The safety and effectiveness of YERVOY have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with nivolumab for unresectable or metastatic melanoma, in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults, and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy

[see

6.1 Clinical Trials Experience

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

The data described in the Warnings and Precautions section reflect exposure to YERVOY 3 mg/kg as a single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY 1 mg/kg administered with nivolumab 3 mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA.

Unresectable or Metastatic Melanoma

The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20

[seeClinical Studies (14.1)]

. Study MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients received YERVOY 3 mg/kg by intravenous infusion for 4 doses as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (n=380), or gp100 peptide vaccine as a single agent (n=132). Patients in the trial received a median of 4 doses (range: 1 to 4 doses).

The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% White, and baseline ECOG performance status 0 (56%).

YERVOY was discontinued for adverse reactions in 10% of patients. Table 4 presents adverse reactions from Study MDX010-20.

Table 4: Selected Adverse Reactions (≥5%) in Patients Receiving YERVOY with a Difference Between Arms of >5% for All Grades and >1% for Grades 3 to 5 Compared to gp100 Peptide Vaccine in Study MDX010-20
Adverse Reactions	YERVOY 3 mg/kg n=131		YERVOY 3 mg/kg and gp100 n=380		gp100 n=132
Adverse Reactions	All Grades (%)	Grade 3 to 5 (%)	All Grades (%)	Grade 3 to 5 (%)	All Grades (%)	Grade 3 to 5 (%)
General and Administration-Site Conditions
Fatigue	41	7	34	5	31	3
Gastrointestinal
Diarrhea	32	5	37	4	20	1
Colitis	8	5	5	3	2	0
Dermatologic
Pruritus	31	0	21	<1	11	0
Rash	29	2	25	2	8	0

Unresectable or Metastatic Melanoma: In Combination with Nivolumab

The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma

[seeClinical Studies (14.1)].

The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

Patients were randomized to receive:

•YERVOY 3 mg/kg by intravenous infusion over 90 minutes with nivolumab 1 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (YERVOY and nivolumab arm; n=313), or
•Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm; n=313), or
•YERVOY 3 mg/kg by intravenous infusion over 90 minutes every 3 weeks for up to 4 doses (YERVOY arm; n=311).

The median duration of exposure to nivolumab was 2.8 months (range: 1 day to 36.4 months) for the YERVOY and nivolumab arm. In the YERVOY and nivolumab arm, 39% were exposed to nivolumab for ≥6 months and 30% exposed for >1 year.

Serious adverse reactions (74%), adverse reactions leading to permanent discontinuation (47%) or to dosing delays (58%), and Grade 3 or 4 adverse reactions (72%) occurred in patients treated with YERVOY and nivolumab.

The most frequent (≥10%) serious adverse reactions in the YERVOY and nivolumab arm were diarrhea (13%), colitis (10%), and pyrexia (10%). The most frequent adverse reactions leading to discontinuation of both drugs in the YERVOY and nivolumab arm were colitis (10%), diarrhea (8%), increased ALT (4.8%), increased AST (4.5%), and pneumonitis (1.9%).

The most common (≥20%) adverse reactions in the YERVOY and nivolumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases.

Tables 5 and 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Table 5: Adverse Reactions Occurring in ≥10% of Patients on the YERVOY and Nivolumab Arm or the Nivolumab Arm and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
Toxicity was graded per NCI CTCAE v4. ^aIncludes asthenia and fatigue. ^bIncludes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash. ^cIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. ^dIncludes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. ^eIncludes hypertension and blood pressure increased.
Adverse Reaction	YERVOY and Nivolumab (n=313)		Nivolumab (n=313)		YERVOY (n=311)
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatigue^a	62	7	59	1.6	51	4.2
Pyrexia	40	1.6	16	0	18	0.6
Gastrointestinal
Diarrhea	54	11	36	5	47	7
Nausea	44	3.8	30	0.6	31	1.9
Vomiting	31	3.8	20	1.0	17	1.6
Skin and Subcutaneous Tissue
Rash^b	53	6	40	1.9	42	3.5
Vitiligo	9	0	10	0.3	5	0
Musculoskeletal and Connective Tissue
Musculoskeletal pain^c	32	2.6	42	3.8	36	1.9
Arthralgia	21	0.3	21	1.0	16	0.3
Metabolism and Nutrition
Decreased appetite	29	1.9	22	0	24	1.3
Respiratory, Thoracic and Mediastinal
Cough/productive cough	27	0.3	28	0.6	22	0
Dyspnea/exertional dyspnea	24	2.9	18	1.3	17	0.6
Infections
Upper respiratory tract infection^d	23	0	22	0.3	17	0
Endocrine
Hypothyroidism	19	0.6	11	0	5	0
Hyperthyroidism	11	1.3	6	0	1	0
Investigations
Decreased weight	12	0	7	0	7	0.3
Vascular
Hypertension^e	7	2.2	11	5	9	2.3

Clinically important adverse reactions in <10% of patients who received YERVOY with nivolumab:

Gastrointestinal Disorders:

stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders:

vitiligo

Musculoskeletal and Connective Tissue Disorders:

myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders:

neuritis, peroneal nerve palsy

Table 6: Laboratory Abnormalities Worsening from Baseline^aOccurring in ≥20% of Patients Treated with YERVOY with Nivolumab or Single-Agent Nivolumab and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab (range: 75 to 297); nivolumab (range: 81 to 306); YERVOY (range: 61 to 301)
Laboratory Abnormality	YERVOY and Nivolumab		Nivolumab		YERVOY
Laboratory Abnormality	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Chemistry
Increased ALT	55	16	25	3.0	29	2.7
Hyperglycemia	53	5	46	7	26	0
Increased AST	52	13	29	3.7	29	1.7
Hyponatremia	45	10	22	3.3	26	7
Increased lipase	43	22	32	12	24	7
Increased alkaline phosphatase	41	6	27	2.0	23	2.0
Hypocalcemia	31	1.1	15	0.7	20	0.7
Increased amylase	27	10	19	2.7	15	1.6
Increased creatinine	26	2.7	19	0.7	17	1.3
Hematology
Anemia	52	2.7	41	2.6	41	6
Lymphopenia	39	5	41	4.9	29	4.0

Adjuvant Treatment of Melanoma

The safety of YERVOY was evaluated in Study E1609, an open-label, multicenter, randomized trial for the adjuvant treatment of patients with completely resected node positive cutaneous melanoma

[seeClinical Studies (14.2)]

. Patients received YERVOY 3 mg/kg intravenously every 3 weeks for 4 doses followed by 3 mg/kg every 12 weeks for up to 4 additional doses, or high-dose interferon-α2b (HDI). Among patients who received YERVOY, 55% were exposed for 6 months or longer and 42% were exposed for greater than 1 year.

Fatal adverse reactions occurred in 1.4% of patients who received YERVOY, including gastric perforation (0.2%), and cardiac arrest (0.2%). Permanent discontinuation of YERVOY due to an adverse reaction occurred in 35% of patients.

The most common adverse reactions (≥20%) in the YERVOY arm were fatigue, diarrhea, rash, pruritus, nausea, and headache. Table 7 summarizes adverse reactions in E1609.

Table 7: Adverse Reactions (>10%) in Patients Receiving YERVOY 3 mg/kg in E1609
Adverse Reaction	YERVOY 3 mg/kg n=516		HDI n=520
Adverse Reaction	All Grades (%)	Grade 3 to 4 (%)	All Grades (%)	Grade 3 to 4 (%)
General disorders and administration site conditions
Fatigue	56	3	87	22
Decreased appetite	14	0.6	53	2.1
Pyrexia	10	0	31	0.8
Gastrointestinal
Diarrhea	49	10	34	0.8
Nausea	29	1.2	66	4.2
Abdominal Pain	19	1	9	0.4
Vomiting	11	0.6	26	2.3
Colitis	10	8	1	0.4
Dermatologic
Rash	46	4	18	1
Pruritus	41	2	15	0
Nervous System Disorders
Headache	25	2	45	3
Endocrine
Endocrine disorders, other	19	4.1	2	0
Hypothyroidism	11	0.6	10	0.2
Adrenal insufficiency	10	2	0.6	0

Other Clinical Experience

Across clinical studies in which patients received YERVOY as a single agent at doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence <1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Advanced Renal Cell Carcinoma: In Combination with Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214

[seeClinical Studies (14.3)]

. Patients received YERVOY 1 mg/kg with nivolumab 3 mg/kg intravenously every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg every 2 weeks (n=547) or sunitinib 50 mg orally daily for first 4 weeks of each 6-week cycle (n=535). The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in YERVOY and nivolumab arm. In this trial, 57% of patients in the YERVOY and nivolumab arm were exposed to treatment for greater than 6 months and 38% of patients were exposed to treatment for greater than 1 year.

Serious adverse reactions occurred in 59% of patients receiving YERVOY with nivolumab. The most frequent serious adverse reactions reported in ≥2% of patients treated with YERVOY and nivolumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis.

In patients who received YERVOY with nivolumab, study therapy was discontinued for adverse reactions in 31% and delayed for adverse reactions in 54%.

The most common adverse reactions (≥20%) in the YERVOY and nivolumab arm were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, vomiting, dyspnea, and decreased appetite. Table 8 summarizes adverse reactions in CHECKMATE-214.

Table 8: Adverse Reactions (>15%) in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214
Toxicity was graded per NCI CTCAE v4. ^aIncludes asthenia. ^bIncludes peripheral edema, peripheral swelling. ^cIncludes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. ^dIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
Adverse Reaction	YERVOY 1 mg/kg and Nivolumab n=547		Sunitinib n=535
Adverse Reaction	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
General and Administration Site Conditions
Fatigue^a	58	8	69	13
Pyrexia	25	0.7	17	0.6
Edema^b	16	0.5	17	0.6
Skin and Subcutaneous Tissue
Rash^c	39	3.7	25	1.1
Pruritus/generalized pruritus	33	0.5	11	0
Gastrointestinal
Diarrhea	38	4.6	58	6
Nausea	30	2.0	43	1.5
Vomiting	20	0.9	28	2.1
Abdominal pain	19	1.6	24	1.9
Constipation	17	0.4	18	0
Musculoskeletal and Connective Tissue
Musculoskeletal pain^d	37	4.0	40	2.6
Arthralgia	23	1.3	16	0
Respiratory, Thoracic, and Mediastinal
Cough/productive cough	28	0.2	25	0.4
Dyspnea/exertional dyspnea	20	2.4	21	2.1
Metabolism and Nutrition
Decreased appetite	21	1.8	29	0.9
Nervous System
Headache	19	0.9	23	0.9
Endocrine
Hypothyroidism	18	0.4	27	0.2

Table 9 summarizes the laboratory abnormalities in CHECKMATE-214.

Table 9: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: nivolumab and YERVOY group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).
Laboratory Abnormality	YERVOY 1 mg/kg and Nivolumab^a		Sunitinib^a
Laboratory Abnormality	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Chemistry
Increased lipase	48	20	51	20
Increased creatinine	42	2.1	46	1.7
Increased ALT	41	7	44	2.7
Increased AST	40	4.8	60	2.1
Increased amylase	39	12	33	7
Hyponatremia	39	10	36	7
Increased alkaline phosphatase	29	2.0	32	1.0
Hyperkalemia	29	2.4	28	2.9
Hypocalcemia	21	0.4	35	0.6
Hypomagnesemia	16	0.4	26	1.6
Hematology
Anemia	43	3.0	64	9
Lymphopenia	36	5	63	14

In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the YERVOY with nivolumab group compared to the sunitinib group (31% and 61%, respectively).

MSI-H or dMMR Metastatic Colorectal Cancer

Treatment of MSI -H or dMMR mCRC: In Combination with Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-8HW, a randomized, open-label, three arm trial in immunotherapy naïve patients with MSI-H or dMMR mCRC

[seeClinical Studies (14.4)]

. Patients received one of the following:

•YERVOY 1 mg/kg every 3 weeks and nivolumab 240 mg every 3 weeks for a maximum of 4 doses, then nivolumab 480 mg every 4 weeks.
•Nivolumab 240 mg every 2 weeks for 6 doses, then nivolumab 480 mg every 4 weeks.
•Investigator’s choice chemotherapy: mFOLFOX or FOLFIRI
[seeClinical Studies (14.4)]
.

In the YERVOY and nivolumab arm, the median duration of exposure to YERVOY was 2.1 months (range 1 day to 3.7 months); patients received a median of 4 doses (range 1-4). The median duration of treatment in the YERVOY and nivolumab arm was 20.5 months (range: 1 day to 35.9 months); 70% were exposed to treatment for >6 months, and 63% were exposed for >1 year. The median duration of treatment was 16.4 months (range: 1 day to 36 months) in the nivolumab-only arm; 64% were exposed to treatment for >6 months, and 54% were exposed for >1 year.

Serious adverse reactions occurred in 46% of patients receiving YERVOY in combination with nivolumab, and 39% of patients receiving nivolumab alone. The most frequent serious adverse reactions reported in ≥1% of patients who received YERVOY with nivolumab were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune-mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO, as a single agent, were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism (1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%).

Fatal adverse reactions occurred in 2 (0.6%) patients who received YERVOY in combination with nivolumab; these included myocarditis, and pneumonitis (1 each).

YERVOY and/or nivolumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1.4%), immune-mediated enterocolitis (1.1%), and pneumonitis (1.1%). Nivolumab was permanently discontinued in 13% of patients receiving single agent nivolumab. Adverse reactions leading to the delay of YERVOY and/or nivolumab occurred in 48% of patients receiving the combination; single agent nivolumab was delayed in 37% of patients due to adverse reactions.

The most common adverse reactions reported in ≥20% of patients treated with YERVOY in combination with nivolumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in ≥20% of patients treated with nivolumab as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.

Tables 10 and 11 summarize the adverse reactions and selected laboratory abnormalities, for YERVOY in combination with nivolumab and nivolumab arms respectively, in CHECKMATE-8HW.

Table 10: Adverse Reactions in ≥10% in Patient and a Difference Between Arms of >5% for All Grades in - CHECKMATE-8HW
Toxicity was graded per NCI CTCAE v5.
^aIncludes colitis, diarrhea, enterocolitis, immune-mediated enterocolitis
Adverse Reaction	YERVOY and Nivolumab (n=352)		Nivolumab (n=351)
Adverse Reaction	All Grades (%)	Grades 3 or 4 (%)	All Grades (%)	Grades 3 or 4 (%)
Gastrointestinal
Diarrheaa	35	4.5	30	3.4
Skin and Subcutaneous Tissue
Pruritus	30	0	23	0
Musculoskeletal and Connective Tissue
Arthralgia	20	0.6	15	0.6
Endocrine
Hypothyroidism	18	0.6	10	0
Hyperthyroidism	12	0	5	0

Table 11: Laboratory Values Worsening from Baseline^ain ≥10% of Patients and a Difference Between Arms of >5% for All Grades - CHECKMATE-8HW
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 108 to 343 patients) or nivolumab group (range: 102 to 348 patients).
Laboratory Abnormality^a	YERVOY and Nivolumab (n=352)		Nivolumab (n=351)
Laboratory Abnormality^a	All Grades (%)	Grades 3-or 4 (%)	All Grades (%)	Grades 3 or -4 (%)
Hematology
Lymphocytes decreased	30	5	37	4
Neutrophils decreased	21	1.7	12	0.6
Chemistry
Lipase increased	44	10	32	11
Amylase increased	41	4.6	33	5
ALT increased	39	3.5	32	1.4
AST increased	38	3.2	29	1.4
Sodium decreased	36	3.2	30	2.3
Creatinine increased	32	2	25	1.4
Potassium increased	29	1.2	35	0.9
Glucose decreased	17	0	12	0

Hepatocellular Carcinoma: In Combination with Nivolumab

Unresectable or Metastatic Hepatocellular Carcinoma (HCC)

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC

[seeClinical Studies (14.5)]

. Patients received YERVOY in combination with nivolumab (n=332) or investigator’s choice of lenvatinib (n=275) or sorafenib (n=50) at the following dosage:

•YERVOY 3 mg/kg administered intravenously over 30 minutes in combination with nivolumab 1 mg/kg administered intravenously over 30 minutes every 3 weeks, for a maximum of 4 doses, followed by single agent nivolumab at 480 mg administered intravenously over 30 minutes every 4 weeks, or
•Investigator’s choice:
- oLenvatinib 8 mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight ≥60 kg), or
- oSorafenib 400 mg orally twice daily

In the YERVOY and nivolumab arm, the median duration of exposure to nivolumab was 4.7 months (range: <0.1 to 24.4 months), 45% were exposed for >6 months and 30% were exposed for >1 year.

Serious adverse reactions occurred in 53% of patients treated with YERVOY in combination with nivolumab. The most frequent non-liver-related serious adverse reactions reported in ≥2% were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%).

Liver-related serious adverse reactions occurred in 17% of patients treated with YERVOY in combination with nivolumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in ≥1% of patients were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%).

Fatal adverse reactions occurred in 12 (3.6%) patients who received YERVOY in combination with nivolumab; these included 4 (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure.

Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated with YERVOY in combination with nivolumab. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), and hepatic failure (1.2%).

Dosage interruptions due to an adverse reaction occurred in 62% of patients treated with YERVOY in combination with nivolumab. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%).

The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea.

Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW.

Table 12: Adverse Reactions Occurring in ≥10% of YERVOY in combination with Nivolumab-Treated Patients - CHECKMATE-9DW
Toxicity was graded per NCI CTCAE v5
^aRepresents a composite of multiple related terms.
Adverse Reaction	YERVOY and Nivolumab (n=332)		Lenvatinib or Sorafenib (n=325)
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rash^a	36	3.6	15	1.2
Pruritus	34	1.5	7	0.3
General
Fatigue^a	33	2.4	39	4
Pyrexia^a	15	0.6	9	1.5
Edema^a	13	1.2	13	1.5
Gastrointestinal
Diarrhea	25	6	39	3.4
Abdominal pain^a	14	1.2	27	2.5
Nausea	10	0.3	16	0.9
Musculoskeletal and Connective Tissue
Musculoskeletal pain^a	17	0.6	23	0.3
Arthralgia	12	0.3	13	0.6
Metabolism and Nutrition
Decreased appetite	16	1.2	28	1.8
Endocrine
Hypothyroidism^a	14	0	27	0
Hyperthyroidism	11	0.6	1.5	0
Respiratory, Thoracic and Mediastinal
Cough^a	13	0	8	0

Clinically important adverse reactions reported in <10% of patients who received YERVOY with nivolumab were hyperglycemia (8%), adrenal insufficiency (4.2%), pneumonitis (2.7%), and pancreatitis (2.4%).

Table 13: Laboratory Values Worsening from Baselinea Occurring in ≥20% of YERVOY in combination with Nivolumab-Treated Patients - CHECKMATE-9DW
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 168 to 331 patients) and lenvatinib or sorafenib group (range: 145 to 315 patients).
Laboratory Abnormality	YERVOY and Nivolumab (n=332)		Lenvatinib or Sorafenib (n=325)
Laboratory Abnormality	Grades 1-4 (%)	Grades 3-4 (%)		Grades 1-4 (%)	Grades 3-4 (%)
Chemistry
Increased AST	62	29		51	14
Increased ALT	61	17		46	9
Increased lipase	58	16		39	5
Decreased albumin	48	0.9		57	0.6
Hyponatremia	45	6		42	3.8
Hyperglycemia	44	15		32	2.1
Increased bilirubin	44	10		44	8
Increased amylase	41	6		26	1
Increased alkaline phosphatase	36	1.2		38	5
Hypocalcemia	29	0.9		46	0
Increased creatinine	26	2.4		23	0.6
Hypokalemia	21	2.1		20	2.6
Hematology
Anemia	44	5		40	3.8
Lymphopenia	40	6.1		40	8
Thrombocytopenia	27	4		44	4.8
Neutropenia	24	4		32	3.5

Previously Treated Hepatocellular Carcinoma

The safety of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in a subgroup of 49 patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort 4 of CHECKMATE-040. YERVOY and nivolumab were administered every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.

During the YERVOY and nivolumab combination period, 33 of 49 (67%) patients received all four planned doses of YERVOY and nivolumab. During the entire treatment period, the median duration of exposure to YERVOY was 2.1 months (range: 0 to 4.5 months) and to nivolumab was 5.1 months (range: 0 to 35+ months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.

Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis.

Table 14 summarizes the adverse reactions and Table 15 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040.

Table 14: Adverse Reactions Occurring in ≥10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040
Adverse Reaction	YERVOY and Nivolumab (n=49)
	All Grades (%)	Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rash	53	8
Pruritus	53	4
Musculoskeletal and Connective Tissue
Musculoskeletal pain	41	2
Arthralgia	10	0
Gastrointestinal
Diarrhea	39	4
Abdominal pain	22	6
Nausea	20	0
Ascites	14	6
Constipation	14	0
Dry mouth	12	0
Dyspepsia	12	2
Vomiting	12	2
Stomatitis	10	0
Respiratory, Thoracic and Mediastinal
Cough	37	0
Dyspnea	14	0
Pneumonitis	10	2
Metabolism and Nutrition
Decreased appetite	35	2
General
Fatigue	27	2
Pyrexia	27	0
Malaise	18	2
Edema	16	2
Influenza-like illness	14	0
Chills	10	0
Nervous System
Headache	22	0
Dizziness	20	0
Endocrine
Hypothyroidism	20	0
Adrenal insufficiency	18	4
Investigations
Weight decreased	20	0
Psychiatric
Insomnia	18	0
Blood and Lymphatic System
Anemia	10	4
Infections
Influenza	10	2
Vascular
Hypotension	10	0

Clinically important adverse reactions reported in <10% of patients receiving YERVOY with nivolumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).

Table 15: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040
Laboratory Abnormality	YERVOY and Nivolumab (n=47)
	All Grades (%)	Grades 3-4 (%)
Hematology
Lymphopenia	53	13
Anemia	43	4.3
Neutropenia	43	9
Leukopenia	40	2.1
Thrombocytopenia	34	4.3
Chemistry
Increased AST	66	40
Increased ALT	66	21
Increased bilirubin	55	11
Increased lipase	51	26
Hyponatremia	49	32
Hypocalcemia	47	0
Increased alkaline phosphatase	40	4.3
Increased amylase	38	15
Hypokalemia	26	2.1
Hyperkalemia	23	4.3
Increased creatinine	21	0
Hypomagnesemia	11	0

In patients who received YERVOY with nivolumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.

First-line Treatment of Metastatic NSCLC: In Combination with Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations

[seeClinical Studies (14.6)]

. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received YERVOY 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks and nivolumab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received YERVOY and nivolumab for >6 months and 23% of patients received YERVOY and nivolumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.

Serious adverse reactions occurred in 58% of patients. YERVOY and nivolumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.

The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.

Tables 16 and 17 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Table 16: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-227
^aIncludes fatigue and asthenia. ^bIncludes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema. ^cIncludes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption. ^dIncludes pruritus and pruritus generalized. ^eIncludes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity. ^fIncludes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral. ^gIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. ^hIncludes dyspnea and dyspnea exertional. ⁱIncludes cough and productive cough. ^jIncludes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased. ^kIncludes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased. ^lContains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased. ^mIncludes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia.
Adverse Reaction	YERVOY and Nivolumab (n=576)		Platinum-Doublet Chemotherapy (n=570)
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatigue^a	44	6	42	4.4
Pyrexia	18	0.5	11	0.4
Edema^b	14	0.2	12	0.5
Skin and Subcutaneous Tissue
Rash^c	34	4.7	10	0.4
Pruritus^d	21	0.5	3.3	0
Metabolism and Nutrition
Decreased appetite	31	2.3	26	1.4
Musculoskeletal and Connective Tissue
Musculoskeletal pain^e	27	1.9	16	0.7
Arthralgia	13	0.9	2.5	0.2
Gastrointestinal
Diarrhea/colitis^f	26	3.6	16	0.9
Nausea	21	1.0	42	2.5
Constipation	18	0.3	27	0.5
Vomiting	13	1.0	18	2.3
Abdominal pain^g	10	0.2	9	0.7
Respiratory, Thoracic, and Mediastinal
Dyspnea^h	26	4.3	16	2.1
Coughⁱ	23	0.2	13	0
Hepatobiliary
Hepatitis^j	21	9	10	1.2
Endocrine
Hypothyroidism^k	16	0.5	1.2	0
Hyperthyroidism^l	10	0	0.5	0
Infections and Infestations
Pneumonia^m	13	7	8	4.0
Nervous System
Headache	11	0.5	6	0

Other clinically important adverse reactions in CHECKMATE-227 were:

Skin and Subcutaneous Tissue:

urticaria, alopecia, erythema multiforme, vitiligo

Gastrointestinal:

stomatitis, pancreatitis, gastritis

Musculoskeletal and Connective Tissue:

arthritis, polymyalgia rheumatica, rhabdomyolysis

Nervous System:

peripheral neuropathy, autoimmune encephalitis

Blood and Lymphatic System:

eosinophilia

Eye Disorders:

blurred vision, uveitis

Cardiac:

atrial fibrillation, myocarditis

Table 17: Laboratory Values Worsening from Baseline^aOccurring in ≥20% of Patients on YERVOY and Nivolumab - CHECKMATE-227
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients).
Laboratory Abnormality	YERVOY and Nivolumab		Platinum-doublet Chemotherapy
Laboratory Abnormality	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Hematology
Anemia	46	3.6	78	14
Lymphopenia	46	5	60	15
Chemistry
Hyponatremia	41	12	26	4.9
Increased AST	39	5	26	0.4
Increased ALT	36	7	27	0.7
Increased lipase	35	14	14	3.4
Increased alkaline phosphatase	34	3.8	20	0.2
Increased amylase	28	9	18	1.9
Hypocalcemia	28	1.7	17	1.3
Hyperkalemia	27	3.4	22	0.4
Increased creatinine	22	0.9	17	0.2

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Nivolumab and Platinum-Doublet Chemotherapy

The safety of YERVOY in combination with nivolumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA

[seeClinical Studies (14.6)]

. Patients received either YERVOY 1 mg/kg administered every 6 weeks in combination with nivolumab 360 mg administered every 3 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in YERVOY in combination with nivolumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received YERVOY and nivolumab for >6 months and 13% of patients received YERVOY and nivolumab for >1 year.

Serious adverse reactions occurred in 57% of patients who were treated with YERVOY in combination with nivolumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Study therapy with YERVOY in combination with nivolumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Tables 18 and 19 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Table 18: Adverse Reactions in >10% of Patients Receiving YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA
Toxicity was graded per NCI CTCAE v4. ^aIncludes fatigue and asthenia. ^bIncludes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis. ^cIncludes colitis, ulcerative colitis, diarrhea, and enterocolitis. ^dIncludes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain. ^eIncludes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blennorrhagica, palmar-plantar erythrodysesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria. ^fIncludes pruritus and generalized pruritus. ^gIncludes cough, productive cough, and upper-airway cough syndrome. ^hIncludes dyspnea, dyspnea at rest, and exertional dyspnea. ⁱIncludes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine. ^jIncludes dizziness, vertigo and positional vertigo
Adverse Reaction	YERVOY and Nivolumab and Platinum-Doublet Chemotherapy (n=358)		Platinum-Doublet Chemotherapy (n=349)
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatigue^a	49	5	40	4.9
Pyrexia	14	0.6	10	0.6
Musculoskeletal and Connective Tissue
Musculoskeletal pain^b	39	4.5	27	2.0
Gastrointestinal
Nausea	32	1.7	41	0.9
Diarrhea^c	31	6	18	1.7
Constipation	21	0.6	23	0.6
Vomiting	18	2.0	17	1.4
Abdominal pain^d	12	0.6	11	0.9
Skin and Subcutaneous Tissue
Rash^e	30	4.7	10	0.3
Pruritus^f	21	0.8	2.9	0
Alopecia	11	0.8	10	0.6
Metabolism and Nutrition
Decreased appetite	28	2.0	22	1.7
Respiratory, Thoracic and Mediastinal
Cough^g	19	0.6	15	0.9
Dyspnea^h	18	4.7	14	3.2
Endocrine
Hypothyroidismⁱ	19	0.3	3.4	0
Nervous System
Headache	11	0.6	7	0
Dizziness^j	11	0.6	6	0

Table 19: Laboratory Values Worsening from Baseline^aOccurring in >20% of Patients on YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).
Laboratory Abnormality	YERVOY and Nivolumab and Platinum-Doublet Chemotherapy		Platinum-Doublet Chemotherapy
Laboratory Abnormality	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Hematology
Anemia	70	9	74	16
Lymphopenia	41	6	40	11
Neutropenia	40	15	42	15
Leukopenia	36	10	40	9
Thrombocytopenia	23	4.3	24	5
Chemistry
Hyperglycemia	45	7	42	2.6
Hyponatremia	37	10	27	7
Increased ALT	34	4.3	24	1.2
Increased lipase	31	12	10	2.2
Increased alkaline phosphatase	31	1.2	26	0.3
Increased amylase	30	7	19	1.3
Increased AST	30	3.5	22	0.3
Hypomagnesemia	29	1.2	33	0.6
Hypocalcemia	26	1.4	22	1.8
Increased creatinine	26	1.2	23	0.6
Hyperkalemia	22	1.7	21	2.1

First-line Treatment of Unresectable Malignant Pleural Mesothelioma: In Combination with Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma

[seeClinical Studies (14.7)]

. Patients received either YERVOY 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks and nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received YERVOY and nivolumab for >6 months and 24% of patients received YERVOY and nivolumab for >1 year.

Serious adverse reactions occurred in 54% of patients who were treated with YERVOY in combination with nivolumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.

Both YERVOY and nivolumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. An additional 4.7% of patients permanently discontinued YERVOY alone due to adverse reactions.

The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.

Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.

Table 20: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-743
^aIncludes fatigue and asthenia. ^bIncludes pyrexia and tumor-associated fever. ^cIncludes edema, generalized edema, peripheral edema, and peripheral swelling. ^dIncludes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain. ^eIncludes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blennorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria. ^fIncludes pruritus, allergic pruritus, and generalized pruritus. ^gIncludes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis. ^hIncludes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain. ⁱIncludes dyspnea, dyspnea at rest, and exertional dyspnea. ^jIncludes cough, productive cough, and upper-airway cough syndrome. ^kIncludes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism. ^lIncludes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. ^mIncludes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia.
Adverse Reaction	YERVOY and Nivolumab (n=300)		Chemotherapy (n=284)
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatigue^a	43	4.3	45	6
Pyrexia^b	18	1.3	4.6	0.7
Edema^c	17	0	8	0
Musculoskeletal and Connective Tissue
Musculoskeletal pain^d	38	3.3	17	1.1
Arthralgia	13	1.0	1.1	0
Skin and Subcutaneous Tissue
Rash^e	34	2.7	11	0.4
Pruritus^f	21	1.0	1.4	0
Gastrointestinal
Diarrhea^g	32	6	12	1.1
Nausea	24	0.7	43	2.5
Constipation	19	0.3	30	0.7
Abdominal pain^h	15	1	10	0.7
Vomiting	14	0	18	2.1
Respiratory, Thoracic, and Mediastinal
Dyspneaⁱ	27	2.3	16	3.2
Cough^j	23	0.7	9	0
Metabolism and Nutrition
Decreased appetite	24	1.0	25	1.4
Endocrine
Hypothyroidism^k	15	0	1.4	0
Infections and Infestations
Upper respiratory tract infection^l	12	0.3	7	0
Pneumonia^m	10	4.0	4.2	2.1

Table 21: Laboratory Values Worsening from Baseline^aOccurring in ≥20% of Patients on YERVOY and Nivolumab - CHECKMATE-743
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).
Laboratory Abnormality	YERVOY and Nivolumab		Chemotherapy
Laboratory Abnormality	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
Chemistry
Hyperglycemia	53	3.7	34	1.1
Increased AST	38	7	17	0
Increased ALT	37	7	15	0.4
Increased lipase	34	13	9	0.8
Hyponatremia	32	8	21	2.9
Increased alkaline phosphatase	31	3.1	12	0
Hyperkalemia	30	4.1	16	0.7
Hypocalcemia	28	0	16	0
Increased amylase	26	5	13	0.9
Increased creatinine	20	0.3	20	0.4
Hematology
Lymphopenia	43	8	57	14
Anemia	43	2.4	75	15

First-line Treatment of Unresectable Advanced or Metastatic ESCC: In Combination with Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC

[seeClinical Studies (14.8)].

Patients received one of the following treatments:

•YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks.
•5-FU (fluorouracil) 800 mg/m²/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m²intravenously on day 1 (of a 4-week cycle).

Among patients who received YERVOY and nivolumab, the median duration of exposure was 2.8 months (range: 0 to 24 months).

Serious adverse reactions occurred in 69% of patients receiving YERVOY in combination with nivolumab.

The most frequent serious adverse reactions reported in ≥2% of patients who received YERVOY with nivolumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).

Fatal adverse reactions occurred in 5 (1.6%) patients who received YERVOY in combination with nivolumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.

YERVOY and/or nivolumab were discontinued in 23% of patients and delayed in 46% of patients for an adverse reaction.

The most common adverse reactions reported in ≥20% of patients treated with YERVOY in combination with nivolumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.

Tables 22 and 23 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.

Table 22: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-648
Adverse Reaction	YERVOY and Nivolumab (n=322)		Cisplatin and 5-FU (n=304)
Adverse Reaction	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
Toxicity was graded per NCI CTCAE v4. ^aIncludes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic. ^bIncludes tumor associated fever. ^cIncludes asthenia and malaise. ^dIncludes aphthous ulcer, mouth ulceration, and mucosal inflammation. ^eIncludes abdominal discomfort, abdominal pain lower, and abdominal pain upper. ^fIncludes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain. ^gIncludes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal. ^hIncludes productive cough.
Skin and Subcutaneous Tissue
Rash^a	31	3.1	7	0
Pruritis	17	0.9	3.6	0
General
Fatigue^c	28	2.5	41	4.9
Pyrexia^b	23	0.9	12	0.3
Gastrointestinal
Nausea	22	0.6	56	2.6
Diarrhea	22	1.9	20	2.0
Constipation	20	0.3	43	1.0
Vomiting	15	1.6	19	3.0
Dysphagia	12	5	12	4.9
Stomatitis^d	11	0.6	35	3.0
Abdominal pain^e	10	0.9	11	0.7
Metabolism and Nutrition
Decreased appetite	17	4.0	50	6
Musculoskeletal and Connective Tissue
Musculoskeletal pain^f	14	0.6	8	0.3
Infections and Infestations
Pneumonia^g	14	8	10	2.6
Endocrine
Hypothyroidism	14	0	0.3	0
Respiratory, Thoracic and Mediastinal
Cough^h	13	0.3	13	0.3
Investigations
Weight decreased	12	1.9	11	1.0

Table 23: Laboratory Values Worsening from Baseline^aOccurring in ≥10% of Patients on YERVOY and Nivolumab - CHECKMATE-648
Laboratory Abnormality	YERVOY and Nivolumab (n=322)		Cisplatin and 5-FU (n=304)
Laboratory Abnormality	Grades 1-4 (%)	Grades 3-4 (%)	Grades 1-4 (%)	Grades 3-4 (%)
^aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 59 to 307 patients) or Cisplatin and 5-FU group (range: 56 to 283 patients).
Hematology
Anemia	52	7	66	14
Lymphopenia	50	13	44	8
Neutropenia	13	1.3	48	13
Thrombocytopenia	12	1.0	29	2.8
Chemistry
Hyponatremia	45	11	40	8
Hyperglycemia	43	4.3	36	0.8
Increased AST	39	6	11	1.4
Increased ALT	33	6	8	0.7
Hypocalcemia	32	0	23	0.7
Increased alkaline phosphatase	31	3.3	15	0
Hyperkalemia	23	1.6	24	0.7
Hypokalemia	19	5	17	6
Hypercalcemia	15	2.0	8	0
Hypoglycemia	15	1.2	7	0
Increased creatinine	15	0.7	31	0.7
Hypomagnesemia	15	0	25	1.8

12.3 Pharmacokinetics

The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range of 0.3 mg/kg to 10 mg/kg. Following administration of YERVOY every 3 weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean minimum concentration (C_min) at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks.

Elimination

The mean (percent coefficient of variation) terminal half-life (t_1/2) was 15.4 days (34%) and then mean (percent coefficient of variation) clearance (CL) was 16.8 mL/h (38%).

The CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies.

Specific Populations

The CL of ipilimumab increased with increasing body weight supporting the recommended body weight (mg/kg) based dosing. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, performance status, renal impairment (glomerular filtration rate ≥15 mL/min/1.73 m²), mild hepatic impairment (total bilirubin [TB] >1 to 1.5 times the upper limit of normal [ULN] or AST > ULN), previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-White racial groups. YERVOY has not been studied in patients with moderate (TB >1.5 to 3 times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment.

Pediatric Patients

The exposures of ipilimumab in pediatric patients 12 years and older are comparable to those in adult patients at the recommended dosage.

Drug Interaction Studies

Ipilimumab with Nivolumab

When YERVOY 1 mg/kg was administered with nivolumab 3 mg/kg every 3 weeks, the CL of ipilimumab was unchanged compared to when YERVOY was administered alone.

When YERVOY 3 mg/kg every 3 weeks was administered in combination with nivolumab 1 mg/kg every 3 weeks, the CL of ipilimumab was unchanged compared to ipilimumab administered alone and the CL of nivolumab was increased by 29% compared to nivolumab administered alone.

When YERVOY 1 mg/kg every 6 weeks was administered in combination with nivolumab 3 mg/kg every 2 weeks, the CL of ipilimumab increased by 30% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.

When YERVOY 1 mg/kg every 6 weeks was administered in combination with nivolumab 360 mg every 3 weeks and chemotherapy, the CL of ipilimumab increased by 22% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.

14.4 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

Treatment of MSI-H or dMMR mCRC In Combination with Nivolumab

CHECKMATE-8HW (NCT03143153) was a randomized, 3-arm, open-label trial in immunotherapy-naive patients across all lines of therapy with unresectable or metastatic CRC with known tumor MSI-H or dMMR (MSI-H/dMMR) status as determined in accordance with local standard of practice using PCR, NGS or IHC, assays. Central assessment of MSI-H status using PCR (Idylla MSI) test and dMMR status using IHC (Omnis MMR) test was conducted retrospectively on patient tumor specimens used for local MSI-H/dMMR status determination. Patients with confirmed MSI-H/dMMR status by either central test comprised the primary study population.

The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or had been treated with checkpoint inhibitors.

Patients were randomized to receive one of the following treatments:

•YERVOY 1 mg/kg every 3 weeks and nivolumab 240 mg every 3 weeks for a maximum of 4 doses, then nivolumab 480 mg every 4 weeks
•Nivolumab 240 mg every 2 weeks for 6 doses, then nivolumab 480 mg every 4 weeks.
•Investigator’s choice chemotherapy
- omFOLFOX6 (oxaliplatin, leucovorin, and FU) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m², leucovorin 400 mg/m², and FU 400 mg/m²bolus followed by FU 2400 mg/m²over 46 hours every 2 weeks. Bevacizumab 5 mg/kg or cetuximab 500 mg/m²administered prior to mFOLFOX6 every 2 weeks.
- oFOLFIRI (irinotecan, leucovorin, and FU) with or without either bevacizumab or cetuximab: Irinotecan 180 mg/m², leucovorin 400 mg/m², and FU 400 mg/m²bolus and FU 2400 mg/m²over 46 hours every 2 weeks. Bevacizumab 5 mg/kg on or cetuximab 500 mg/m²administered prior to FOLFIRI every 2 weeks.

Randomization was stratified by tumor location (right vs left) and by prior lines of therapy (0, 1, 2L+). Patients randomized to the chemotherapy arm could receive YERVOY plus nivolumab combination upon progression assessed by BICR.

Study treatment was administered until disease progression, unacceptable toxicity, or for up to 2 years for patients who received YERVOY plus nivolumab or nivolumab monotherapy. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as a single agent. Nivolumab with or without YERVOY could be administered beyond RECIST 1.1-assessed progressive disease if there was a clinical benefit as determined by investigator and therapy was tolerated. Tumor assessments per RECIST v1.1 were conducted every 6 weeks for the first 24 weeks, then every 8 weeks thereafter up until week 96, then every 16 weeks thereafter up until week 144, and then every 24 weeks.

The evaluation of efficacy relied on the comparison of patients with centrally confirmed MSI-H/dMMR mCRC randomized to YERVOY in combination with nivolumab versus chemotherapy in the first-line (1L) setting and the comparison of patients with centrally confirmed MSI-H/dMMR mCRC randomized to YERVOY in combination with nivolumab vs nivolumab in all lines setting.

The major efficacy outcome measure was BICR-assessed PFS per RECIST 1.1. Additional efficacy measures included ORR and duration of response assessed by BICR and OS.

The baseline characteristics of the total of 839 patients randomized were: the median age was 63 years (range: 20 to 87), with 46% ≥65 years of age and 14% ≥75 years of age; 50% were male and 87% were White, 9.3% were Asian, 1.5% Black or African American, and 2.3% other race; 9.2% were Hispanic or Latino, 50% Not Hispanic or Latino, 41% ethnicity unknown. Baseline ECOG performance status was 0 (52%) and (48%); number of prior lines of therapy was 0 (56%) and 1 (24%), and ≥2 (19%); tumor location was right-sided or left-sided for 69% and 31% of patients. The baseline characteristics in patients with centrally confirmed MSI-H/dMMR is consistent with all randomized patients.

First Line YERVOY in combination with nivolumab

Among 303 patients in the first-line setting were randomly assigned to YERVOY in combination with nivolumab (202) and to chemotherapy (101), 171 and 84 patients had centrally confirmed MSI-H/dMMR status in YERVOY in combination with nivolumab arm and chemotherapy arm, respectively.

In the 1L setting, 200 of 202 patients assigned to receive YERVOY in combination with nivolumab and 88 of 101 patients assigned to received chemotherapy received at least 1 dose of study treatment. Among the 88 patients who received chemotherapy, 58% and 42% of patients received oxaliplatin-containing regimens and irinotecan-containing regimens, respectively, and 66 (75%) patients received a targeted agent, either bevacizumab (64%) or cetuximab (11%).

The BICR-assessed PFS efficacy results for patients with centrally confirmed MSI-H/dMMR randomized to the YERVOY and nivolumab arm compared with chemotherapy in the 1L setting are presented in Table 29 and Figure 5. The comparative results of ORR and OS between arms were not available at the time of the PFS analysis due to statistical testing strategy.

Table 29: Efficacy Results - CHECKMATE-8HW
NR: Not Reached; NE: Not Estimable.
Minimum follow-up was 6.1 months at data cutoff date 12Oct2023.
^aBased on log-rank test stratified by the same factors as used in the Cox proportional hazards model. The p-value threshold for statistical significance was 0.0209.
^bBased on Kaplan-Meier estimates.
^cHR from a Cox proportional hazards model stratified by tumor sidedness (left vs right) per IRT
	YERVOY and Nivolumab (n=171)	Chemotherapy (n=84)
Progression-free Survival
Disease progression or death (%)	48 (28)	52 (62)
Median in months^b(95% CI)	NR (38.4, NE)	5.8 (4.4, 7.8)
Hazard ratio^c(95% CI)	0.21 (0.14, 0.32)
p-value^a	<0.0001

Figure 5: Progression-free Survival, (First line YERVOY + nivolumab vs Chemotherapy)- CHECKMATE-8HW

All Lines YERVOY in combination with nivolumab

Among 707 patients across all treatment lines who were randomly assigned to YERVOY in combination with nivolumab (354) and to nivolumab (353) single agent, 296 and 286 patients had centrally confirmed MSI-H/dMMR status in the YERVOY in combination with nivolumab arm and in the nivolumab arm, respectively. Patients receiving at least 1 dose of study treatment included 352 of 354 patients randomized to OPDIVO in combination with ipilimumab, and 351 of 353 patients randomized to single agent OPDIVO.

The BICR-assessed PFS and ORR efficacy results for patients with centrally confirmed MSI-H/dMMR randomized to the YERVOY in combination with nivolumab compared with nivolumab single agent across all treatment lines setting are presented in Table 30 and Figure 6. At the time of PFS analysis OS between arms were not available due to statistical testing strategy.

Table 30: Efficacy Results All Lines - CHECKMATE-8HW
NR: Not Reached; NE: Not Estimable.
Minimum follow-up was 16.7 months at data cutoff date 28Aug2024.
^aBased on log-rank test stratified by the same factors as used in the Cox proportional hazards model. The p-value threshold for statistical significance was 0.0095.
^bBased on Kaplan-Meier estimates.
^cHR from a Cox proportional hazards model stratified by tumor sidedness (left vs right) and prior lines of therapy (0, 1, ≥2) per IRT.
^dBased on Cochran-Mantel-Haenszel test stratified by the same factors as used in the Cox proportional hazards model. The p-value threshold for statistical significance was 0.006.
	YERVOY and Nivolumab (n=296)	Nivolumab (n=286)
Progression-free Survival
Disease progression or death n (%)	101 (34)	136 (48)
Median (months)^b (95% CI)	NR (53.82, NE)	39.3 (22.1, NE)
Hazard ratio^c(95% CI)	0.62 (0.48, 0.81)
p-value^a	0.0003
Objective Response Rate (ORR)
Response Rate, n (%) (95% CI)	209 (71%) (65, 76)	165 (58%) (52, 63)
Complete Response Rate, n (%)	90 (30%)	80 (28%)
Partial Response, n (%)	119 (40%)	65 (30%)
p-value^d	0.0011

Figure 6: Progression-free Survival (All lines (YERVOY + Nivolumab vs Nivolumab)- CHECKMATE-8HW

]

The safety and effectiveness of YERVOY have not been established in pediatric patients younger than 12 years old with unresectable or metastatic melanoma or MSI-H or dMMR mCRC.

The safety and effectiveness of YERVOY have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma and esophageal cancer.

In a dose-finding trial (NCT01445379), 33 patients aged 2 to 21 years (median 13 years) with relapsed or refractory solid tumors were evaluated including unresectable stage IIIc or stage IV melanoma (12), progressive or refractory sarcomas (17), renal or bladder carcinoma (3), and neuroblastoma (1). No responses in the patients with non-melanoma solid tumors and no new safety signals were observed in pediatric patients in this study.