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.

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.

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).

YERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

YERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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.

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

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).

Select patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.6)].

Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

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

Table 1: Recommended Dosages for YERVOY as a Single Agent

Indication	Recommended YERVOY Dosage	Duration of Therapy
Unresectable or metastatic melanoma	3 mg/kg every 3 weeks 30-minute intravenous infusion	Maximum of 4 doses
Adjuvant treatment of melanoma	10 mg/kg every 3 weeks followed by 10 mg/kg every 12 weeks (90-minute intravenous infusion)	Every 3 weeks up to a maximum of 4 doses Every 12 weeks for up to 3 years

The recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate.

Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents*

* Refer to the Prescribing Information for the agents administered in combination with YERVOY for recommended dosing information, as appropriate. † Refer to the Prescribing Information for nivolumab for dosage information after completing use in combination with YERVOY. ‡ 30-minute intravenous infusion on the same day.
Indication	Recommended YERVOY Dosage	Duration of Therapy
Unresectable or metastatic melanoma	3 mg/kg every 3 weeks‡ with nivolumab 1 mg/kg‡	In combination with nivolumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.†
Advanced renal cell carcinoma	1 mg/kg every 3 weeks‡ with nivolumab 3 mg/kg‡	In combination with nivolumab for a maximum of 4 doses. After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.†
Microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) metastatic colorectal cancer	1 mg/kg every 3 weeks‡ with nivolumab 3 mg/kg‡	After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.†
Hepatocellular carcinoma	3 mg/kg every 3 weeks‡ with nivolumab 1 mg/kg‡	In combination with nivolumab for 4 doses. After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity.†
Metastatic non-small cell lung cancer expressing PD‑L1	1 mg/kg every 6 weeks with nivolumab 360 mg‡ every 3 weeks	In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.†
Metastatic or recurrent non-small cell lung cancer	1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks‡ and histology-based platinum‑doublet chemotherapy every 3 weeks	In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.†
		2 cycles of histology-based platinum-doublet chemotherapy
Malignant pleural mesothelioma	1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks‡	In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.†
Esophageal squamous cell carcinoma	1 mg/kg every 6 weeks (30-minute intravenous infusion) with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks (30-minute intravenous infusion)	In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years

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.

Table 3: Recommended Dosage Modifications for Adverse Reactions

ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of normal * Based on Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 a Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST/ALT are less than or equal to ULN at baseline, withhold or permanently discontinue YERVOY based on recommendations for hepatitis with no liver involvement. c This guidance is only applicable to HCC patients who are being treated with YERVOY in combination with nivolumab. d Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.
Adverse Reaction	Severity*	Dosage Modifications
Immune-Mediated Adverse Reactions [See Warnings and Precautions (5.1)]
Colitis	Grade 2	Withholda
	Grade 3 or 4	Permanently discontinue
Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC	AST or ALT increases to more than 3 times and up to 5 times the ULN or Total bilirubin increases to more than 1.5 times and up to 3 times the ULN	Withholda
	AST or ALT more than 5 times the ULN or Total bilirubin more than 3 times the ULN	Permanently discontinue
Hepatitis with tumor involvement of the liverb/HCCc	Baseline AST/ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST/ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN.	Withholda
	AST/ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN.	Permanently discontinue
Exfoliative Dermatologic Conditions	Suspected SJS, TEN, or DRESS	Withhold
	Confirmed SJS, TEN, or DRESS	Permanently discontinue
Endocrinopathiesd	Grades 3 or 4	Withhold until clinically stable or permanently discontinue depending on severity
Pneumonitis	Grade 2	Withholda
	Grade 3 or 4	Permanently discontinue
Nephritis with Renal Dysfunction	Grade 2 or 3 increased blood creatinine	Withholda
	Grade 4 increased blood creatinine	Permanently discontinue
Neurological Toxicities	Grade 2	Withholda
	Grade 3 or 4	Permanently discontinue
Myocarditis	Grade 2, 3 or 4	Permanently discontinue
Ophthalmologic	Grade 2, 3, or 4 that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment	Permanently discontinue
Other Adverse Reactions
Infusion-Related Reactions [see Warnings and Precautions (5.2)]	Grade 1 or 2	Interrupt or slow the rate of infusion
	Grade 3 or 4	Permanently discontinue

• Do not shake product.
• 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.

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 10 mg/kg as a Single Agent

Immune-mediated colitis occurred in 31% (144/471) of patients who received YERVOY 10 mg/kg as a single agent, including fatal (0.2%), Grade 4 (1.5%), Grade 3 (14%), and Grade 2 (14%). Colitis led to permanent discontinuation of YERVOY in 61% of patients and 3.8% of patients missed at least one dose of YERVOY due to colitis.

Systemic corticosteroids were required in 85% (123/144) of patients with immune-mediated colitis. Approximately 26% of the 144 patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 90% of the 144 patients. Of the 18 patients who missed one or more doses of YERVOY for colitis, 17 received additional treatment after symptom improvement; of these, 14 had recurrence of colitis.

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 10 mg/kg as a Single Agent

Immune-mediated hepatitis occurred in 15% (73/471) of patients who received YERVOY 10 mg/kg as a single agent, including Grade 4 (2.8%), Grade 3 (8%), and Grade 2 (5%). Hepatitis led to permanent discontinuation of YERVOY in 56% of patients and 1.1% of patients missed at least one dose of YERVOY due to hepatitis.

Systemic corticosteroids were required in 85% (62/73) of patients with immune-mediated hepatitis. Approximately 15% of the 73 patients required the coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 93% of 73 patients. Of the 5 patients who missed one or more doses of YERVOY for hepatitis, 5 received additional treatment after symptom improvement; of these, 1 had recurrence of hepatitis.

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 10 mg/kg as a Single Agent

Immune-mediated rash occurred in 25% (118/471) of patients who received YERVOY 10 mg/kg as a single agent, including Grade 3 (4%) and Grade 2 (21%). Rash led to permanent discontinuation in 8% of patients and 1.5% of patients missed at least one dose of YERVOY due to rash.

Systemic corticosteroids were required in 70% (83/118) of patients with immune-mediated rash. Rash resolved in 81% of 118 patients. Of the 7 patients who missed one or more doses of YERVOY for rash, 5 received additional treatment after symptom improvement; of these, 3 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 10 mg/kg as a Single Agent

Immune-mediated endocrinopathies occurred in 28% of patients (132/471), including Grade 4 (0.6%), Grade 3 (8%) and Grade 2 (20%).

Of the 39 patients with Grade 3 to 4 endocrinopathies, 35 patients had hypopituitarism (associated with one or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. Twenty-seven of the 39 patients (69%) were hospitalized for endocrinopathies. Of the 39 patients, 10% were reported to have resolution.

Of the 93 patients with Grade 2 endocrinopathy, 74 had primary hypopituitarism associated with one or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism, 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. Of the 93 patients, 20% were reported to have resolution.

One hundred twenty-four patients received systemic corticosteroids as immunosuppression and/or adrenal hormone replacement for Grade 2 to 4 endocrinopathy. Of these, 42 (34%) were able to discontinue corticosteroids. Seventy-three patients received thyroid hormones for treatment of Grade 2 to 4 hypothyroidism. Of these, 14 patients (19%) were able to discontinue thyroid replacement therapy.

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.

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 2.9% (28/982) of patients who received single-agent YERVOY 3 mg/kg or 10 mg/kg for the 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.

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 (6.3)]. Consider the benefit versus risks of treatment with YERVOY after allogeneic HSCT.

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)].

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.

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 10 mg/kg as a single agent in 471 patients in Study CA184-029; 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.