1.1 Unresectable or Metastatic Melanoma

YERVOY, as a single agent or in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult and pediatric patients 12 years and older.

1.2 Adjuvant Treatment of Melanoma

YERVOY is indicated for the adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

1.3 Advanced Renal Cell Carcinoma

YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

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

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YERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).

1.5 Hepatocellular Carcinoma

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YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).

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YERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib.

1.6 Metastatic Non-Small Cell Lung Cancer

YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.

YERVOY, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.

1.7 Malignant Pleural Mesothelioma

YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

1.8 Esophageal Cancer

YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.1)].

2.1 Patient Selection

Information on FDA-approved tests for patient selection is available at:

https://www.fda.gov/CompanionDiagnostics

2.2 Recommended Dosage

The recommended dosages of YERVOY as a single agent are presented in Table 1.

Administer YERVOY as a 30-minute intravenous infusion [see Preparation and Administration (2.4)].

The recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2. Administer YERVOY on the same day as other therapeutic agents.

Refer to the respective Prescribing Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate.

2.3 Recommended Dosage Modifications for Adverse Reactions

No dose reduction for YERVOY is recommended. In general, withhold YERVOY for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue YERVOY for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, persistent moderate (Grade 2) or severe (Grade 3) reactions lasting 12 weeks or longer after last YERVOY dose (excluding endocrinopathy), or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for YERVOY or YERVOY in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized in Table 3.

When YERVOY is administered in combination with nivolumab, withhold or permanently discontinue both YERVOY and nivolumab for toxicity.

2.4 Preparation and Administration

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Do not shake product.

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Visually inspect for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

YERVOY is a fully human monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response with the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting YERVOY. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of YERVOY.

Early identification and management are essential to ensure safe use of YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3)]. In general, if YERVOY 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.

Immune-Mediated Colitis

YERVOY can cause immune-mediated colitis, which may be fatal. 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.

YERVOY 3 mg/kg as a Single Agent

Immune-mediated colitis occurred in 12% (62/511) of patients who received YERVOY 3 mg/kg as a single agent, including Grade 3-5 (7%) and Grade 2 (5%). Colitis led to permanent discontinuation of YERVOY in 4.3% and withholding of at least one dose of YERVOY in 0.2% of patients.

Systemic corticosteroids were required in 74% (46/62) of patients with immune-mediated colitis. Five patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 76% of the 62 patients. One patient was withheld one or more doses of YERVOY for colitis, and no patient received additional treatment after symptom improvement.

YERVOY 1 mg/kg with 3 mg/kg Nivolumab

Immune-mediated colitis occurred in 9% (60/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (4.4%), and Grade 2 (3.7%). Colitis led to permanent discontinuation of YERVOY and nivolumab in 3.2% and withholding of YERVOY and nivolumab in 2.7% of patients.

In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated colitis. Systemic corticosteroids were therefore required in 100% (60/60) of patients with immune-mediated colitis. Approximately 23% of patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom YERVOY or nivolumab was withheld for colitis, 16 received additional treatment after symptom improvement; of these, 10 had recurrence of colitis.

YERVOY 3 mg/kg with 1 mg/kg Nivolumab

Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of YERVOY with nivolumab in 14% and withholding of treatment in 4.4% of patients.

Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of 115 patients. Of the 20 patients in whom YERVOY with nivolumab was withheld for colitis, 16 reinitiated treatment after symptom improvement, and 9 had recurrence of colitis.

Immune-Mediated Hepatitis

YERVOY 3 mg/kg as a Single Agent

Immune-mediated hepatitis occurred in 4.1% (21/511) of patients who received YERVOY 3 mg/kg as a single agent, including Grade 3-5 (1.6%) and Grade 2 (2.5%). Hepatitis led to permanent discontinuation of YERVOY in 0.4% of patients and withholding of at least one dose of YERVOY in none of the patients.

Systemic corticosteroids were required in 29% (6/21) of patients with immune-mediated hepatitis. No patients required the coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 86% of the 21 patients.

YERVOY 3 mg/kg with Vemurafenib

The safety and effectiveness of YERVOY in combination with vemurafenib have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg or 720 mg twice daily).

YERVOY 1 mg/kg with 3 mg/kg Nivolumab

Immune-mediated hepatitis occurred in 7% (48/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%). Hepatitis led to permanent discontinuation of YERVOY and nivolumab in 3.6% and withholding of YERVOY and nivolumab in 2.6% of patients.

In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated hepatitis. Systemic corticosteroids were therefore required in 100% (48/48) of patients with immune-mediated hepatitis. Approximately 19% of patients required coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom YERVOY or nivolumab was withheld for hepatitis, 14 received additional treatment after symptom improvement; of these, 10 had recurrence of hepatitis.

YERVOY 3 mg/kg with 1 mg/kg Nivolumab

Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of YERVOY with nivolumab in 8% and withholding of treatment in 3.5% of patients.

Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom YERVOY with nivolumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement, and 8 had recurrence of hepatitis.

Immune-Mediated Dermatologic Adverse Reactions

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3)].

YERVOY 3 mg/kg as a Single Agent

Immune-mediated rash occurred in 15% (76/511) of patients who received YERVOY 3 mg/kg as a single agent, including Grade 3-5 (2.5%) and Grade 2 (12%). Rash led to permanent discontinuation of YERVOY in 0.2% and withholding of at least one dose of YERVOY in 1.4% of patients.

Systemic corticosteroids were required in 43% (33/76) of patients with immune-mediated rash. Rash resolved in 71% of the 76 patients. Of the 7 patients in whom YERVOY was withheld for rash, 3 received additional treatment after symptom improvement; of these, 1 had recurrence of rash.

YERVOY 1 mg/kg with 3 mg/kg Nivolumab

Immune-mediated rash occurred in 16% (108/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (3.5%) and Grade 2 (4.2%). Rash led to permanent discontinuation of YERVOY and nivolumab in 0.5% of patients and withholding of YERVOY and nivolumab in 2.0% of patients.

In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated rash. Systemic corticosteroids were therefore required in 100% (108/108) of patients. Rash resolved in 75% of 108 patients. Of the 13 patients in whom YERVOY or nivolumab was withheld for rash, 11 received additional treatment after symptom improvement; of these, 5 had recurrence of rash.

YERVOY 3 mg/kg with 1 mg/kg Nivolumab

Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of YERVOY with nivolumab in 0.4% and withholding of treatment in 3.9% of patients.

Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 of patients. Of the 18 patients in whom YERVOY with nivolumab was withheld for rash, 15 reinitiated treatment after symptom improvement, and 8 had recurrence of rash.

Immune-Mediated Endocrinopathies

YERVOY 3 mg/kg as a Single Agent

Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients who received YERVOY 3 mg/kg as a single agent.

Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 patients (1.8%). All 9 of these patients had hypopituitarism with some patients having additional concomitant endocrinopathies, such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushing’s syndrome.

Of the 21 patients with moderate to life-threatening endocrinopathy, 17 required long-term hormone replacement therapy, including adrenal hormones (n=10) and thyroid hormones (n=13).

YERVOY 1 mg/kg with 3 mg/kg Nivolumab

Hypophysitis:

YERVOY can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3)].

Hypophysitis occurred in 4.4% (29/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%). Hypophysitis led to permanent discontinuation of YERVOY and nivolumab in 1.2% and withholding of YERVOY with nivolumab in 2.1% of patients. Approximately 72% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 72% (21/29) of patients with immune-mediated hypophysitis. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom YERVOY or nivolumab was withheld for hypophysitis, 11 received additional treatment after symptom improvement; of these, 2 had recurrence of hypophysitis.

Adrenal Insufficiency:

Adrenal insufficiency occurred in 7% (48/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). Adrenal insufficiency led to permanent discontinuation of YERVOY with nivolumab in 1.2% and withholding of YERVOY with nivolumab in 2.1% of patients. Approximately 94% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 94% (45/48) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom YERVOY or nivolumab was withheld for adrenal insufficiency, 11 received additional treatment after symptom improvement; of these, 2 had recurrence of adrenal insufficiency.

Hyperthyroidism:

Hyperthyroidism occurred in 12% (80/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (0.6%) and Grade 2 (4.5%). No patients discontinued YERVOY for hyperthyroidism. Hyperthyroidism led to withholding of YERVOY with nivolumab in 2.3% of patients. Approximately 19% received a thyroid synthesis inhibitor. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom YERVOY or nivolumab was withheld for hyperthyroidism, 11 received additional treatment after symptom improvement; of these, 3 had recurrence of hyperthyroidism.

Hypothyroidism:

Hypothyroidism occurred in 18% (122/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (0.6%) and Grade 2 (11%). Hypothyroidism led to permanent discontinuation of YERVOY with nivolumab in 0.2% and withholding of YERVOY with nivolumab in 1.4% of patients. Approximately 82% received thyroid hormone replacement. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom YERVOY or nivolumab was withheld for hypothyroidism, 5 received additional treatment after symptom improvement; of these, one patient had recurrence of hypothyroidism.

Thyroiditis:

Thyroiditis occurred in 2.7% (22/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (4.5%) and Grade 2 (2.2%). Thyroiditis led to permanent discontinuation of YERVOY with nivolumab in 0.2% and withholding of YERVOY with nivolumab in 0.8% of patients. Systemic corticosteroids were required in 18% (4/22) of patients with thyroiditis. Thyroiditis resolved in 64% of the 22 patients. Of the 5 patients in whom YERVOY or nivolumab was withheld for thyroiditis, 5 received additional treatment after symptom improvement; of these, no patients had recurrence of thyroiditis.

Type 1 Diabetes Mellitus:

Diabetes occurred in 2.7% (15/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%). Diabetes led to the permanent discontinuation of YERVOY with nivolumab in 0.5% and withholding of YERVOY with nivolumab in 0.5% of patients. Systemic corticosteroids were required in 7% (1/15) of patients with diabetes. Diabetes resolved in 27% of the 15 patients. Of the 3 patients in whom YERVOY or nivolumab was withheld for diabetes, 2 received additional treatment after symptom improvement; of these, none had recurrence of diabetes.

YERVOY 3 mg/kg with 1 mg/kg Nivolumab

Hypophysitis:

Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of YERVOY with nivolumab in 0.9% and withholding of treatment in 4.2% of patients.

Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom YERVOY with nivolumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement, and 1 had recurrence of hypophysitis.

Adrenal Insufficiency:

Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of YERVOY with nivolumab in 0.4% of patients and withholding of treatment in 2.0% of patients.

Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom YERVOY with nivolumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement, and all required hormone replacement therapy for their ongoing adrenal insufficiency.

Hypothyroidism:

Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of YERVOY with nivolumab in 0.9% of patients and withholding of treatment in 0.9% of patients.

Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom YERVOY with nivolumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement, and none had recurrence of hypothyroidism.

Hyperthyroidism:

Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to permanent discontinuation of YERVOY with nivolumab in no patients and withholding of treatment in 2.4% of patients.

Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom YERVOY with nivolumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement, and 1 had recurrence of hyperthyroidism.

Immune-Mediated Pneumonitis

YERVOY 1 mg/kg with 3 mg/kg Nivolumab

Immune-mediated pneumonitis occurred in 3.9% (26/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (1.4%) and Grade 2 (2.6%). Pneumonitis led to permanent discontinuation of YERVOY and nivolumab in 1.8% and withholding of YERVOY and nivolumab in 1.5% of patients.

In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated pneumonitis. Systemic corticosteroids were therefore required in 100% (26/26) of patients with immune-mediated pneumonitis. Approximately 8% required coadministration of another immunosuppressant with corticosteroids. Pneumonitis resolved in 92% of the 26 patients. Of the 10 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 10 received additional treatment after symptom improvement; of these, 4 had recurrence of pneumonitis.

In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The median duration was 1.5 months (range: 5 days to 25+ months). Immune-mediated pneumonitis led to permanent discontinuation of YERVOY with nivolumab in 5% of patients and withholding of YERVOY with nivolumab in 3.6% of patients.

Systemic corticosteroids were required in 100% of patients with pneumonitis followed by a corticosteroid taper. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after re-initiation of YERVOY with nivolumab.

YERVOY 3 mg/kg with 1 mg/kg Nivolumab

Immune-mediated pneumonitis occurred in 7% (31/456) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC or melanoma, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). Immune-mediated pneumonitis led to permanent discontinuation or withholding of treatment in 2.9% and 3.9% of patients, respectively.

Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 94% of the patients. Of the 13 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 13 received additional treatment after symptom improvement, and 4 had recurrence of pneumonitis.

Immune-Mediated Nephritis with Renal Dysfunction

YERVOY 1 mg/kg with 3 mg/kg Nivolumab

Immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%). Nephritis with renal dysfunction led to permanent discontinuation of YERVOY and nivolumab in 1.2% and withholding of nivolumab and YERVOY in 1.8% of patients.

In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated nephritis with renal dysfunction. Systemic corticosteroids were therefore required in 100% (27/27) of patients with immune-mediated nephritis with renal dysfunction. Nephritis with renal dysfunction resolved in 67% of the 27 patients. Of the 12 patients in whom YERVOY or nivolumab was withheld for nephritis, 10 received additional treatment after symptom improvement; of these, 4 had recurrence of nephritis.

Other Immune-Mediated Adverse Reactions

Across clinical trials of YERVOY administered as a single agent or in combination with nivolumab, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified, as shown below:

Nervous System: Autoimmune neuropathy (2%), meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, nerve paresis, motor dysfunction

Cardiovascular: Angiopathy, myocarditis, pericarditis, temporal arteritis, vasculitis

Ocular: Blepharitis, episcleritis, iritis, orbital myositis, scleritis, uveitis. Some cases can be associated with retinal detachment. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Gastrointestinal: Duodenitis, gastritis, pancreatitis (1.3%)

Musculoskeletal and Connective Tissue: Arthritis, myositis, polymyalgia rheumatica, polymyositis, rhabdomyolysis

Other (hematologic/immune): Aplastic anemia, conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), hypersensitivity vasculitis, meningitis, neurosensory hypoacusis, psoriasis, sarcoidosis, systemic inflammatory response syndrome, and solid organ transplant rejection.

5.2 Infusion-Related Reactions

Severe infusion-related reactions can occur with YERVOY. Discontinue YERVOY in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions [see Dosage and Administration (2.3)]. Infusion-related reactions occurred in 0.6% (3/511) of patients who received single-agent YERVOY 3 mg/kg for the unresectable or metastatic treatment of melanoma. Infusion-related reactions occurred in 5% (33/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or CRC. Infusion-related reactions occurred in 8% (4/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks.

5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplant after YERVOY

Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive YERVOY either before or after allogeneic hematopoietic stem cell transplantation (HSCT). These complications may occur despite intervening therapy between CTLA-4 receptor blocking antibody and allogeneic HSCT.

Follow patients closely for evidence of GVHD and intervene promptly [see Adverse Reactions (6.2)]. Consider the benefit versus risks of treatment with YERVOY after allogeneic HSCT.

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, YERVOY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight) and higher incidences of infant mortality in a dose-related manner. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.5 Risks Associated When Administered in Combination with Nivolumab

YERVOY is indicated for use in combination with nivolumab for patients with advanced RCC, MSI-H or dMMR mCRC, HCC, and NSCLC. Refer to the nivolumab Full Prescribing Information for additional risk information that applies to the combination use treatment.

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of YERVOY. 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.

Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH)

Immune System: graft-versus-host disease, solid organ transplant rejection

Skin and Subcutaneous Tissue: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

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 Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

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.

8.5 Geriatric Use

Single Agent

Of the 511 patients treated with YERVOY in Study MDX010-20 (unresectable or metastatic melanoma), 28% were 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.

In Combination with Nivolumab

Of the 314 patients randomized to YERVOY administered with nivolumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

Of the 576 patients randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received YERVOY with nivolumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.6)].

Of the 303 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab.

Of the 550 patients randomized to YERVOY 1 mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was observed between these patients and younger patients. In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed.

Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to nivolumab, as a single agent, 45% were 65 years or older and 13% were 75 years or older. There was a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%). There was a higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab [see Clinical Studies (14.4)].

Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients.

Of the 49 patients who received YERVOY 3 mg/kg with nivolumab in Cohort 4 of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients.

Of the 325 patients who received YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients.

Study CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

In Combination with Nivolumab and Platinum-Doublet Chemotherapy

Of the 361 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and platinum-doublet chemotherapy every 3 weeks (for 2 cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received YERVOY with nivolumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to YERVOY in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.

12.1 Mechanism of Action

CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response.

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 (Cmin) 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 (t1/2) 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.

12.6 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 below with the incidence of ADA in other studies, including those of YERVOY or of other ipilimumab products.

Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab developed anti-ipilimumab antibodies and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for anti-ipilimumab antibodies using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for anti-ipilimumab antibodies.

Of the 499 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-214 and CHECKMATE-142, 27 (5.4%) were positive for anti-ipilimumab antibodies; there were no patients with neutralizing antibodies against ipilimumab. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies.

Of 483 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-227 Part 1, 8.5% were positive for treatment-emergent anti-ipilimumab antibodies. No patients had neutralizing antibodies against ipilimumab. In Part 1 of the same study, of 491 patients evaluable for anti-nivolumab antibodies, 36.7% were positive for anti-nivolumab antibodies and 1.4% had neutralizing antibodies against nivolumab.

Of 305 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-9LA, 8% were positive for anti-ipilimumab antibodies and 1.6% were positive for anti-ipilimumab neutralizing antibodies. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies. Of 308 patients evaluable for anti-nivolumab antibodies in CHECKMATE-9LA, 34% were positive for anti-nivolumab antibodies and 2.6% had neutralizing antibodies against nivolumab.

Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13.7% were positive for anti-ipilimumab antibodies and 0.4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25.7% were positive for anti-nivolumab antibodies and 0.7% had neutralizing antibodies against nivolumab.

Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 24.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies, and the genotoxic potential of ipilimumab has not been evaluated.

Fertility studies have not been performed with ipilimumab.

14.1 Unresectable or Metastatic Melanoma

The efficacy of YERVOY was investigated in a Study MDX010-20, a randomized (3:1:1), double-blind, double-dummy trial (NCT00094653) that included patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. The trial enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The trial excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients were randomized to YERVOY administered at a dose of 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses with an investigational peptide vaccine with incomplete Freund’s adjuvant - gp100 administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses; gp100 administered at a dose of 2 mg by deep subcutaneous injection every 3 weeks for 4 doses as a single agent with a placebo; or YERVOY administered at a dose of 3 mg/kg by intravenous infusion every 3 weeks for 4 doses with a placebo. The major efficacy outcome measure was overall survival (OS) in the YERVOY and gp100 arm compared to that in the single-agent gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY and gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) as assessed by the investigator at week 24 between each of the trial arms, and duration of response. Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.

A total of 676 patients were randomized, 403 to YERVOY and gp100 arm, 137 to YERVOY single agent arm and 136 to gp100 single agent arm. Of the randomized patients, 61%, 59%, and 54% in the YERVOY and gp100, YERVOY, and gp100 arms, respectively, were male. Twenty-nine percent were ≥65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either YERVOY-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months.

The efficacy results are shown in Table 25 and Figure 1.

Figure 1: Kaplan-Meier Curves for Overall Survival in Study MDX010-20

Previously Untreated Metastatic Melanoma: In Combination with Nivolumab

CHECKMATE-067 (NCT01844505) was a multicenter, randomized (1:1:1), double-blind trial in which 945 patients with previously untreated, unresectable or metastatic melanoma were randomized to one of the following arms: YERVOY and nivolumab, nivolumab, or YERVOY. Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients were randomized to receive:

•

YERVOY 3 mg/kg with nivolumab 1 mg/kg intravenously 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),

•

Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm), or

•

YERVOY 3 mg/kg intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks (YERVOY arm)

Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and duration of response.

The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).

CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for patients randomized to either nivolumab-containing arm as compared with the YERVOY arm. The trial was not designed to assess whether adding YERVOY to nivolumab improves PFS or OS compared to nivolumab as a single agent. Efficacy results are shown in Table 26 and Figure 2.

Table 26: Efficacy Results - CHECKMATE-067

a   OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and ORR (secondary endpoint) results were based on primary analysis with 9 months of minimum follow-up. b   Based on a stratified proportional hazards model. c   Based on stratified log-rank test. d   If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure), then both p-values are considered significant. e   p-value is compared with 0.005 of the allocated alpha for final PFS treatment comparisons. f   Based on the stratified Cochran-Mantel-Haenszel test. + Censored observation
	YERVOY and Nivolumab (n=314)	Nivolumab (n=316)	YERVOY (n=315)
Overall Survivala
Deaths (%)	128 (41)	142 (45)	197 (63)
Hazard ratiob (vs. YERVOY)                (95% CI)	0.55 (0.44, 0.69)	0.63 (0.50, 0.78)
p-valuec, d	<0.0001	<0.0001
Progression-free Survivala
Disease progression or death	151 (48%)	174 (55%)	234 (74%)
Median (months)                (95% CI)	11.5 (8.9, 16.7)	6.9 (4.3, 9.5)	2.9 (2.8, 3.4)
Hazard ratiob (vs. YERVOY)                (95% CI)	0.42 (0.34, 0.51)	0.57 (0.47, 0.69)
p-valuec, e	<0.0001	<0.0001
Confirmed Overall Response Ratea	50%	40%	14%
(95% CI)	(44, 55)	(34, 46)	(10, 18)
p-valuef	<0.0001	<0.0001
Complete response	8.9%	8.5%	1.9%
Partial response	41%	31%	12%
Duration of Response
Proportion ≥6 months in duration	76%	74%	63%
Range (months)	1.2+ to 15.8+	1.3+ to 14.6+	1.0+ to 13.8+

Figure 2: Overall Survival - CHECKMATE-067

Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the YERVOY and nivolumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the nivolumab arm and 19.9 months (95% CI: 16.9, 24.6) in the YERVOY arm.

Based on a minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9, 21.9) in the YERVOY and nivolumab arm, 6.9 months (95% CI: 4.3, 9.5) in the nivolumab arm, and 2.9 months (95% CI: 2.8, 3.2) in the YERVOY arm. Based on a minimum follow-up of 28 months, the proportion of responses lasting ≥24 months was 55% in the YERVOY and nivolumab arm, 56% in the nivolumab arm, and 39% in the YERVOY arm.

14.2 Adjuvant Treatment of Melanoma

The efficacy of YERVOY was evaluated in Study E1609 (NCT01274338), an open-label, multicenter, randomized trial for the adjuvant treatment of cutaneous melanoma in patients with completely resected node positive disease (either clinically detectable or any size with ulceration or mitosis ≥1/mm2), in transit metastasis, satellites, or metastatic disease. The trial excluded patients with a history of prior therapy for melanoma and autoimmune disease requiring steroid treatment. Patients were randomized to receive one of the following regimens:

•

YERVOY 3 mg/kg intravenously every 3 weeks for 4 doses, followed by the same dose every 12 weeks for up to 4 additional doses,

•

High-dose interferon α-2b (HDI) intravenously at 20 million units/m2 per day, 5 days per week, for 4 weeks (induction), followed by 10 million units/m2 per day SC every other day, 3 days per week, for 48 weeks (maintenance), or

•

YERVOY 10 mg/kg intravenously every 3 weeks for 4 doses, followed by the same dose every 12 weeks for up to 4 additional doses.

Randomization was stratified by AJCC 7th edition stage (IIIB, IIIC, M1a, or M1b). Tumor assessments were conducted every 3 months in patients <2 years from study entry, then every 6 months in patients 2-5 years from study entry, and every 12 months in patients >5 years from study entry for up to 20 years. Treatment continued for a maximum of 60 weeks with ipilimumab or 52 weeks with HDI, or until unacceptable toxic effects, disease progression, or withdrawal of consent. The major efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) by imaging (for CNS lesions) or imaging and positive cytology or histology (for non-CNS lesions) and overall survival (OS). Only the efficacy results for the recommended starting dose of 3 mg/kg YERVOY are described below.

A total of 1051 patients were randomized to YERVOY 3 mg/kg (n=523) and HDI (n=528). The median age was 54 years (range: 18 to 83), 62% were male, 97% were white, 0.3% were Asian, and 0.4% were Black. Regarding disease stage, 53% had Stage IIIB, 40% had Stage IIIC (with no in-transit metastases), and 7% had Stage IV disease.

The efficacy results are in Table 27 and Figure 3.

Figure 3: Kaplan-Meier Curves for Overall Survival with Ipilimumab 3 mg/kg vs. HDI in Study E1609

14.3 Advanced Renal Cell Carcinoma

The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-214 (NCT02231749), a randomized (1:1), open-label study in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were randomized to nivolumab 3 mg/kg and YERVOY 1 mg/kg administered intravenously every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every two weeks or to sunitinib administered orally 50 mg daily for the first 4 weeks of each 6-week cycle. Treatment continued until disease progression or unacceptable toxicity. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region. The major efficacy outcome measures were OS, PFS (IRRC-assessed), and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. Intermediate/poor risk patients had at least 1 or more of 6 prognostic risk factors as per the IMDC criteria: less than one year from time of initial RCC diagnosis to randomization, Karnofsky performance status (KPS) <80%, hemoglobin less than the lower limit of normal, corrected calcium >10 mg/dL, platelet count >ULN, and absolute neutrophil count >ULN.

A total of 847 patients were randomized, 425 to YERVOY with nivolumab and 422 to sunitinib. The median age was 61 years (range: 21 to 85) with 38% ≥65 years of age and 8% ≥75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.

Efficacy results from CHECKMATE-214 are presented in Table 28 and Figure 4. In intermediate/poor risk patients, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to YERVOY and nivolumab arm as compared with sunitinib arm. OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS.

Figure 4: Kaplan-Meier Curves for Overall Survival (Intermediate/Poor Risk Population) in CHECKMATE-214

CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to nivolumab and YERVOY (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving nivolumab and YERVOY compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of nivolumab and YERVOY in previously untreated renal cell carcinoma with favorable risk disease has not been established.

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

o

mFOLFOX6 (oxaliplatin, leucovorin, and FU) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus followed by FU 2400 mg/m2 over 46 hours every 2 weeks. Bevacizumab 5 mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6 every 2 weeks.

o

FOLFIRI (irinotecan, leucovorin, and FU) with or without either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and FU 400 mg/m2 bolus and FU 2400 mg/m2 over 46 hours every 2 weeks. Bevacizumab 5 mg/kg on or cetuximab 500 mg/m2 administered 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.
a   Based 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.
b   Based on Kaplan-Meier estimates.
c   HR 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 monthsb (95% CI)	NR (38.4, NE)	5.8 (4.4, 7.8)
Hazard ratioc (95% CI)	0.21 (0.14, 0.32)
p-valuea	<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.
a   Based 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.
b   Based on Kaplan-Meier estimates.
c   HR from a Cox proportional hazards model stratified by tumor sidedness (left vs right) and prior lines of therapy (0, 1, ≥2) per IRT.
d   Based 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 ratioc (95% CI)	0.62 (0.48, 0.81)
p-valuea	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-valued	0.0011

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

14.5 Hepatocellular Carcinoma

Treatment of Unresectable or Metastatic Hepatocellular Carcinoma (HCC)

CHECKMATE-9DW (NCT04039607) was a randomized (1:1), open-label trial in adults (18 years of age or older) with unresectable or metastatic HCC. Patients had histologically confirmed HCC, Child Pugh Class A, ECOG performance status 0 or 1, and no prior systemic therapy for advanced disease. Esophagogastroduodenoscopy was not mandated prior to enrollment. The trial excluded patients with active autoimmune disease, brain or leptomeningeal metastases, a history of hepatic encephalopathy (within 12 months of randomization), a platelet count <60,000, clinically significant ascites, medical conditions requiring systemic immunosuppression, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV).

Patients were randomized to receive either:

•

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:

o

Lenvatinib 8 mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight ≥60 kg), or

o

Sorafenib 400 mg orally twice daily

Randomization was stratified by etiology (HBV vs. HCV vs. non-viral), macrovascular invasion and/or extrahepatic spread (present or absent), and alpha-fetoprotein levels (≥400 or <400 ng/mL). Study treatment for YERVOY in combination with nivolumab continued until disease progression, unacceptable toxicity, or up to 2 years. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as a single agent. Treatment beyond RECIST 1.1 defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at week 9 and week 16, then every 8 weeks up to 48 weeks, and then every 12 weeks thereafter until disease progression, treatment discontinuation, or initiation of subsequent therapy. The primary efficacy outcome measure was OS in all randomized patients. Additional efficacy measures included BICR-assessed ORR and DOR based on RECIST 1.1 criteria.

A total of 668 patients were randomized to receive YERVOY in combination with nivolumab (n=335) or investigator’s choice (n=333) of lenvatinib or sorafenib. In the investigator arm, 85% and 15% of treated patients received lenvatinib or sorafenib, respectively. The trial population characteristics were: median age was 66 years (range: 20 to 89), with 53% ≥65 years old; 82% male; 53% White, 44% Asian, 2.2% Black; 12% Hispanic or Latino, 48% Not Hispanic or Latino, 40% not reported. Baseline ECOG performance status was 0 (71%) or 1 (29%). Thirty-four percent (34%) of patients had HBV infection, 28% had HCV infection, and 36% had no evidence of HBV or HCV infection.

Nineteen percent (19%) of patients had alcoholic liver disease and 11% had non-alcoholic fatty liver disease. The majority of patients had BCLC stage C (73%) disease at baseline, 19% had stage B, and 6% had stage A. Patients with Child-Pugh scores of 5, 6, and 7 were 77%, 20%, and 3%, respectively; 1 patient with Child Pugh 8 was enrolled. A total of 54% of patients had extrahepatic spread; 25% had macrovascular invasion; and 33% had AFP levels ≥400 µg/L.

CHECKMATE-9DW demonstrated a statistically significant improvement in OS and ORR. The minimum follow-up was 26.8 months. Efficacy results are shown in Table 31 and Figure 7.

Table 31: Efficacy Results - CHECKMATE-9DW

a   Based on stratified Cox proportional hazard model.
b   Based on a 2-sided stratified log-rank test. Boundary for statistical significance: p-value ≤0.0257
c   Assessed by BICR using RECIST 1.1
d   Based on a 2-sided stratified Cochran-Mantel-Haenszel test. Boundary for statistical significance: p-value ≤0.025
e   NR: Not Reached
+ Censored observation
	YERVOY and Nivolumab (n=335)	Lenvatinib or Sorafenib (n=333)
Overall Survival
Deaths (%)	194 (58%)	228 (68%)
Median (months) (95% CI)	23.7 (18.8, 29.4)	20.6 (17.5, 22.5)
Hazard ratio (95% CI) a	0.79 (0.65, 0.96)
p-value b	0.0180
Overall Response Rate, n (%)c	121 (36.1)	44 (13.2)
(95% CI)	(31.0, 41.5)	(9.8, 17.3)
p-value d	<0.0001
Complete response (%)	23 (6.9)	6 (1.8)
Partial response (%)	98 (29.3)	38 (11.4)
Duration of Response (months) c
Median (95% CI)	30.4 (21.2, NRe)	12.9 (10.2, 31.2)
Range	1.5+, 36.9+	2.1+, 32.5+

Figure 7: Overall Survival - CHECKMATE-9DW

14.6 Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC) Expressing PD-L1 (≥1%): In Combination with Nivolumab

CHECKMATE-227 (NCT02477826) was a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC. The study included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer [ASLC] classification), ECOG performance status 0 or 1, and no prior anticancer therapy. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

Primary efficacy results were based on Part 1a of the study, which was limited to patients with PD-L1 tumor expression ≥1%. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. Randomization was stratified by tumor histology (non-squamous versus squamous). The evaluation of efficacy relied on the comparison between:

•

YERVOY 1 mg/kg administered intravenously over 30 minutes every 6 weeks in combination with nivolumab 3 mg/kg administered intravenously over 30 minutes every 2 weeks; or

•

Platinum-doublet chemotherapy

Chemotherapy regimens consisted of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or pemetrexed (500 mg/m2) and carboplatin (AUC 5 or 6) for non-squamous NSCLC or gemcitabine (1000 or 1250 mg/m2) and cisplatin (75 mg/m2) or gemcitabine (1000 mg/m2) and carboplatin (AUC 5) (gemcitabine was administered on Days 1 and 8 of each cycle) for squamous NSCLC.

Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to YERVOY were permitted to continue nivolumab as a single agent. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

In Part 1a, a total of 793 patients were randomized to receive either YERVOY in combination with nivolumab (n=396) or platinum-doublet chemotherapy (n=397). The median age was 64 years (range: 26 to 87) with 49% of patients ≥65 years and 10% of patients ≥75 years, 76% White, and 65% male. Baseline ECOG performance status was 0 (34%) or 1 (65%), 50% with PD-L1 ≥50%, 29% with squamous and 71% with non-squamous histology, 10% had brain metastases, and 85% were former/current smokers.

The study demonstrated a statistically significant improvement in OS for PD-L1 ≥1% patients randomized to the YERVOY and nivolumab arm compared to platinum-doublet chemotherapy arm. The OS results are presented in Table 33 and Figure 8.

Table 33: Efficacy Results (PD-L1 ≥1%) - CHECKMATE-227 Part 1a

a   Kaplan-Meier estimate. b   Based on a stratified Cox proportional hazard model.
	YERVOY and Nivolumab (n=396)	Platinum-Doublet Chemotherapy (n=397)
Overall Survival
Events (%)	258 (65%)	298 (75%)
Median (months)a           (95% CI)	17.1 (15, 20.1)	14.9 (12.7, 16.7)
Hazard ratio (95% CI)b	0.79 (0.67, 0.94)
Stratified log-rank p-value	0.0066

Figure 8: Overall Survival (PD-L1 ≥1%) - CHECKMATE-227

BICR-assessed PFS showed a HR of 0.82 (95% CI: 0.69, 0.97), with a median PFS of 5.1 months (95% CI: 4.1, 6.3) in the YERVOY and nivolumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm. The BICR-assessed confirmed ORR was 36% (95% CI: 31, 41) in the YERVOY and nivolumab arm and 30% (95% CI: 26, 35) in the platinum-doublet chemotherapy arm. Median duration of response observed in the YERVOY and nivolumab arm was 23.2 months and 6.2 months in the platinum-doublet chemotherapy arm.

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

CHECKMATE-9LA (NCT03215706) was a randomized, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment.

Patients were randomized 1:1 to receive either:

•

YERVOY 1 mg/kg administered intravenously over 30 minutes every 6 weeks, nivolumab 360 mg administered intravenously over 30 minutes every 3 weeks, and platinum-doublet chemotherapy administered intravenously every 3 weeks for 2 cycles, or

•

platinum-doublet chemotherapy administered every 3 weeks for 4 cycles.

Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as a single agent as part of the study. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

A total of 719 patients were randomized to receive either YERVOY in combination with nivolumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ≥65 years and 10% of patients ≥75 years. The majority of patients were White (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumors with PD-L1 expression ≥1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR. Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) are presented in Table 34.

Table 34: Efficacy Results - CHECKMATE-9LA

a   Based on a stratified Cox proportional hazard model. b   p-value is compared with the allocated alpha of 0.033 for this interim analysis. c   p-value is compared with the allocated alpha of 0.0252 for this interim analysis. d   Kaplan-Meier estimate. e   Confidence interval based on the Clopper and Pearson Method. f   p-value is compared with the allocated alpha of 0.025 for this interim analysis.
	YERVOY and Nivolumab and Platinum-Doublet Chemotherapy (n=361)	Platinum-Doublet Chemotherapy (n=358)
Overall Survival
Events (%)	156 (43.2)	195 (54.5)
Median (months)            (95% CI)	14.1 (13.2, 16.2)	10.7 (9.5, 12.5)
Hazard ratio (96.71% CI)a	0.69 (0.55, 0.87)
Stratified log-rank p-valueb	0.0006
Progression-free Survival per BICR
Events (%)	232 (64.3)	249 (69.6)
Hazard ratio (97.48% CI)a	0.70 (0.57, 0.86)
Stratified log-rank p-valuec	0.0001
Median (months)d            (95% CI)	6.8 (5.6, 7.7)	5.0 (4.3, 5.6)
Overall Response Rate per BICR (%)	38	25
(95% CI)e	(33, 43)	(21, 30)
Stratified CMH test p-valuef	0.0003
Duration of Response per BICR
Median (months)            (95% CI)d	10.0 (8.2, 13.0)	5.1 (4.3, 7.0)

With an additional 4.6 months of follow-up the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving YERVOY and nivolumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 9).

Figure 9: Overall Survival - CHECKMATE-9LA

14.7 Malignant Pleural Mesothelioma

CHECKMATE-743 (NCT02899299) was a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed and previously untreated malignant pleural mesothelioma with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial. Patients were randomized 1:1 to receive 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

•

cisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin 5 AUC and pemetrexed 500 mg/m2 administered every 3 weeks for 6 cycles.

Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to YERVOY were permitted to continue nivolumab as a single agent. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.

A total of 605 patients were randomized to receive either YERVOY in combination with nivolumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients ≥65 years and 26% ≥75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was 0 (40%) or 1 (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression ≥1%, and 22% had tumors with PD-L1 expression <1%.

The trial demonstrated a statistically significant improvement in OS for patients randomized to YERVOY in combination with nivolumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 35 and Figure 10.