
Dyspneaß	14	1.9	12	1.2
Renal and Urinary
Hematuriaà	12	2.3	8	1.6
*    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

Table 26: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Urothelial
Carcinoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-045

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks		Chemotherapy
	All Grades† %	Grades 3-4 %	All Grades† %	Grades 3-4 %
Chemistry
Hyperglycemia	52	8	60	7
Anemia	52	13	68	18
Lymphopenia	45	15	55	26
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
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: intravenous pembrolizumab n=232 and chemotherapy n=222. †    Graded per NCI CTCAE v4.0

BCG-unresponsive High-risk NMIBC

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab was 4.3 months (range: 1 day to 25.6 months).

Intravenous pembrolizumab was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of intravenous pembrolizumab was pneumonitis (1.4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 22% of patients; the most common (≥ 2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of intravenous pembrolizumab-treated patients. The most frequent serious adverse reactions (≥ 2%) in intravenous pembrolizumab-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 intravenous pembrolizumab in KEYNOTE-057.

Table 27: Adverse Reactions Occurring in ≥ 10% of Patients Receiving Intravenous
Pembrolizumab in KEYNOTE-057

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks N=148
	All Grades* (%)	Grades 3-4 (%)
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
Coughþ	19	0
Infections
Urinary tract infection	12	2.0
Nasopharyngitis	10	0
Endocrine
Hypothyroidism	11	0
*    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

Table 28: Laboratory Abnormalities Worsened from Baseline Occurring in
≥ 20% of BCG-unresponsive NMIBC Patients Receiving Intravenous
Pembrolizumab in KEYNOTE-057

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks
	AAll Grades† (%)	Grades 3-4 (%)
Chemistry
Hyperglycemia	59	7
Increased ALT	25	2.7
Hyponatremia	24	7
Hypophosphatemia	24	6
Hypoalbuminemia	24	1.4
Hyperkalemia	23	1.4
Hypocalcemia	22	0.7
Increased AST	20	2.7
Increased creatinine	20	0.7
Hematology
Anemia	35	1.4
Lymphopenia	29	1.6
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 124 to 147 patients) †    Graded per NCI CTCAE v4.03

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

The safety of intravenous pembrolizumab was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.7)]. The median duration of exposure to intravenous pembrolizumab was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received intravenous pembrolizumab as a single agent.

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 intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent.

Gastric Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma

The safety of intravenous pembrolizumab was evaluated in 696 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 350 patients treated with intravenous pembrolizumab 200 mg, trastuzumab, and CAPOX (n=297) or FP (n=53) every 3 weeks, compared to 346 patients treated with placebo, trastuzumab, and CAPOX (n=298) or FP (n=48) every 3 weeks [see Clinical Studies (14.10)].

The median duration of exposure to intravenous pembrolizumab was 9.2 months (range: 1 day to 33.6 months).

Fatal adverse reactions occurred in 3 patients who received intravenous pembrolizumab in combination with trastuzumab and CAPOX or FP and included pneumonitis in 2 patients and hepatitis in 1 patient.

Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. Adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab in ≥ 1% of patients were pneumonitis (2.0%) and pneumonia (1.1%).

Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 71% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥ 2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (7%), pneumonia (5%), anemia (4.9%), COVID-19 (3.1%), hypokalemia (3.1%), fatigue/asthenia (4.9%), decreased appetite (4%), increased AST (3.7%), increased blood bilirubin (4.6%), increased ALT (2.9%), vomiting (2.6%), pneumonitis (2.3%), pyrexia (2.3%), increased blood creatinine (2%), and colitis (2%).

In the intravenous pembrolizumab arm versus placebo, there was a difference of ≥ 5% incidence between patients treated with intravenous pembrolizumab versus standard of care for diarrhea (53% vs. 47%), rash (35% vs. 28%), hypothyroidism (11% vs. 5%), and pneumonia (11% vs. 5%). 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 intravenous pembrolizumab versus standard of care for decreased leukocytes (60% vs. 54%), decreased calcium (56% vs. 46%), decreased lymphocytes (59% vs. 51%), decreased potassium (41% vs. 36%), increased bilirubin (33% vs. 25%), increased creatinine (28% vs. 18%), and decreased glucose (17% vs. 11%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma

The safety of intravenous pembrolizumab was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with intravenous pembrolizumab 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.9)].

The median duration of exposure to intravenous pembrolizumab was 6.2 months (range: 1 day to 33.7 months).

Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received intravenous pembrolizumab, including infection (2.3%) and thromboembolism (1.3%).

Permanent discontinuation of intravenous pembrolizumab due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab in ≥ 1% were infections (1.8%) and diarrhea (1.0%).

Dosage interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥ 2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%).

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-859.

Table 29: Adverse Reactions Occurring in ≥ 20% of Patients Receiving Intravenous Pembrolizumab
in KEYNOTE-859

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks and FP or CAPOX n=785		Placebo and FP or CAPOX n=787
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
Nervous System
Peripheral neuropathy†	47	5	48	6
Gastrointestinal
Nausea	46	3.7	46	4.4
Diarrhea	36	6	32	5
Vomiting	34	5	27	5
Abdominal Pain‡	26	2.8	24	2.9
Constipation	22	0.5	21	0.8
General
Fatigue§	40	8	39	9
Metabolism and Nutrition
Decreased appetite	29	3.3	29	2.5
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia syndrome	25	3.1	22	1.8
Investigations
Weight loss	20	2.8	19	2.7
*    Graded per NCI CTCAE v4.03 †    Includes dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy ‡    Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal tenderness, abdominal pain upper, epigastric discomfort, gastrointestinal pain §    Includes asthenia, fatigue

Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab in KEYNOTE-859

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks and FP or CAPOX		Placebo and FP or CAPOX
	All Grades† %	Grades 3-4 %	All Grades† %	Grades 3-4 %
Hematology
Anemia	65	15	69	13
Thrombocytopenia	64	12	62	10
Neutropenia	63	25	58	20
Leukopenia	59	7	56	6
Lymphopenia	57	20	51	16
Chemistry
Increased AST	57	4.7	48	3.6
Hypoalbuminemia	55	4.1	52	2.9
Hyperglycemia	53	6	52	4.6
Hypocalcemia	49	3.6	45	3.3
Increased alkaline phosphatase	48	6	41	5
Hyponatremia	40	13	40	12
Increased ALT	40	4.2	29	2.9
Hypokalemia	35	10	27	9
Bilirubin increased	32	5	30	5
Hypophosphatemia	30	10	27	8
Hypomagnesemia	29	0.3	22	0.7
Increased creatinine	21	3.5	18	1.7
Hyperkalemia	20	3.7	18	2.9
Increased INR	20	1.4	22	0
*    Each test incidence is based on the number of patients who had both baseline and at least one onstudy laboratory measurement available: intravenous pembrolizumab/FP or CAPOX (range: 210 to 766 patients) and placebo/FP or CAPOX (range: 190 to 762 patients) †    Graded per NCI CTCAE v4.03

Esophageal Cancer

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

The safety of intravenous pembrolizumab, 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 intravenous pembrolizumab 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 intravenous pembrolizumab combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm.

Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥ 1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 67% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥ 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 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-590.

Table 31: Adverse Reactions Occurring in ≥ 20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-590

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks Cisplatin FU n=370		Placebo Cisplatin FU n=370
	All Grades* (%)	Grades 3-4† (%)	All Grades* (%)	Grades 3-4† (%)
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	9
Investigations
Weight loss	24	3.0	24	5
*    Graded per NCI CTCAE v4.03 †    One fatal event of diarrhea was reported in each arm. ‡    Includes asthenia, fatigue

Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Esophageal
Cancer Patients Receiving Intravenous Pembrolizumab in KEYNOTE-590

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks Cisplatin FU		Chemotherapy (Cisplatin and FU)
	All Grades† %	Grades 3-4 %	All Grades† %	Grades 3-4 %
Hematology
Anemia	84	21	87	25
Neutropenia	77	44	73	41
Leukopenia	73	21	73	17
Lymphopenia	57	23	53	18
Thrombocytopenia	43	5	46	8
Chemistry
Hyperglycemia	56	7	55	6
Hyponatremia	53	19	53	19
Hypoalbuminemia	53	2.8	52	2.3
Increased creatinine	45	2.5	42	2.5
Hypocalcemia	44	3.9	37	2
Hypophosphatemia	37	9	31	10
Hypokalemia	30	12	34	15
Increased alkaline phosphatase	29	1.9	29
Hyperkalemia	28	3.6	28	2.5
Increased AST	25	4.4	22	2.8
Increased ALT	23	3.6	18	1.7
*    Each test incidence is based on the number of patients who had both baseline and at least one onstudy laboratory measurement available: intravenous pembrolizumab/cisplatin/FU (range: 353 to 365 patients) and placebo/cisplatin/FU (range: 347 to 359 patients) †    Graded per NCI CTCAE v4.03

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 intravenous pembrolizumab, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent.

Cervical Cancer

FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy

The safety of intravenous pembrolizumab in combination with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18, a placebocontrolled, randomized (1:1), multicenter, double-blind trial including 597 patients with FIGO 2014 Stage III-IVA cervical cancer [see Clinical Studies (14.11)]. Two hundred ninety-four patients received intravenous pembrolizumab in combination with chemoradiotherapy and 303 patients received placebo in combination with chemoradiotherapy.

The median duration of exposure to intravenous pembrolizumab was 20 months (range: 1 day to 32 months).

Fatal adverse reactions occurred in 1.4% of patients receiving intravenous pembrolizumab in combination with chemoradiotherapy, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage.

Serious adverse reactions occurred in 34% of patients receiving intravenous pembrolizumab in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥ 1% of patients included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%).

Intravenous pembrolizumab was discontinued for adverse reactions in 9% of patients. The most common adverse reaction (≥ 1%) resulting in permanent discontinuation was diarrhea (1%).

Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 47% of patients; the most common adverse reactions leading to interruption of intravenous pembrolizumab (≥ 2%) were anemia (7%), COVID-19 (7%), SARS-CoV-2 test positive (4.8%), diarrhea (4.1%), increased ALT (4.1%), increased AST (3.4%) decreased neutrophil count (3.1%), and urinary tract infection (2.7%).

Table 33 and Table 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-A18.

Table 33: Adverse Reactions Occurring in ≥ 10% of Patients with FIGO 2014 Stage III-IVA Cervical
Cancer Receiving Intravenous Pembrolizumab in KEYNOTE-A18

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy n=294		Placebo with chemoradiotherapy n=303
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
Gastrointestinal
Nausea	56	0	62	2.3
Diarrhea	51	4.4	50	4.3
Vomiting	34	1.0	35	1.7
Constipation	20	0	19	0.7
Abdominal pain	13	1.0	14	1.7
Infections
Urinary tract infection†	35	4.8	34	5
COVID-19	10	0	7	1.0
General
Fatigue‡	28	1.0	28	1.3
Pyrexia	14	0.7	15	0
Endocrine
Hypothyroidism§	23	0.7	8	0
Hyperthyroidism	13	0.3	3.3	0
Investigations
Weight loss	19	2.4	19	1.0
Metabolism and Nutrition
Decreased appetite	18	0.7	17	0.3
Renal and Urinary
Dysuria	12	0.3	12	0
Skin and Subcutaneous Tissue Disorders
Rash¶	12	1.0	8	0.3
Musculoskeletal and Connective Tissues Disorders
Back pain	11	0.7	11	0.7
Reproductive System
Pelvic pain	11	1.0	14	1.7
*    Graded per NCI CTCAE v5.0 †    Includes urinary tract infection, urinary tract infection pseudomonal, pyelonephritis acute, cystitis, Escherichia urinary tract infection ‡    Includes fatigue, asthenia §    Includes hypothyroidism, autoimmune hypothyroidism ¶    Includes erythema multiforme, dermatitis, drug eruption, eczema, rash, skin exfoliation, dermatitis bullous, rash maculo-papular, lichen planus, dyshidrotic eczema, dermatitis acneiform

Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients with
FIGO 2014 Stage III-IVA Cervical Cancer Receiving Intravenous Pembrolizumab in KEYNOTE-A18

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy		Placebo with chemoradiotherapy
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
Hematology
Lymphopenia	99	96	99	92
Leukopenia	96	48	94	49
Anemia	87	33	82	27
Neutropenia	76	33	76	33
Thrombocytopenia	64	9	62	7
Chemistry
Hypomagnesemia	61	4.2	63	3.7
Hyponatremia	56	4.8	50	4.7
Increased AST	50	1.7	44	2.3
Increased ALT	49	3.1	46	1
Hypocalcemia	45	5	43	5
Hypokalemia	44	15	41	11
Increased creatinine	44	7	46	6
Hypoalbuminemia	38	2.4	37	2.3
Increased alkaline phosphatase	38	0.3	35	0.3
Hyperkalemia	21	2.0	16	1
*    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: Intravenous pembrolizumab + chemoradiotherapy (range: 288 to 293 patients) and placebo + chemoradiotherapy (range: 299 to 301 patients) †    Graded per NCI CTCAE v5.0

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of intravenous pembrolizumab 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 radiosensitizing agent [see Clinical Studies (14.11)][see Clinical Studies (14.11)]. A total of 616 patients, regardless of tumor PD-L1 expression, received intravenous pembrolizumab 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 intravenous pembrolizumab was 9.9 months (range: 1 day to 26 months).

Fatal adverse reactions occurred in 4.6% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab 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%).

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

Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥ 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 intravenous pembrolizumab, 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 35 and Table 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-826.

Table 35: Adverse Reactions Occurring in ≥ 20% of Patients Receiving Intravenous Pembrolizumab
in KEYNOTE-826

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks and chemotherapy* with or without evacizumab n=307		Placebo and chemotherapy* with or without bevacizumab n=309
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
Nervous System
Peripheral neuropathy‡	58	4.2	57
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
*    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

Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab in KEYNOTE-826

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks and chemotherapy† with or without evacizumab n=307		Placebo and chemotherapy† with or without bevacizumab n=309
	All Grades‡ (%)	Grades 3-4 (%)	All Grades‡ (%)	Grades 3-4 (%)
Hematology
Anemia	80	35	77	33
Leukopenia	76	27	69	19
Neutropenia	73	43	62	32
Lymphopenia	64	35	59	35
Thrombocytopenia	57	19	53	15
Chemistry
Hyperglycemia	51	4.7	46	2.3
Hypoalbuminemia	46	1.4	37	5
Hyponatremia	39	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	4.1	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
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab plus chemotherapy (range: 296 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

y5

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 intravenous pembrolizumab was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving intravenous pembrolizumab. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 37 and 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-158.

Table 37: Adverse Reactions Occurring in ≥ 10% of Patients with Cervical
Cancer in KEYNOTE-158

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks N=98
	All Grades* (%)	Grades 3-4 (%)
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 painþ	22	3.1
Nausea	19	0
Vomiting	19	1.0
Constipation	14	0
Metabolism and Nutrition
Decreased appetite	21	0
Vascular
Hemorrhageß	19	5
Infections
UTIà	18	6
Infection (except UTI)è	16	4.1
Skin and Subcutaneous Tissue
Rashð	17	2.0
Endocrine
Hypothyroidism	11	0
Nervous System
Headache	11	2.0
Respiratory, Thoracic and Mediastinal
Dyspnea	10	1.0
*    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

Table 38: Laboratory Abnormalities Worsened from Baseline Occurring
in ≥ 20% of Patients with Cervical Cancer in KEYNOTE-158

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks
	All Grades† (%)	Grades 3-4 (%)
Hematology
Anemia	54	24
Lymphopenia	45	9
Chemistry
Hypoalbuminemia	44	5
Increased alkaline phosphatase	40	1.3
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
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 76 to 79 patients) †    Graded per NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥ 10% of patients receiving intravenous pembrolizumab were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (17% 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 (10% 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

Previously Treated HCC

The safety of intravenous pembrolizumab was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC. Patients were randomized (2:1) and received intravenous pembrolizumab 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.12)].

The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the intravenous pembrolizumab arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab was ascites (2.3%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥ 2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%).

Tables 39 and 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-394.

Table 39: Adverse Reactions Occurring in ≥ 10% of Patients with HCC Receiving Intravenous
Pembrolizumab in KEYNOTE-394

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks n=299		Placebo n=153
	All Grades* (%)	Grades 3-5 (%)	All Grades* (%)	Grades 3-5 (%)
General
Pyrexia	18	0.7	14	0
Skin and Subcutaneous Tissue
Rash†	18	0.7	7	0
Pruritus	12	0	4	0
Gastrointestinal
Diarrhea	16	1.7	9	0
Metabolism and Nutrition
Decreased appetite	15	0.3	9	0
Infections
Upper respiratory tract infection	11	1.0	7	0.7
Respiratory, Thoracic, and Mediastinal
Cough	11	0	9	0
Endocrine
Peripheral neuropathy‡Hypothyroidism	10	0	7	0
*    Graded per NCI CTCAE v4.03 †    Includes dermatitis, dermatitis allergic, dermatitis bullous, rash, rash erythematous, rash maculo-papular, rash pustular, and blister.

Table 40: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients with
HCC Receiving Intravenous Pembrolizumab in KEYNOTE-394

Laboratory Test*	Intravenous Pembrolizumab		Placebo
	All Grades† %	Grades 3-4 %	All Grades† %	Grades 3-4 %
Chemistry
Increased AST	54	14	44	12
Increased bilirubin	47	11	36	7
Increased ALT	47	7	32	4.6
Increased gamma-glutamyl transferase (GGT)	40	20	39	15
Hypoalbuminemia	40	0.7	20	0.7
Increased alkaline phosphatase	39	4.1	34	4
Hyperglycemia	36	3.3	26	1.4
Hyponatremia	36	11	28	5
Hypophosphatemia	30	6	17	4
Hypocalcemia	24	1.4	15	0.7
Hematology
Lymphopenia	44	11	34	4.6
Anemia	36	7	30	3.3
Decreased platelets	32	4.7	29	2
Leukopenia	30	1.3	21	0.7
Neutropenia	25	4.4	21	2
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 223 to 297 patients) and placebo (range: 144 to 151 patients). †    Graded per NCI CTCAE v4.03

BTC

The safety of intravenous pembrolizumab in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.13)]. A total of 1063 patients received either intravenous pembrolizumab 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks.

The median duration of exposure to intravenous pembrolizumab was 6 months (range: 1 day to 28 months).

Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab (≥ 1%) was pneumonitis (1.3%).

Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥ 2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).

In the intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥ 5% incidence in adverse reactions between patients treated with intravenous pembrolizumab versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of ≥ 5% incidence in laboratory abnormalities between patients treated with intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

MCC

Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.14)], the median duration of exposure to intravenous pembrolizumab was 6.3 months (range 1 day to 28 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 intravenous pembrolizumab as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).

RCC

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

The safety of intravenous pembrolizumab in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.15)]. 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib. Serious adverse reactions in ≥ 1% of patients receiving intravenous pembrolizumab 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 intravenous pembrolizumab or axitinib occurred in 31% of patients; 13% intravenous pembrolizumab only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (> 1%) resulting in permanent discontinuation of intravenous pembrolizumab, 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 intravenous pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving intravenous pembrolizumab in combination with axitinib. This includes interruption of intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with axitinib received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction.

Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with intravenous pembrolizumab and axitinib in KEYNOTE-426.

Table 41: Adverse Reactions Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab with Axitinib in KEYNOTE-426

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks and Axitinib n=429		Sunitinib n=425
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
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
*    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, druginduced 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

Table 42: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab with Axitinib in KEYNOTE-426

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks and Axitinib		Sunitinib
	All Grades† %	Grades 3-4 %	All Grades* %	Grades 3-4 %
Chemistry
Hyperglycemia	62	9	54	3.2
Increased ALT	60	20	44	5
Increased AST	57	13	56	5
Increased creatinine	43	4.3	40	2.4
Hyponatremia	35	8	29	8
Hyperkalemia	34	6	22	1.7
Hypoalbuminemia	32	0.5	34	1.7
Hypercalcemia	27	0.7	15	1.9
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	47	9
Anemia	29	2.1	65	8
Thrombocytopenia	27	1.4	78	14
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 421 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.

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

The safety of intravenous pembrolizumab was evaluated in KEYNOTE-581 [see Clinical Studies (14.15)]. Patients received intravenous pembrolizumab 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 intravenous pembrolizumab and lenvatinib was 17 months (range: 0.1 to 39).

Fatal adverse reactions occurred in 4.3% of patients treated with intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving intravenous pembrolizumab in combination with lenvatinib; 29% intravenous pembrolizumab only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥ 2%) resulting in permanent discontinuation of intravenous pembrolizumab, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions of intravenous pembrolizumab, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving intravenous pembrolizumab in combination with lenvatinib. Intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with lenvatinib received an oral prednisone equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction.

Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥ 20% of patients treated with intravenous pembrolizumab and lenvatinib in KEYNOTE-581.

Table 43: Adverse Reactions Occurring in ≥ 20% of Patients Receiving Intravenous Pembrolizumab
with Lenvatinib in KEYNOTE-581

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks with Lenvatinib N=352		Sunitinib 50 mg N=340
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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
Hypertensionþ	56	29	43	20
Hemorrhagic eventsß	27	5	26	4
Metabolism
Decreased appetiteà	41	4	31	1
Skin and Subcutaneous Tissue
Rashè	37	5	17	1
Palmar-plantar erythrodysesthesia syndromeð	29	4	38	4
Investigations
Weight loss	30	8	9	0.3
Respiratory, Thoracic and Mediastinal
Dysphonia	30	0	4	0
Renal and Urinary
Proteinuriaø	30	8	13	3
Acute kidney injuryý	21	5	16	2
Hepatobiliary
Hepatotoxicity£	25	9	21	5
Nervous System
Headache	23	1	16	1
*    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, elaena, 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

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

Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% (All Grades) of
Patients Receiving Intravenous Pembrolizumab with Lenvatinib in KEYNOTE-581

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks with Lenvatinib		Sunitinib 50 mg
	All Grades %†	Grades 3-4 %†	All Grades %†	Grades 3-4 %†
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
Hypophosphatemia	29	7	50	8
Hypomagnesemia	25	2	15	3
Increased creatine phosphokinase	24	6	36	5
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
*    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 postbaseline laboratory measurement for each parameter: intravenous pembrolizumab with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients).

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 intravenous pembrolizumab and lenvatinib (n=38) and was not observed on rechallenge with intravenous pembrolizumab alone (n=3).

Adjuvant treatment of RCC

The safety of intravenous pembrolizumab 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 intravenous pembrolizumab by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.15)]. The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab. 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 intravenous pembrolizumab, including one case of pneumonia.

Discontinuation of intravenous pembrolizumab 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 intravenous pembrolizumab 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 45 and 46 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-564.

Table 45: Selected* Adverse Reactions Occurring in ≥ 10% of Patients Receiving
Intravenous Pembrolizumab in KEYNOTE-564

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks n=488		Placebo n=496
	All Grades† (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
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 painþ	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
Headacheà	15	0.2	13	0
Hepatobiliary
Hepatotoxicityè	14	3.7	7	0
Renal and Urinary
Acute kidney injuryð	13	1.2	10	0.2
* 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

Table 46: Selected* Laboratory Abnormalities Worsened from Baseline
Occurring in ≥ 20% of Patients Receiving Intravenous Pembrolizumab in
KEYNOTE-564

Laboratory Test†	Intravenous Pembrolizumab 200 mg every 3 weeks		Placebo
	All Grades‡ %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	48	8	45	4.5
Increased creatinine	39	1.1	28	0.2
Increased INR	29	1.0	20	0.9
Hyponatremia	21	3.3	13	1.9
Increased ALT	20	3.6	11	0.2
Hematology
Anemia	28	0.5	20	0.4
*    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: intravenous pembrolizumab (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: intravenous pembrolizumab n=199 and placebo n=224. ‡    Graded per NCI CTCAE v4.03

Endometrial Carcinoma

Primary Advanced or Recurrent Endometrial Carcinoma

The safety of intravenous pembrolizumab in combination with chemotherapy (paclitaxel and carboplatin) was investigated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial that enrolled patients with advanced or recurrent endometrial carcinoma [see Clinical Studies (14.16)]. A total of 759 patients received intravenous pembrolizumab 200 mg every 3 weeks and chemotherapy for 6 cycles followed by intravenous pembrolizumab 400 mg every 6 weeks for up to 14 cycles (n=382) or placebo and chemotherapy for 6 cycles followed by placebo for up to 14 cycles (n=377). The median duration of exposure to intravenous pembrolizumab was 5.6 months (range: 1 day to 24.0 months).

Serious adverse reactions occurred in 35% of patients receiving intravenous pembrolizumab in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy.

Fatal adverse reactions occurred in 1.6% of patients receiving intravenous pembrolizumab in combination with chemotherapy, including COVID-19 (0.5%), and cardiac arrest (0.3%).

Intravenous pembrolizumab was discontinued for an adverse reaction in 14% of patients. Chemotherapy dose reduction was required in 29% of patients receiving intravenous pembrolizumab in combination with chemotherapy, compared to 23% of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms.

Adverse reactions occurring in patients treated with intravenous pembrolizumab and chemotherapy were generally similar to those observed with intravenous pembrolizumab alone or chemotherapy alone with the exception of rash (33% all Grades; 2.9% Grades 3-4).

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

The safety of intravenous pembrolizumab 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 (14.16)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab and lenvatinib. Serious adverse reactions (≥ 3%) were hypertension (4.4%) and urinary tract infections (3.2%).

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

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

Tables 47 and 48 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with lenvatinib in KEYNOTE-775.

Table 47: Adverse Reactions Occurring in ≥ 20% of Patients with Endometrial Carcinoma in
KEYNOTE-775

	Endometrial Carcinoma (pMMR or not MSI-H)
Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks and Lenvatinib n=342		Doxorubicin or Paclitaxel n=325
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
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
Stomatitisþ	35	2.6	26	1.2
Abdominal painß	34	2.6	21	1.2
Constipation	27	0	25	0.6
Musculoskeletal and Connective Tissue
Musculoskeletal disordersà	53	5	27	0.6
Metabolism
Decreased appetiteè	44	7	21	0
Investigations
Weight loss	34	10	6	0.3
Renal and Urinary
Proteinuriað	29	6	3.4	0.3
Infections
Urinary tract infectionø	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 erythrodysesthesiaý	23	2.9	0.9	0
Rash£	20	2.3	4.9	0
*    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 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

Table 48: 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†	Intravenous Pembrolizumab 200 mg every 3 weeks and Lenvatinib		Doxorubicin or Paclitaxel
	All Grades‡ %	Grades 3-4 %	All Grades‡ %	Grades 3-4 %
Chemistry
Hypertriglyceridemia	70	6	45	1.7
Increased aspartate aminotransferase	58	9	23	1.6
Hyperglycemia	58	8	45	4.4
Hypomagnesemia	46	0	27	1.3
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
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	51	18	66	23
Thrombocytopenia	50	8	30	4.7
Anemia	49	8	84	14
Leukopenia	43	3.5	83	43
*    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 postbaseline laboratory measurement for each parameter: intravenous pembrolizumab and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). ‡    Graded per NCI CTCAE v4.03

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 (14.16)] treated with intravenous pembrolizumab as a single agent, the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab as a single agent.

TMB-H Cancer

The safety of intravenous pembrolizumab was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.17)]. The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 (14.18)], the median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab 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 intravenous pembrolizumab in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with intravenous pembrolizumab 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 intravenous pembrolizumab arm received at least 1 dose of intravenous pembrolizumab in combination with neoadjuvant chemotherapy followed by intravenous pembrolizumab 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 (14.19)].

The median duration of exposure to intravenous pembrolizumab 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 intravenous pembrolizumab, 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 intravenous pembrolizumab. Serious adverse reactions in ≥ 2% of patients who received intravenous pembrolizumab included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥ 1%) resulting in permanent discontinuation of intravenous pembrolizumab were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 57% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥ 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 49 and 50 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-522.

Table 49: Adverse Reactions Occurring in ≥ 20% of Patients Receiving Intravenous Pembrolizumab
in KEYNOTE-522

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy*/ Intravenous Pembrolizumab n=778		Placebo with chemotherapy*/Placebo n=389
	All Grades† (%)	Grades 3-4 (%)	All Grades† (%)	Grades 3-4 (%)
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 neuropathyþ	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
Coughß	26	0.1	24	0
Metabolism and Nutrition
Decreased appetite	23	0.9	17	0.3
Psychiatric
Insomnia	21	0.5	19	0
*    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

Table 50: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of
Patients Receiving Intravenous Pembrolizumab in KEYNOTE-522

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy†/Intravenous Pembrolizumab		Placebo with chemotherapy†/Placebo
	All Grades? %	Grades 3-4 %	All Grades? %	Grades 3-4 %
Hematology
Anemia	97	22	96	19
Leukopenia	93	41	91	32
Neutropenia	88	62	89	62
Lymphopenia	79	28	74	22
Thrombocytopenia	57	10	56	8
Chemistry
Increased ALT	70	9	67	3.9
Increased AST	65	6	56	1.5
Hyperglycemia	63	4.3	61	2.8
Increased alkaline phosphatase	37	1	35	0.5
Hyponatremia	35	9	25	4.6
Hypoalbuminemia	34	1.0	30	1.3
Hypocalcemia	31	2.2	28	3.1
Hypokalemia	31	6	22	2.8
Hypophosphatemia	20	6	15	4.2
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab in combination with chemotherapy followed by intravenous pembrolizumab as a single agent (range: 762 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 381 to 389 patients). †    Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide ?    Graded per NCI CTCAE v4.0

Locally Recurrent Unresectable or Metastatic TNBC

The safety of intravenous pembrolizumab 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 (14.19)]. A total of 596 patients (including 34 patients from a safety run-in) received intravenous pembrolizumab 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin.

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

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

Serious adverse reactions occurred in 30% of patients receiving intravenous pembrolizumab 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%).

Intravenous pembrolizumab was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab (≥ 1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 50% of patients. The most common adverse reactions leading to interruption of intravenous pembrolizumab (≥ 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 51 and 52 summarize the adverse reactions and laboratory abnormalities in patients on intravenous pembrolizumab in KEYNOTE-355.

Table 51: Adverse Reactions Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab with Chemotherapy in KEYNOTE-355

Adverse Reaction	Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy n=596		Placebo every 3 weeks with chemotherapy n=281
	All Grades* (%)	Grades 3-4 (%)	All Grades* (%)	Grades 3-4 (%)
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
*    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 headache, migraine, tension headache

Table 52: Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 20% of Patients
Receiving Intravenous Pembrolizumab with Chemotherapy in KEYNOTE-355

Laboratory Test*	Intravenous Pembrolizumab 200 mg every 3 weeks with chemotherapy		Placebo every 3 weeks with chemotherapy
	All Grades† %	Grades 3-4 %	All Grades† %	Grades 3-4 %
Hematology
Anemia	90	20	85	19
Leukopenia	85	39	86	39
Neutropenia	78	50	79	53
Lymphopenia	73	28	71	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	36	2.0	32	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
*    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients). †    Graded per NCI CTCAE v4.03

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous pembrolizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal: Exocrine pancreatic insufficiency

Hepatobiliary: sclerosing cholangitis

Drug Interactions for Keytruda Qlex

No information provided.

Warnings for Keytruda Qlex

Included as part of the PRECAUTIONS section.

Precautions for Keytruda Qlex

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA QLEX is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immunemediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)]. In general, if KEYTRUDA QLEX requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

KEYTRUDA QLEX can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving intravenous pembrolizumab, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of intravenous pembrolizumab in 1.3% (36) of patients and withholding of intravenous pembrolizumab in 0.9% (26) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients.

In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received intravenous pembrolizumab as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of intravenous pembrolizumab in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted intravenous pembrolizumab, 63% discontinued intravenous pembrolizumab, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA QLEX can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%), and Grade 2 (0.4%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (< 0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of intravenous pembrolizumab in 0.5% (15) of patients and withholding of intravenous pembrolizumab in 0.5% (13) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA QLEX can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (< 0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of intravenous pembrolizumab in 0.2% (6) of patients and withholding of intravenous pembrolizumab in 0.3% (9) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients.

In Combination with Axitinib

KEYTRUDA QLEX in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA QLEX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA QLEX and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.4)].

Intravenous Pembrolizumab in Combination with Axitinib

With the combination of intravenous pembrolizumab and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥ 3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either intravenous pembrolizumab (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥ 3 times ULN was observed in 1 patient receiving intravenous pembrolizumab, 16 patients receiving axitinib, and 24 patients receiving both intravenous pembrolizumab and axitinib. All patients with a recurrence of ALT ≥ 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)].

Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%), and Grade 2 (0.8%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (< 0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of intravenous pembrolizumab in < 0.1% (1) of patients and withholding of intravenous pembrolizumab in 0.3% (8) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.

Hypophysitis

KEYTRUDA QLEX can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)].

Intravenous Pembrolizumab as a Single Agent

Hypophysitis occurred in 0.6% (17/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (< 0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of intravenous pembrolizumab in 0.1% (4) of patients and withholding of intravenous pembrolizumab in 0.3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.

Thyroid Disorders

KEYTRUDA QLEX can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)].

Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%).

Intravenous Pembrolizumab as a Single Agent

Thyroiditis occurred in 0.6% (16/2799) of patients receiving intravenous pembrolizumab, including Grade 2 (0.3%). No patients discontinued intravenous pembrolizumab due to thyroiditis. Intravenous pembrolizumab was withheld in < 0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of intravenous pembrolizumab in < 0.1% (2) of patients and withholding of intravenous pembrolizumab in 0.3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.

The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving intravenous pembrolizumab as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism.

Hypothyroidism occurred in 8% (237/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of intravenous pembrolizumab in < 0.1% (1) of patients and withholding of intravenous pembrolizumab in 0.5% (14) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement.

The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving intravenous pembrolizumab as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism.

The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving intravenous pembrolizumab as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)].

Type 1 diabetes mellitus occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy.

Intravenous Pembrolizumab as a Single Agent

Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving intravenous pembrolizumab.
Type 1 diabetes mellitus led to permanent discontinuation in < 0.1% (1) of patients and withholding of intravenous pembrolizumab in < 0.1% (1) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy.

Immune-Mediated Nephritis with Renal Dysfunction

KEYTRUDA QLEX can cause immune-mediated nephritis.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving intravenous pembrolizumab, including Grade 4 (< 0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of intravenous pembrolizumab in 0.1% (3) of patients and withholding of intravenous pembrolizumab in 0.1% (3) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA QLEX can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PDL1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA QLEX depending on severity [see Dosage and Administration (2.4)].

Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%), and Grade 3 (0.8%) adverse reactions.

Intravenous Pembrolizumab as a Single Agent

Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving intravenous pembrolizumab, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of intravenous pembrolizumab in 0.1% (2) of patients and withholding of intravenous pembrolizumab in 0.6% (16) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients who received KEYTRUDA QLEX, intravenous pembrolizumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis (2.8%), duodenitis.

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica

Endocrine: Hypoparathyroidism

Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection

Hypersensitivity and Administration-Related Reactions

KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. In Study MK-3475A-D77, hypersensitivity and administration-related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX, including Grade 2 (2.8%). Monitor patients for signs and symptoms of administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate hypersensitivity and administration-related systemic reactions. For severe or life-threatening hypersensitivity and administration-related systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX [see Dosage and Administration (2.4)].

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 steroidrequiring 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.

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

In two randomized trials in patients with multiple myeloma, the addition of intravenous pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PDL1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials.

Embryo-Fetal Toxicity

Based on its mechanism of action, KEYTRUDA QLEX can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA QLEX and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

KEYTRUDA QLEX contains pembrolizumab and berahyaluronidase alfa.

Pembrolizumab

No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity.

Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

Berahyaluronidase alfa

Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of berahyaluronidase alfa.

In a fertility and early embryonic development study, male and female rats were administered daily subcutaneous injections of 280,000, 840,000, or 2,520,000 U/kg berahyaluronidase alfa. Males were dosed for 9 weeks prior to mating and throughout mating to termination. Females were dosed for 2 weeks prior to mating, throughout mating, and up to gestation day 7. Although treatment with ≥ 840,000 U/kg berahyaluronidase alfa (> 5,200 times higher than the human dose) resulted in an increased incidence of abnormal sperm morphology, there were no adverse effects on mating, fertility or embryogenesis observed at doses up to 2,520,000 U/kg (> 15,000 times higher than the human dose).

Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-1/PD-L1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 and PD-L1 knockout mice and mice receiving PD-L1-blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.

OVERDOSAGE

No information provided.

Contraindications for Keytruda Qlex

KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients.

Clinical Pharmacology for Keytruda Qlex

Mechanism of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

In syngeneic mouse tumor models, combination treatment of a PD-1 blocking antibody and kinase inhibitor lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth compared to either treatment alone.

Berahyaluronidase alfa, an endoglycosidase, is a variant of human hyaluronidase PH20 that temporarily and locally breaks down hyaluronan. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan.

In the doses administered, the effects of berahyaluronidase alfa are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Pharmacodynamics

There are no clinically significant exposure-response relationships for efficacy or safety for intravenous pembrolizumab across the approved dosing regimens, regardless of cancer type. The exposures from subcutaneous KEYTRUDA QLEX doses of 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks are within the range of exposures from intravenous pembrolizumab doses.

Pharmacokinetics

Pembrolizumab pharmacokinetics were characterized at Cycle 1 and at steady state in patients with advanced solid tumors at the approved recommended dosages and are presented as mean (CV%) unless otherwise specified.

When comparing pembrolizumab exposure following subcutaneous administration every 6 weeks to that of intravenous administration every 6 weeks in Study MK-3475A-D77 [see Clinical Studies (14.1)], the geometric mean ratio (GMR) for Cycle 1 AUC_0-6wks was 1.14 (96% CI: 1.06, 1.22) and Cycle 3 C_trough (i.e., steady state) was 1.67 (94% CI: 1.52, 1.84).

Pembrolizumab steady state was reached by 16 weeks. At steady state following subcutaneous administration, the mean pembrolizumab AUC_0-6wks was 2,798 mcg•day/mL for the every 6 week dosing and pembrolizumab AUC_0-3wks was 1,343 mcg•day/mL for the every 3 week dosing. Pembrolizumab C_trough was 39 mcg/mL for the every 6 week dosing and 49 mcg/mL for the every 3 week dosing.

The systemic accumulation ratio was 1.6-fold following administration of KEYTRUDA QLEX
790 mg/9,600 units every 6 weeks and 2.5-fold following administration of KEYTRUDA QLEX
395 mg/4,800 units every 3 weeks.

Absorption

Pembrolizumab bioavailability (CV%) is approximately 60% (14%). Peak concentrations occurred by approximately 4 days.

Distribution

The volume of distribution is 6 L.

Elimination

Pembrolizumab clearance decreases over time, resulting in a steady state clearance (CV%) of - 195 mL/day (40%); this decrease in clearance with time is not considered clinically significant. The terminal half-life is 22 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of pembrolizumab were observed based on age (37 to 87 years), race (63% White, 28% Asian, 3% Black), sex, body weight (37 to 144 kg), tumor type, injection site (thigh or abdomen), estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m², and mild to moderate hepatic impairment (total bilirubin ≤ 3 times ULN and any AST). The effect of severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on pembrolizumab pharmacokinetics is unknown.

Pediatric Patients

Pembrolizumab exposures in pediatric patients 12 years and older who weigh greater than 40 kg are predicted to be within range of those observed in adult patients at the same dosage.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described in this section with the incidence of ADA in other studies, including those of KEYTRUDA QLEX or of other pembrolizumab products or berahyaluronidase alfa products.

With a median (min, max) duration of treatment on KEYTRUDA QLEX of 6.9 months (1 day, 1 year) in Study MK-3475A-D77, 1.4% (3/211) of patients developed anti-pembrolizumab antibodies, and one ADApositive patient developed neutralizing antibodies (NAb) against pembrolizumab. The incidence of antiberahyaluronidase alfa antibodies was 1.5% (3/194). No analysis of neutralizing antibodies was performed for berahyaluronidase alfa ADA-positive samples. Because of the low occurrence of antipembrolizumab or anti-berahyaluronidase antibodies, the effect of these antibodies on the pharmacokinetics, safety and effectiveness of KEYTRUDA QLEX is unknown.