YERVOY- ipilimumab injection 
E.R. Squibb & Sons, L.L.C.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use YERVOY safely and effectively. See full prescribing information for YERVOY.

YERVOY® (ipilimumab) injection, for intravenous use
Initial U.S. Approval: 2011

RECENT MAJOR CHANGES

Boxed Warning, Removed     6/2020

Indications and Usage (1)     5/2021

Dosage and Administration (2)     5/2021

Warnings and Precautions (5)     5/2021

INDICATIONS AND USAGE

YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for:

Melanoma

Treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older. (1.1)
Treatment of adult patients with unresectable or metastatic melanoma, in combination with nivolumab. (1.1)
Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2)

Renal Cell Carcinoma (RCC)

Treatment of patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3)

Colorectal Cancer

Treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.4)

Hepatocellular Carcinoma

Treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib, in combination with nivolumab. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.5)

Non-Small Cell Lung Cancer (NSCLC)

Treatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab. (1.6)
Treatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy. (1.6)
 
Malignant Pleural Mesothelioma
Treatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab. (1.7)

DOSAGE AND ADMINISTRATION

Administer by intravenous infusion based upon recommended infusion rate for each indication. (2)
Unresectable or Metastatic Melanoma:
YERVOY 3 mg/kg every 3 weeks for a maximum of 4 doses. (2.2)
YERVOY 3 mg/kg immediately following nivolumab 1 mg/kg on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in the Full Prescribing Information for nivolumab. (2.2)
Adjuvant Treatment of Melanoma: YERVOY 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years. (2.2)
Advanced Renal Cell Carcinoma: YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2)
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer: YERVOY 1 mg/kg intravenously over 30 minutes immediately following nivolumab 3 mg/kg intravenously over 30 minutes on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2)
Hepatocellular Carcinoma: YERVOY 3 mg/kg intravenously over 30 minutes immediately following nivolumab 1 mg/kg intravenously over 30 minutes on the same day, every 3 weeks for 4 doses. After completion 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2)
Metastatic non-small cell lung cancer:
YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks. (2.2)
YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2)
Malignant pleural mesothelioma: YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks. (2.2)

DOSAGE FORMS AND STRENGTHS

Injection: 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) in a single-dose vial. (3)

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

Severe and Fatal Immune-Mediated Adverse Reactions: Immune-mediated adverse reactions (IMAR) can occur in any organ system or tissue, including the following: immune-mediated colitis, immune-mediated hepatitis, immune-mediated dermatologic adverse reactions, immune-mediated endocrinopathies, immune-mediated pneumonitis, and immune-mediated nephritis with renal dysfunction, and can occur at any time during treatment or after discontinuation. Monitor for symptoms and signs that may be clinical manifestations of IMAR. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function at baseline and before each dose. In general, withhold YERVOY for severe (grade 3) and permanently discontinue for life-threatening (grade 4) immune-mediated adverse reactions. See Full Prescribing Information for additional dosage modifications. (2.3, 5.1)
Infusion-Related Reactions: Discontinue for severe and life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions. (2.3, 5.2)
Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with YERVOY. (5.3)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3)

ADVERSE REACTIONS

Most common adverse reactions (≥5%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse reactions at the 10 mg/kg dose (≥5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. (6.1)

Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab are fatigue, rash, pruritus, diarrhea, musculoskeletal pain, cough, pyrexia, decreased appetite, nausea, abdominal pain, arthralgia, headache, vomiting, dyspnea, dizziness, hypothyroidism, and decreased weight. (6.1)

Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab and platinum-doublet chemotherapy are fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 5/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Unresectable or Metastatic Melanoma

1.2 Adjuvant Treatment of Melanoma

1.3 Advanced Renal Cell Carcinoma

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

1.5 Hepatocellular Carcinoma

1.6 Metastatic Non-Small Cell Lung Cancer

1.7 Malignant Pleural Mesothelioma

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

2.2 Recommended Dosage

2.3 Recommended Dosage Modifications for Adverse Reactions

2.4 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

5.2 Infusion-Related Reactions

5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplant after YERVOY

5.4 Embryo-Fetal Toxicity

5.5 Risks Associated When Administered in Combination with Nivolumab

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

6.3 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Unresectable or Metastatic Melanoma

14.2 Adjuvant Treatment of Melanoma

14.3 Advanced Renal Cell Carcinoma

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

14.5 Hepatocellular Carcinoma

14.6 Metastatic Non-Small Cell Lung Cancer

14.7 Malignant Pleural Mesothelioma

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Unresectable or Metastatic Melanoma

YERVOY is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older.

YERVOY, in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult patients.

1.2 Adjuvant Treatment of Melanoma

YERVOY is indicated for the adjuvant treatment of 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 patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

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

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.

1.5 Hepatocellular Carcinoma

YERVOY, in combination with nivolumab, is indicated for the treatment of 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.

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.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

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.

2.2 Recommended Dosage

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

(90-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.

Indication

Recommended YERVOY Dosage

Duration of Therapy

Unresectable or metastatic melanoma

3 mg/kg every 3 weeks

(90-minute intravenous infusion)

with nivolumab 1 mg/kg

(30-minute intravenous infusion on the same day)

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

(30-minute intravenous infusion on the same day)

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

(30-minute intravenous infusion on the same day)

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

(30-minute intravenous infusion on the same day)

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 3 mg/kg every 2 weeks

(30-minute intravenous infusion)

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

(30-minute intravenous infusion)

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

(30-minute intravenous infusion)

In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

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.

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

2.4 Preparation and Administration

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.

Preparation of Solution

Allow the vial(s) to stand at room temperature for approximately 5 minutes prior to preparation of infusion.
Withdraw the required volume of YERVOY and transfer into an intravenous bag.
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion.
After preparation, store the diluted solution either refrigerated at 2°C to 8°C (36°F to 46°F) or at room temperature of 20°C to 25°C (68°F to 77°F) for no more than 24 hours from the time of preparation to the time of infusion.
Discard partially used or empty vials of YERVOY.

Administration

Do not co-administer other drugs through the same intravenous line.
Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.
Administer diluted solution through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.
When administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day. When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day. Use separate infusion bags and filters for each infusion.

3 DOSAGE FORMS AND STRENGTHS

Injection: 50 mg/10 mL (5 mg/mL) or 200 mg/40 mL (5 mg/mL) as a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

     

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 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.

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 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.

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 (6.3)]. 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 ADVERSE REACTIONS

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

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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.

Unresectable or Metastatic Melanoma

The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20 [see Clinical Studies (14.1)]. Study MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients received YERVOY 3 mg/kg by intravenous infusion for 4 doses as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (n=380), or gp100 peptide vaccine as a single agent (n=132). Patients in the trial received a median of 4 doses (range: 1 to 4 doses).

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

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

Table 4: Selected Adverse Reactions (≥5%) in Patients Receiving YERVOY with a Difference Between Arms of >5% for All Grades and >1% for Grades 3 to 5 Compared to gp100 Peptide Vaccine in Study MDX010-20

Adverse Reactions

YERVOY 3 mg/kg

n=131

YERVOY 3 mg/kg and gp100

n=380

gp100

n=132

All Grades (%)

Grade
3 to 5 (%)

All Grades

(%)

Grade
3 to 5 (%)

All Grades (%)

Grade
3 to 5 (%)

General and Administration-Site Conditions

     Fatigue

41

7

34

5

31

3

Gastrointestinal

     Diarrhea

32

5

37

4

20

1

     Colitis

8

5

5

3

2

0

Dermatologic

     Pruritus

31

0

21

<1

11

0

     Rash

29

2

25

2

8

0

Unresectable or Metastatic Melanoma: In Combination with Nivolumab

The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

Patients were randomized to receive:

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

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

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

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

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

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

Table 5: Adverse Reactions Occurring in ≥10% of Patients on the YERVOY and Nivolumab Arm or the Nivolumab Arm and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.

Adverse Reaction

YERVOY and
Nivolumab
(n=313)


Nivolumab

(n=313)


YERVOY

(n=311)

All Grades (%)

Grades
3-4 (%)

All Grades (%)

Grades
3-4 (%)

All Grades (%)

Grades
3-4 (%)

General

     Fatiguea

62

7

59

1.6

51

4.2

     Pyrexia

40

1.6

16

0

18

0.6

Gastrointestinal

     Diarrhea

54

11

36

5

47

7

     Nausea

44

3.8

30

0.6

31

1.9

     Vomiting

31

3.8

20

1.0

17

1.6

Skin and Subcutaneous Tissue

     Rashb

53

6

40

1.9

42

3.5

     Vitiligo

9

0

10

0.3

5

0

Musculoskeletal and Connective Tissue

     Musculoskeletal painc

32

2.6

42

3.8

36

1.9

     Arthralgia

21

0.3

21

1.0

16

0.3

Metabolism and Nutrition

     Decreased appetite

29

1.9

22

0

24

1.3

Respiratory, Thoracic and Mediastinal

     Cough/productive cough

27

0.3

28

0.6

22

0

     Dyspnea/exertional dyspnea

24

2.9

18

1.3

17

0.6

Infections

     Upper respiratory tract infectiond

23

0

22

0.3

17

0

Endocrine

     Hypothyroidism

19

0.6

11

0

5

0

     Hyperthyroidism

11

1.3

6

0

1

0

Investigations

     Decreased weight

12

0

7

0

7

0.3

Vascular

     Hypertensione

7

2.2

11

5

9

2.3

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

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 6: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥20% of Patients Treated with YERVOY with Nivolumab or Single-Agent Nivolumab and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab (range: 75 to 297); nivolumab (range: 81 to 306); YERVOY (range: 61 to 301)

Laboratory Abnormality

YERVOY and
Nivolumab


Nivolumab


YERVOY

All Grades (%)

Grade
3-4 (%)

All Grades (%)

Grade
3-4 (%)

All Grades (%)

Grade
3-4 (%)

Chemistry

     Increased ALT

55

16

25

3.0

29

2.7

     Hyperglycemia

53

5

46

7

26

0

     Increased AST

52

13

29

3.7

29

1.7

     Hyponatremia

45

10

22

3.3

26

7

     Increased lipase

43

22

32

12

24

7

     Increased alkaline phosphatase

41

6

27

2.0

23

2.0

     Hypocalcemia

31

1.1

15

0.7

20

0.7

     Increased amylase

27

10

19

2.7

15

1.6

     Increased creatinine

26

2.7

19

0.7

17

1.3

Hematology

     Anemia

52

2.7

41

2.6

41

6

     Lymphopenia

39

5

41

4.9

29

4.0

Adjuvant Treatment of Melanoma

The safety of YERVOY was evaluated in 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma in Study CA184-029 [see Clinical Studies (14.2)]. Study CA184-029 excluded patients with prior systemic therapy for melanoma, autoimmune disease, a condition requiring systemic immunosuppression, or a positive test for hepatitis B, hepatitis C, or HIV. Patients received YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to a maximum of 3 years. In this trial, 36% of patients received YERVOY for longer than 6 months and 26% of patients received YERVOY for longer than 1 year. YERVOY-treated patients in the trial received a median of 4 doses (range: 1 to 16).

The trial population characteristics were: median age 51 years (range: 18 to 84 years), 62% male, 99% White, and baseline ECOG performance status 0 (94%).

YERVOY was discontinued for adverse reactions in 52% of patients. Table 7 presents selected adverse reactions from Study CA184-029.

Table 7: Adverse Reactions (≥5%) in Patients Receiving YERVOY with a Difference Between Arms >5% Compared to Placebo in Study CA184-029

Adverse Reaction

YERVOY 10 mg/kg
n=471

Placebo
n=474

All Grades (%)

Grade 3 to 5 (%)

All Grades (%)

Grade 3 to 5 (%)

Dermatologic

     Rash

50

2.1

20

0

     Pruritus

45

2.3

15

0

Gastrointestinal

     Diarrhea

49

10

30

2.1

     Nausea

25

0.2

18

0

     Colitis

16

8

1.5

0.4

     Vomiting

13

0.4

6

0.2

General and Administration-Site Conditions

     Fatigue

46

2.3

38

1.5

     Weight Decreased

32

0.2

9

0.4

     Pyrexia

18

1.1

4.9

0.2

Nervous System

     Headache

33

0.8

18

0.2

Metabolism and Nutrition

     Decreased Appetite

14

0.2

3.4

0.2

Psychiatric

     Insomnia

10

0

4.4

0

Table 8 presents selected laboratory abnormalities from Study CA184-029.

Table 8: Laboratory Abnormalities (>5%) Worsening from Baseline in Patients Receiving YERVOY with a Difference Between Arms of >5% Compared to Placebo in CA184-029a
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients). For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients).

Laboratory Abnormality

YERVOY 10 mg/kga

Placeboa

All Grades
(%)

Grade 3 to 4

(%)

All Grades
(%)

Grade 3 to 4
(%)

Chemistry

    Increased ALT

46

10

16

0

    Increased AST

38

9

14

0.2

    Increased lipase

26

9

17

4.5

    Increased amylase

17

2.0

7

0.6

    Increased alkaline phosphatase

17

0.6

6

0.2

    Increased bilirubin

11

1.5

9

0

    Increased creatinine

10

0.2

6

0

Hematology

    Decreased hemoglobin

25

0.2

14

0

Other Clinical Experience

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

Advanced Renal Cell Carcinoma: In Combination with Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214 [see Clinical Studies (14.3)]. Patients received YERVOY 1 mg/kg with nivolumab 3 mg/kg intravenously every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg every 2 weeks (n=547) or sunitinib 50 mg orally daily for first 4 weeks of each 6-week cycle (n=535). The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in YERVOY and nivolumab arm. In this trial, 57% of patients in the YERVOY and nivolumab arm were exposed to treatment for greater than 6 months and 38% of patients were exposed to treatment for greater than 1 year.

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

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

The most common adverse reactions (≥20%) in the YERVOY and nivolumab arm were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, vomiting, dyspnea, and decreased appetite. Table 9 summarizes adverse reactions in CHECKMATE-214.

Table 9: Adverse Reactions (>15%) in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.

Adverse Reaction

YERVOY 1 mg/kg and Nivolumab
n=547

Sunitinib
n=535

Grades 1-4

(%)

Grades 3-4

(%)

Grades 1-4

(%)

Grades 3-4

(%)

General and Administration Site Conditions

     Fatiguea

58

8

69

13

     Pyrexia

25

0.7

17

0.6

     Edemab

16

0.5

17

0.6

Skin and Subcutaneous Tissue

     Rashc

39

3.7

25

1.1

     Pruritus/generalized pruritus

33

0.5

11

0

Gastrointestinal

     Diarrhea

38

4.6

58

6

     Nausea

30

2.0

43

1.5

     Vomiting

20

0.9

28

2.1

     Abdominal pain

19

1.6

24

1.9

     Constipation

17

0.4

18

0

Musculoskeletal and Connective Tissue

     Musculoskeletal paind

37

4.0

40

2.6

     Arthralgia

23

1.3

16

0

Respiratory, Thoracic, and Mediastinal

     Cough/productive cough

28

0.2

25

0.4

     Dyspnea/exertional dyspnea

20

2.4

21

2.1

Metabolism and Nutrition

     Decreased appetite

21

1.8

29

0.9

Nervous System

     Headache

19

0.9

23

0.9

Endocrine

     Hypothyroidism

18

0.4

27

0.2

Table 10 summarizes the laboratory abnormalities in CHECKMATE-214.

Table 10: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: nivolumab and YERVOY group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).

Laboratory Abnormality

YERVOY 1 mg/kg and Nivolumaba

Sunitiniba

Grades 1-4
(%)

Grades 3-4
(%)

Grades 1-4
(%)

Grades 3-4
(%)

Chemistry

     Increased lipase

48

20

51

20

     Increased creatinine

42

2.1

46

1.7

     Increased ALT

41

7

44

2.7

     Increased AST

40

4.8

60

2.1

     Increased amylase

39

12

33

7

     Hyponatremia

39

10

36

7

     Increased alkaline phosphatase

29

2.0

32

1.0

     Hyperkalemia

29

2.4

28

2.9

     Hypocalcemia

21

0.4

35

0.6

     Hypomagnesemia

16

0.4

26

1.6

Hematology

     Anemia

43

3.0

64

9

     Lymphopenia

36

5

63

14

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

MSI-H or dMMR Metastatic Colorectal Cancer: In Combination with Nivolumab

The safety of YERVOY with nivolumab was evaluated in 119 patients with previously treated MSI-H or dMMR mCRC in a single-arm cohort of CHECKMATE-142 [see Clinical Studies (14.4)]. All patients had received prior fluorouracil-based chemotherapy for metastatic disease; 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan and 29% had received an anti-EGFR antibody. Patients received YERVOY 1 mg/kg and nivolumab 3 mg/kg on Day 1 of each 21-day cycle for 4 doses, then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure for YERVOY was 2.1 months.

Serious adverse reactions occurred in 47% of patients receiving YERVOY and nivolumab. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration.

The most common adverse reactions (≥20%) in the YERVOY and nivolumab cohort were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting. Table 11 summarizes adverse reactions in CHECKMATE-142.

Table 11: Adverse Reactions Occurring in ≥10% of Patients (CHECKMATE-142)
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema and peripheral swelling.
c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.
e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.
f Includes nasopharyngitis and rhinitis.

Adverse Reaction

YERVOY and Nivolumab MSI-H/dMMR Cohort

(n=119)

All Grades (%)

Grades 3-4 (%)

General and Administration Site Conditions

     Fatiguea

49

6

     Pyrexia

36

0

     Edemab

7

0

Gastrointestinal

     Diarrhea

45

3.4

     Abdominal painc

30

5

     Nausea

26

0.8

     Vomiting

20

1.7

     Constipation

15

0

Musculoskeletal and Connective Tissue

     Musculoskeletal paind

36

3.4

     Arthralgia

14

0.8

Skin and Subcutaneous Tissue

     Pruritus

28

1.7

     Rashe

25

4.2

     Dry Skin

11

0

Infections and Infestations

     Upper respiratory tract infectionf

9

0

Metabolism and Nutrition

     Decreased appetite

20

1.7

Respiratory, Thoracic, and Mediastinal

     Cough

19

0.8

     Dyspnea

13

1.7

Nervous System

     Headache

17

1.7

     Dizziness

11

0

Endocrine

     Hyperglycemia

6

1

     Hypothyroidism

14

0.8

     Hyperthyroidism

12

0

Investigations

     Weight decreased

10

0

Psychiatric

     Insomnia

13

0.8

Other clinically important adverse reactions reported in <10% of patients receiving YERVOY in CHECKMATE-142 were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Table 12 summarizes laboratory abnormalities in CHECKMATE-142.

Table 12: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients (CHECKMATE-142)
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 87 to 114 for nivolumab with YERVOY and from 62 to 71 for nivolumab.

Laboratory Abnormality

YERVOY and Nivolumab MSI-H/dMMR Cohort
(n=119)

All Grades (%)

Grades 3-4 (%)

Hematology

     Anemia

42

9

     Thrombocytopenia

26

0.9

     Lymphopenia

25

6

     Neutropenia

18

0

Chemistry

     Increased AST

40

12

     Increased lipase

39

12

     Increased amylase

36

3.4

     Increased ALT

33

12

     Increased alkaline phosphatase

28

5

     Hyponatremia

26

5

     Increased creatinine

25

3.6

     Hyperkalemia

23

0.9

     Increased bilirubin

21

5

     Hypomagnesemia

18

0

     Hypocalcemia

16

0

     Hypokalemia

15

1.8

Hepatocellular Carcinoma: In Combination with Nivolumab

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

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

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

Table 13 summarizes the adverse reactions and Table 14 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040.

Table 13: Adverse Reactions Occurring in ≥10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040

Adverse Reaction

YERVOY and Nivolumab

(n=49)

All Grades (%)

Grades 3-4 (%)

Skin and Subcutaneous Tissue

     Rash

53

8

     Pruritus

53

4

Musculoskeletal and Connective Tissue

     Musculoskeletal pain

41

2

     Arthralgia

10

0

Gastrointestinal

     Diarrhea

39

4

     Abdominal pain

22

6

     Nausea

20

0

     Ascites

14

6

     Constipation

14

0

     Dry mouth

12

0

     Dyspepsia

12

2

     Vomiting

12

2

     Stomatitis

10

0

Respiratory, Thoracic and Mediastinal

     Cough

37

0

     Dyspnea

14

0

     Pneumonitis

10

2

Metabolism and Nutrition

     Decreased appetite

35

2

General

     Fatigue

27

2

     Pyrexia

27

0

     Malaise

18

2

     Edema

16

2

     Influenza-like illness

14

0

     Chills

10

0

Nervous System

     Headache

22

0

     Dizziness

20

0

Endocrine

     Hypothyroidism

20

0

     Adrenal insufficiency

18

4

Investigations

     Weight decreased

20

0

Psychiatric

     Insomnia

18

0

Blood and Lymphatic System

     Anemia

10

4

Infections

     Influenza

10

2

Vascular

     Hypotension

10

0

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

Table 14: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040

Laboratory Abnormality

YERVOY and Nivolumab

(n=47)

All Grades (%)

Grades 3-4 (%)

Hematology

     Lymphopenia

53

13

     Anemia

43

4.3

     Neutropenia

43

9

     Leukopenia

40

2.1

     Thrombocytopenia

34

4.3

Chemistry

     Increased AST

66

40

     Increased ALT

66

21

     Increased bilirubin

55

11

     Increased lipase

51

26

     Hyponatremia

49

32

     Hypocalcemia

47

0

     Increased alkaline phosphatase

40

4.3

     Increased amylase

38

15

     Hypokalemia

26

2.1

     Hyperkalemia

23

4.3

     Increased creatinine

21

0

     Hypomagnesemia

11

0

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

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

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.6)]. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received YERVOY 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks and nivolumab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received YERVOY and nivolumab for >6 months and 23% of patients received YERVOY and nivolumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.

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

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

Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Table 15: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-227
a Includes fatigue and asthenia.
b Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema.
c Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption.
d Includes pruritus and pruritus generalized.
e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity.
f Includes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral.
g Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.
h Includes dyspnea and dyspnea exertional.
i Includes cough and productive cough.
j Includes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased.
k Includes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased.
l Contains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased.
m Includes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia.

Adverse Reaction

YERVOY and Nivolumab
(n=576)

Platinum-doublet Chemotherapy
(n=570)

All Grades
(%)

Grades 3-4
(%)

All Grades
(%)

Grades 3-4
(%)

General

     Fatiguea

44

6

42

4.4

     Pyrexia

18

0.5

11

0.4

     Edemab

14

0.2

12

0.5

Skin and Subcutaneous Tissue

     Rashc

34

4.7

10

0.4

     Pruritusd

21

0.5

3.3

0

Metabolism and Nutrition

     Decreased appetite

31

2.3

26

1.4

Musculoskeletal and Connective Tissue

     Musculoskeletal paine

27

1.9

16

0.7

     Arthralgia

13

0.9

2.5

0.2

Gastrointestinal

     Diarrhea/colitisf

26

3.6

16

0.9

     Nausea

21

1.0

42

2.5

     Constipation

18

0.3

27

0.5

     Vomiting

13

1.0

18

2.3

     Abdominal paing

10

0.2

9

0.7

Respiratory, Thoracic, and Mediastinal

     Dyspneah

26

4.3

16

2.1

     Coughi

23

0.2

13

0

Hepatobiliary

     Hepatitisj

21

9

10

1.2

Endocrine

     Hypothyroidismk

16

0.5

1.2

0

     Hyperthyroidisml

10

0

0.5

0

Infections and Infestations

     Pneumoniam

13

7

8

4.0

Nervous System

     Headache

11

0.5

6

0

Other clinically important adverse reactions in CHECKMATE-227 were:

Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo

Gastrointestinal: stomatitis, pancreatitis, gastritis

Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis

Nervous System: peripheral neuropathy, autoimmune encephalitis

Blood and Lymphatic System: eosinophilia

Eye Disorders: blurred vision, uveitis

Cardiac: atrial fibrillation, myocarditis

Table 16: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on YERVOY and Nivolumab - CHECKMATE-227
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients).

Laboratory Abnormality

YERVOY and Nivolumab

Platinum-doublet Chemotherapy

Grades 1-4
(%)

Grades 3-4
(%)

Grades 1-4
(%)

Grades 3-4
(%)

Hematology

     Anemia

46

3.6

78

14

     Lymphopenia

46

5

60

15

Chemistry

     Hyponatremia

41

12

26

4.9

     Increased AST

39

5

26

0.4

     Increased ALT

36

7

27

0.7

     Increased lipase

35

14

14

3.4

     Increased alkaline phosphatase

34

3.8

20

0.2

     Increased amylase

28

9

18

1.9

     Hypocalcemia

28

1.7

17

1.3

     Hyperkalemia

27

3.4

22

0.4

     Increased creatinine

22

0.9

17

0.2

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

The safety of YERVOY in combination with nivolumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.6)]. Patients received either YERVOY 1 mg/kg administered every 6 weeks in combination with nivolumab 360 mg administered every 3 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in YERVOY in combination with nivolumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received YERVOY and nivolumab for >6 months and 13% of patients received YERVOY and nivolumab for >1 year.

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

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

Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Table 17: Adverse Reactions in >10% of Patients Receiving YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis
c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis
d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain
e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blenorrhagica, palmar-plantar erythrodysaesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria
f Includes pruritus and generalized pruritus
g Includes cough, productive cough, and upper-airway cough syndrome
h Includes dyspnea, dyspnea at rest, and exertional dyspnea
i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine
j Includes dizziness, vertigo and positional vertigo

Adverse Reaction

YERVOY and Nivolumab and Platinum-Doublet Chemotherapy
(n=358)

Platinum-Doublet Chemotherapy
(n=349)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

     Fatiguea

49

5

40

4.9

     Pyrexia

14

0.6

10

0.6

Musculoskeletal and Connective Tissue

     Musculoskeletal painb

39

4.5

27

2.0

Gastrointestinal

     Nausea

32

1.7

41

0.9

     Diarrheac

31

6

18

1.7

     Constipation

21

0.6

23

0.6

     Vomiting

18

2.0

17

1.4

     Abdominal paind

12

0.6

11

0.9

Skin and Subcutaneous Tissue

     Rashe

30

4.7

10

0.3

     Pruritusf

21

0.8

2.9

0

     Alopecia

11

0.8

10

0.6

Metabolism and Nutrition

     Decreased appetite

28

2.0

22

1.7

Respiratory, Thoracic and Mediastinal

     Coughg

19

0.6

15

0.9

     Dyspneah

18

4.7

14

3.2

Endocrine

     Hypothyroidismi

19

0.3

3.4

0

Nervous System

     Headache

11

0.6

7

0

     Dizzinessj

11

0.6

6

0

Table 18: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).

Laboratory Abnormality

YERVOY and Nivolumab and Platinum-Doublet Chemotherapy

Platinum-Doublet Chemotherapy

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Hematology

     Anemia

70

9

74

16

     Lymphopenia

41

6

40

11

     Neutropenia

40

15

42

15

     Leukopenia

36

10

40

9

     Thrombocytopenia

23

4.3

24

5

Chemistry

     Hyperglycemia

45

7

42

2.6

     Hyponatremia

37

10

27

7

     Increased ALT

34

4.3

24

1.2

     Increased lipase

31

12

10

2.2

     Increased alkaline phosphatase

31

1.2

26

0.3

     Increased amylase

30

7

19

1.3

     Increased AST

30

3.5

22

0.3

     Hypomagnesemia

29

1.2

33

0.6

     Hypocalcemia

26

1.4

22

1.8

     Increased creatinine

26

1.2

23

0.6

     Hyperkalemia

22

1.7

21

2.1

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

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.7)]. Patients received either YERVOY 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks and nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received YERVOY and nivolumab for >6 months and 24% of patients received YERVOY and nivolumab for >1 year.

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

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

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

Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.

Table 19: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-743
a Includes fatigue and asthenia.
b Includes pyrexia and tumor-associated fever.
c Includes edema, generalized edema, peripheral edema, and peripheral swelling.
d Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain.
e Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blenorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria.
f Includes pruritus, allergic pruritus, and generalized pruritus.
g Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis.
h Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain.
i Includes dyspnea, dyspnea at rest, and exertional dyspnea.
j Includes cough, productive cough, and upper-airway cough syndrome.
k Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism.
l Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
m Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia.

Adverse Reaction

YERVOY and Nivolumab
(n=300)

Chemotherapy
(n=284)

All Grades
(%)

Grades 3-4
(%)

All Grades
(%)

Grades 3-4
(%)

General

     Fatiguea

43

4.3

45

6

     Pyrexiab

18

1.3

4.6

0.7

     Edemac

17

0

8

0

Musculoskeletal and Connective Tissue

     Musculoskeletal paind

38

3.3

17

1.1

     Arthralgia

13

1.0

1.1

0

Skin and Subcutaneous Tissue

     Rashe

34

2.7

11

0.4

     Pruritusf

21

1.0

1.4

0

Gastrointestinal

     Diarrheag

32

6

12

1.1

     Nausea

24

0.7

43

2.5

     Constipation

19

0.3

30

0.7

     Abdominal painh

15

1

10

0.7

     Vomiting

14

0

18

2.1

Respiratory, Thoracic, and Mediastinal

     Dyspneai

27

2.3

16

3.2

     Coughj

23

0.7

9

0

Metabolism and Nutrition

     Decreased appetite

24

1.0

25

1.4

Endocrine

     Hypothyroidismk

15

0

1.4

0

Infections and Infestations

     Upper respiratory tract infectionl

12

0.3

7

0

     Pneumoniam

10

4.0

4.2

2.1

Table 20: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on YERVOY and Nivolumab - CHECKMATE-743

Laboratory Abnormality

YERVOY and Nivolumab

Chemotherapy

Grades 1-4
(%)

Grades 3-4
(%)

Grades 1-4
(%)

Grades 3-4
(%)

Chemistry

     Hyperglycemia

53

3.7

34

1.1

     Increased AST

38

7

17

0

     Increased ALT

37

7

15

0.4

     Increased lipase

34

13

9

0.8

     Hyponatremia

32

8

21

2.9

     Increased alkaline phosphatase

31

3.1

12

0

     Hyperkalemia

30

4.1

16

0.7

     Hypocalcemia

28

0

16

0

     Increased amylase

26

5

13

0.9

     Increased creatinine

20

0.3

20

0.4

Hematology

     Lymphopenia

43

8

57

14

     Anemia

43

2.4

75

15

a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidences of antibodies to other studies or to other products may be misleading.

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.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], YERVOY can cause fetal harm when administered to a pregnant woman. There is insufficient human data for YERVOY exposure in pregnant women. 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 (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Bristol-Myers Squibb at 1-844-593-7869.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the humans exposure based on area under the curve at a dose of 3 mg/kg). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.

Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.

8.2 Lactation

Risk Summary

There are no data on the presence of YERVOY in human milk or its effects on the breastfed child or milk production. In monkeys, ipilimumab was present in milk (see Data). Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with YERVOY and for 3 months following the last dose.

Data

In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing a ratio of up to 0.3% of the steady-state serum concentration of the drug.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating YERVOY [see Use in Specific Populations (8.1)].

Contraception

YERVOY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months following the last dose.

8.4 Pediatric Use

The safety and effectiveness of YERVOY have been established in pediatric patients 12 years and older for the treatment of unresectable or metastatic melanoma or for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY in this age group is supported by evidence from adequate and well-controlled studies of YERVOY in adults and population pharmacokinetic data demonstrating that the exposure at doses of 3 mg/kg and 1 mg/kg in the pediatric and adult populations are comparable. In addition, the tumor biology and course of advanced melanoma and MSI-H or dMMR mCRC are sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients.

The safety and effectiveness for pediatric patients 12 years and older have not been established for the adjuvant treatment of melanoma or for the treatment of renal cell carcinoma. In addition, the safety and effectiveness have not been established with YERVOY for any indication in pediatric patients less than 12 years of age.

YERVOY was evaluated in a total of 45 pediatric patients across two clinical trials. In a dose-finding trial (NCT01445379), 33 pediatric patients with relapsed or refractory solid tumors were evaluated. The median age was 13 years (range 2 to 21 years) and 20 patients were ≥12 years old. YERVOY was also evaluated in an open-label, single-arm trial (NCT01696045) in 12 pediatric patients ≥12 years old (range 12 to 16 years) with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma.

Of the 17 patients ≥12 years of age with melanoma treated with YERVOY across both studies, 2 patients experienced objective responses including one partial response that was sustained for 16 months. There were no responses in patients with non-melanoma solid tumors. No new safety signals were observed in pediatric patients in these two studies.

8.5 Geriatric Use

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.

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.

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.

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 49 patients who received YERVOY 3 mg/kg with nivolumab in Cohort 4 of CHECKMATE-040 (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 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 with 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 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.

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.

11 DESCRIPTION

Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody. Ipilimumab is a recombinant IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.

YERVOY (ipilimumab) injection, for intravenous use is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-dose vials of 50 mg/10 mL or 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.

12 CLINICAL PHARMACOLOGY

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: Based on a population PK analysis using available pooled data from 565 patients from four adult studies (n=521) and two pediatric studies (n=44), body weight normalized clearance of ipilimumab is comparable between adult and pediatric patients. In pediatric patients with a dosing regimen of 3 mg/kg every 3 weeks, the model simulated geometric mean (CV%) steady-state serum peak and trough concentrations of ipilimumab were 65.8 (17.6%) and 20.7 (33.1%) mcg/mL (for 2 to 6 years old), 70.1 (19.6%) and 19.6 (42.9%) mcg/mL (for 6 to <12 years old), and 73.3 (20.6%) and 17.8 (50.8%) mcg/mL (for 12 years and older), which are comparable to those in adult patients.

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.

13 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

14.1 Unresectable or Metastatic Melanoma

The efficacy of YERVOY were 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 21 and Figure 1.

Table 21: Efficacy Results for Study MDX010-20
a Not adjusted for multiple comparisons
b Not reached

YERVOY 3 mg/kg

n=137

YERVOY 3 mg/kg and gp100
n=403

gp100

n=136

Overall Survival

Median in months (95% CI)

10 (8.0, 13.8)

10 (8.5, 11.5)

6 (5.5, 8.7)

Hazard ratio (vs. gp100) (95% CI)

0.66 (0.51, 0.87)

0.68 (0.55, 0.85)

p-value

p=0.0026a

p=0.0004

Hazard ratio (vs. YERVOY) (95% CI)

1.04 (0.83, 1.30)

Best Overall Response Rate (BORR)

(95% CI)

10.9%

(6.3%, 17.4%)

5.7%

(3.7%, 8.4%)

1.5%

(0.2%, 5.2%)

Median duration of response in months

NRb

11.5

NRb

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

yervoy-os-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 22 and Figure 2.

Table 22: 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 .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

yervoy-os-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 for the adjuvant treatment of melanoma was evaluated in Study CA184-029 (NCT00636168), a randomized (1:1), double-blind, placebo-controlled trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) histologically confirmed cutaneous melanoma. Enrollment required complete resection of melanoma with full lymphadenectomy within 12 weeks prior to randomization. Patients with prior therapy for melanoma, autoimmune disease, and prior or concomitant use of immunosuppressive agents were ineligible. Patients were randomized to receive YERVOY 10 mg/kg or placebo as an intravenous infusion every 3 weeks for 4 doses, followed by YERVOY 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (3 years) or until documented disease recurrence or unacceptable toxicity. Randomization was stratified by stage according to American Joint Committee on Cancer (AJCC) 2002 classification (Stage IIIA >1 mm nodal involvement, Stage IIIB, Stage IIIC with 1 to 3 involved lymph nodes, and Stage IIIC with ≥4 involved lymph nodes) and by region (North America, Europe, and Australia). The major efficacy outcome measures were independent review committee (IRC)-assessed recurrence-free survival (RFS), defined as the time between the date of randomization and the earliest date of first recurrence (local, regional, or distant metastasis) or death, and overall survival. Tumor assessment was conducted every 12 weeks for the first 3 years then every 24 weeks until distant recurrence.

Among 951 patients enrolled, 475 were randomized to receive YERVOY and 476 to placebo. Median age was 51 years (range: 18 to 84), 62% were male, 99% were White, 94% had ECOG performance status of 0. With regard to disease stage, 20% had Stage IIIA with lymph nodes >1 mm, 44% had Stage IIIB, and 36% had Stage IIIC (with no in-transit metastases). Other disease characteristics of the trial population were: clinically palpable lymph nodes (58%), 2 or more positive lymph nodes (54%), and ulcerated primary lesions (42%).

The efficacy results are in Table 23 and Figure 3.

Table 23: Efficacy Results for Study CA184-029
a Stratified by disease stage.

YERVOY 10 mg/kg
n=475

Placebo
n=476

Recurrence-Free Survival

Number of events

234 (49%)

294 (62%)

     Recurrence

220

289

     Death

14

5

Median in months (95% CI)

26 (19, 39)

17 (13, 22)

Hazard ratio (95% CI)

0.75 (0.64, 0.90)

p-value (stratified log-ranka)

p<0.002

Overall Survival

Number of deaths

162 (34%)

214 (45%)

Hazard ratio (95% CI)

0.72 (0.58, 0.88)

p-value (stratified log-ranka)

p<0.002

Figure 3: Kaplan-Meier Curves for Overall Survival in Study CA184-029

yervoy-os-ca184-029

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 24 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.

Table 24: Efficacy Results for CHECKMATE-214
a Based on a stratified proportional hazards model.
b Based on a stratified log-rank test.
c p-value is compared to alpha 0.002 in order to achieve statistical significance.
d Based on the stratified DerSimonian-Laird test.
e p-value is compared to alpha 0.001 in order to achieve statistical significance.
f Not Significant at alpha level of 0.009

Efficacy Parameter

Intermediate/Poor-Risk

YERVOY 1 mg/kg and Nivolumab
n=425

Sunitinib
n=422

Overall Survival

     Number of deaths

140 (32.9%)

188 (44.5%)

     Median in months

NE

25.9

     Hazard ratio (99.8% CI)a

0.63 (0.44, 0.89)

     p-valueb,c

<0.0001

Confirmed Objective Response Rate (95% CI)

41.6% (36.9%, 46.5%)

26.5% (22.4%, 31.0%)

     Complete Response

40 (9.4%)

5 (1.2%)

     Partial Response

137 (32.2%)

107 (25.4%)

     Median duration of response in months (95% CI)

NE (21.8, NE)

18.2 (14.8, NE)

p-valued,e

<0.0001

Progression-free Survival

     Number of events (progression or death)

228 (53.6%)

228 (54.0%)

     Median in months

11.6

8.4

     Hazard ratio (99.1% CI)a

0.82 (0.64, 1.05)

     p-valueb

NSf

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

yervoy-os-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

The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-142 (NCT02060188), a multicenter, non-randomized, multiple parallel-cohort, open-label study conducted in patients with locally determined dMMR or MSI-H mCRC who had disease progression during or after prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG PS 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients enrolled in the YERVOY and nivolumab MSI-H or dMMR mCRC cohort received YERVOY 1 mg/kg and nivolumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg intravenously as a single agent every 2 weeks. Efficacy outcome measures were overall response rate (ORR) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DOR). Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter.

A total of 119 patients were enrolled in the YERVOY and nivolumab cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75 years of age; 59% were male and 92% were white. Baseline ECOG PS was 0 (45%) or 1 (55%), and 29% were reported to have Lynch Syndrome. Across the cohort, 69% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.

Efficacy results are shown in Table 25.

Table 25: Efficacy Results in MSI-H/dMMR Cohort of CHECKMATE-142
a Minimum follow-up 27.5 months for all patients treated with YERVOY and nivolumab (n=119).
b Estimated using the Clopper-Pearson method.

YERVOY and Nivolumaba
MSI-H/dMMR Cohort

All Patients
(n=119)

Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan)
(n=82)

Overall Response Rate per BICR; n (%)

71 (60%)

46 (56%)

      (95% CI)b

(50, 69)

(45, 67)

      Complete Response (%)

17 (14%)

11 (13%)

      Partial Response (%)

54 (45%)

35 (43%)

Duration of Response

      Proportion of responders with ≥6 months response duration

89%

87%

      Proportion of responders with ≥12 months response duration

77%

74%

14.5 Hepatocellular Carcinoma

CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.

The efficacy of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in Cohort 4 of CHECKMATE-040. A total of 49 patients received the combination regimen, which was administered every 3 weeks for four doses, followed by single-agent nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity.

The median age was 60 years (range: 18 to 80); 88% were male; 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven percent (57%) of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had alfa-fetoprotein (AFP) levels ≥400 µg/L. Prior treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies.

Efficacy results are shown in Table 26.

Table 26: Efficacy Results - Cohort 4 of CHECKMATE-040
a Confirmed by BICR.
b Confidence interval is based on the Clopper and Pearson method.

YERVOY and Nivolumab
(Cohort 4)
(n=49)

Overall Response Rate per BICR,a n (%), RECIST v1.1

16 (33%)

           (95% CI)b

(20, 48)

     Complete response

4 (8%)

     Partial response

12 (24%)

Duration of Response per BICR,a RECIST v1.1

n=16

     Range (months)

4.6, 30.5+

     Percent with duration ≥6 months

88%

     Percent with duration ≥12 months

56%

     Percent with duration ≥24 months

31%

Overall Response Rate per BICR,a n (%), mRECIST

17 (35%)

           (95% CI)b

(22, 50)

     Complete response

6 (12%)

     Partial response

11 (22%)

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 27 and Figure 5.

Table 27: 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 5: Overall Survival (PD-L1 ≥1%) - CHECKMATE-227

yervoy-os-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 28.

Table 28: 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 6).

Figure 6: Overall Survival - CHECKMATE-9LA

yervoy-os-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 29 and Figure 7.

Table 29: Efficacy Results - CHECKMATE-743
a At the time of the interim analysis, 419 deaths (89% of the deaths needed for the final analysis) had occurred.
b Kaplan-Meier estimate.
c Stratified Cox proportional hazard model.
d p-value is compared with the allocated alpha of 0.0345 for this interim analysis.
e Based on confirmed response by BICR.

YERVOY and Nivolumab
(n=303)

Chemotherapy
(n=302)

Overall Survivala

     Events (%)

200 (66)

219 (73)

     Median (months)b

           (95% CI)

18.1
(16.8, 21.5)

14.1
(12.5, 16.2)

     Hazard ratio (95% CI)c

0.74 (0.61, 0.89)

     Stratified log-rank p-valued

0.002

Progression-free Survival

     Events (%)

218 (72)

209 (69)

     Hazard ratio (95% CI)c

1.0 (0.82, 1.21)

     Median (months)b

               (95% CI)

6.8
(5.6, 7.4)

7.2
(6.9, 8.1)

Overall Response Ratee

40%

43%

      (95% CI)

(34, 45)

(37, 49)

Duration of Response

     Median (months)a
           (95% CI)

11.0
(8.1, 16.5)

6.7
(5.3, 7.1)

Figure 7: Overall Survival - CHECKMATE-743

yervoy-os-checkmate-743

In a prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the YERVOY and nivolumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the YERVOY and nivolumab arm and 8.8 months in the chemotherapy arm.

16 HOW SUPPLIED/STORAGE AND HANDLING

YERVOY (ipilimumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution. YERVOY is available as follows:

Carton Contents

NDC

One 50 mg vial (5 mg/mL), single-dose vial

NDC 0003-2327-11

One 200 mg vial (5 mg/mL), single-dose vial

NDC 0003-2328-22

Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F). Protect YERVOY from light by storing in the original carton until time of use. Do not freeze or shake.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Advise patients that YERVOY can cause immune-mediated adverse reactions including the following [see Warnings and Precautions (5.1)]:

Immune-Mediated Diarrhea or Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of diarrhea or colitis.
Immune-Mediated Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.
Immune-Mediated Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash.
Immune-Mediated Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus
Immune-Mediated Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening symptoms of pneumonitis.
Immune-Mediated Nephritis with Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

Infusion-Related Reactions

Advise patients who are receiving YERVOY of the potential risk of an infusion-related reaction [see Warnings and Precautions (5.2)].

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.3)].
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 (8.3)].
Advise patients who may have been exposed to YERVOY during pregnancy to contact Bristol-Myers Squibb at 1-844-593-7869 [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with YERVOY and for 3 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713

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MEDICATION GUIDE

YERVOY® (yur-voi)
(ipilimumab)
injection

Read this Medication Guide before you start receiving YERVOY and before each infusion. There may be new information. If your healthcare provider prescribes YERVOY in combination with nivolumab (OPDIVO®), also read the Medication Guide that comes with nivolumab. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about YERVOY?

YERVOY is a medicine that may treat certain cancers by working with your immune system. YERVOY can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You may have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Some of these problems may happen more often when YERVOY is used in combination with nivolumab.

Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:

Intestinal problems.

diarrhea (loose stools) or more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucus
severe stomach-area (abdominal) pain or tenderness

Liver problems.

yellowing of your skin or the whites of your eyes
severe nausea or vomiting
pain on the right side of your stomach-area (abdomen)
dark urine (tea colored)
bleeding or bruising more easily than normal

Skin problems.

rash
itching
skin blistering or peeling
painful sores in mouth or nose, throat, or genital area

Hormone gland problems.

headache that will not go away or unusual headaches
eye sensitivity to light
eye problems
rapid heartbeat
increased sweating
extreme tiredness
weight gain or weight loss
feeling more hungry or thirsty than usual
urinating more often than usual
hair loss
feeling cold
constipation
your voice gets deeper
dizziness or fainting
changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness

Lung problems.

new or worsening cough
shortness of breath
chest pain

Kidney problems.

decrease in your amount of urine
blood in your urine
swelling of your ankles
loss of appetite

Eye problems.

blurry vision, double vision, or other vision problems
eye pain or redness

Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with YERVOY. Call or see your healthcare provider right away for any new or worsening signs or symptoms.

Chest pain, irregular heartbeat, shortness of breath or swelling of ankles
Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
Double vision, blurry vision, sensitivity to light, eye pain, changes in eye sight
Persistent or severe muscle pain or weakness, muscle cramps
Low red blood cells, bruising

Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with YERVOY. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with YERVOY if you have severe side effects.

What is YERVOY?

YERVOY is a prescription medicine used:

to treat a kind of skin cancer called melanoma.
o
YERVOY may be used alone in adults and children 12 years of age and older or in combination with nivolumab in adults when melanoma has spread or cannot be removed by surgery.
o
YERVOY may be used alone to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.
in people with kidney cancer (renal cell carcinoma). YERVOY may be used in combination with nivolumab in certain people when their cancer has spread.
in adults and children 12 years of age and older, with a type of colon or rectal cancer (colorectal cancer).
o
YERVOY in combination with nivolumab may be used when your colon or rectal cancer:
has spread to other parts of the body (metastatic),
is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and
you have tried treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.
in people with liver cancer (hepatocellular carcinoma).
o
YERVOY may be used in combination with nivolumab if you have previously received treatment with sorafenib.
in adults with a type of lung cancer called non-small cell lung cancer (NSCLC).
o
YERVOY may be used in combination with nivolumab as your first treatment for NSCLC:
when your lung cancer has spread to other parts of your body (metastatic), and
your tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.
o
YERVOY may be used in combination with nivolumab and 2 cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:
has spread or grown, or comes back, and
your tumor does not have an abnormal EGFR or ALK gene.
in adults with a type of cancer that affects the lining of the lungs and chest wall called malignant pleural mesothelioma.
o
YERVOY may be used in combination with nivolumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.

It is not known if YERVOY is safe and effective in children younger than 12 years of age.

Before you receive YERVOY, tell your healthcare provider about all your medical conditions, including if you:

have immune system problems such as ulcerative colitis, Crohn’s disease, or lupus
have received an organ transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
are pregnant or plan to become pregnant. YERVOY can harm your unborn baby.
 
Females who are able to become pregnant:
 
Your healthcare provider will give you a pregnancy test before you start treatment with YERVOY.
o
You should use an effective method of birth control during your treatment and for 3 months after the last dose of YERVOY. Talk to your healthcare provider about birth control methods that you can use during this time.
o
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with YERVOY. You or your healthcare provider should contact Bristol-Myers Squibb at 1-844-593-7869 as soon as you become aware of a pregnancy.
o
are breastfeeding or plan to breastfeed. It is not known if YERVOY passes into your breast milk.
o
Do not breastfeed during treatment with YERVOY and for 3 months after the last dose of YERVOY.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive YERVOY?

YERVOY alone is given to you into your vein through an intravenous (IV) line over 90 minutes.
When YERVOY is used in combination with nivolumab (except for treating unresectable or metastatic melanoma), nivolumab is given to you into your vein through an IV line over 30 minutes. Then YERVOY is also given through an IV over 30 minutes on the same day.
For unresectable or metastatic melanoma, when YERVOY is used in combination with nivolumab, nivolumab is given to you into your vein through an IV line over 30 minutes. Then YERVOY is also given through an IV over 90 minutes on the same day.
YERVOY in combination with nivolumab is usually given every 3 weeks for 4 doses. After that, nivolumab alone is usually given every 2 or 4 weeks.
o
For NSCLC that has spread to other parts of your body, YERVOY is given every 6 weeks and nivolumab is given either every 2 or 3 weeks for up to 2 years. Your healthcare provider will determine if you will also need to receive chemotherapy every 3 weeks for 2 cycles.
o
For malignant pleural mesothelioma that cannot be removed by surgery, YERVOY is given every 6 weeks and nivolumab is given every 3 weeks for up to 2 years.
Your healthcare provider will decide how many treatments you will need.
Your healthcare provider will do blood tests before starting and during treatment with YERVOY.
If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.

What are the possible side effects of YERVOY?

YERVOY can cause serious side effects, including:

See What is the most important information I should know about YERVOY?
Severe infusion-related reactions. Tell your healthcare provider or nurse right away if you get these symptoms during an infusion of YERVOY:
o
chills or shaking
o
itching or rash
o
flushing
o
shortness of breath or wheezing
o
dizziness
o
feel like passing out
o
fever
o
back or neck pain
Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with YERVOY. Your healthcare provider will monitor you for these complications.

The most common side effects of YERVOY when used alone include:

feeling tired
diarrhea
nausea
itching
rash
vomiting
headache
weight loss
fever
decreased appetite
difficulty falling or staying asleep

The most common side effects of YERVOY when used in combination with nivolumab include:

feeling tired
diarrhea
rash
itching
nausea
pain in muscles, bones, and joints
fever
cough
decreased appetite
vomiting
stomach-area (abdominal) pain
shortness of breath
upper respiratory tract infection
headache
low thyroid hormone levels (hypothyroidism)
decreased weight
dizziness

The most common side effects of YERVOY when used in combination with nivolumab and chemotherapy include:

feeling tired
pain in muscles, bones, and joints
nausea
diarrhea
rash
decreased appetite
constipation
itching

These are not all of the possible side effects of YERVOY.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of YERVOY.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about YERVOY, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about YERVOY that is written for healthcare professionals.

What are the ingredients of YERVOY?

Active ingredient: ipilimumab

Inactive ingredients: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 80, sodium chloride, tris hydrochloride, and Water for Injection

Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA
For more information, call 1-800-321-1335
U.S. License No. 1713

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YERVOY® and OPDIVO® are trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: May 2021

YERVOY 50 mg/10 mL Representative Packaging

See How Supplied section for a complete list of available packages of YERVOY.

NDC 0003-2327-11
Rx only
YERVOY®
(ipilimumab)
Injection
50 mg/10 mL
(5 mg/mL)
For Intravenous Infusion Only
Single-use vial; Discard unused portion
DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT
Bristol-Myers Squibb

yervoy-50mg-carton-serialized

YERVOY 200 mg/40 mL Representative Packaging

NDC 0003-2328-22
Rx only
YERVOY®
(ipilimumab)
Injection
200 mg/40 mL
(5 mg/mL)
For Intravenous Infusion Only
Single-use vial; Discard unused portion
DISPENSE ENCLOSED MEDICATION GUIDE TO EACH PATIENT
Bristol-Myers Squibb

yervoy-200mg-carton-serialized
YERVOY 
ipilimumab injection
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0003-2327
Route of AdministrationINTRAVENOUS
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
IPILIMUMAB (UNII: 6T8C155666) (IPILIMUMAB - UNII:6T8C155666) IPILIMUMAB5 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
TROMETHAMINE HYDROCHLORIDE (UNII: 383V75M34E) 3.15 mg  in 1 mL
SODIUM CHLORIDE (UNII: 451W47IQ8X) 5.85 mg  in 1 mL
MANNITOL (UNII: 3OWL53L36A) 10 mg  in 1 mL
PENTETIC ACID (UNII: 7A314HQM0I) 0.04 mg  in 1 mL
POLYSORBATE 80 (UNII: 6OZP39ZG8H) 0.1 mg  in 1 mL
WATER (UNII: 059QF0KO0R)  
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0003-2327-111 in 1 CARTON03/25/2011
110 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
BLABLA12537703/25/2011
YERVOY 
ipilimumab injection
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0003-2328
Route of AdministrationINTRAVENOUS
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
IPILIMUMAB (UNII: 6T8C155666) (IPILIMUMAB - UNII:6T8C155666) IPILIMUMAB5 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
TROMETHAMINE HYDROCHLORIDE (UNII: 383V75M34E) 3.15 mg  in 1 mL
SODIUM CHLORIDE (UNII: 451W47IQ8X) 5.85 mg  in 1 mL
MANNITOL (UNII: 3OWL53L36A) 10 mg  in 1 mL
PENTETIC ACID (UNII: 7A314HQM0I) 0.04 mg  in 1 mL
POLYSORBATE 80 (UNII: 6OZP39ZG8H) 0.1 mg  in 1 mL
WATER (UNII: 059QF0KO0R)  
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0003-2328-221 in 1 CARTON03/25/2011
140 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
BLABLA12537703/25/2011
Labeler - E.R. Squibb & Sons, L.L.C. (011550092)

Revised: 5/2021
Document Id: 2fbaadf6-c86c-48bb-bbba-803377841733
Set id: 2265ef30-253e-11df-8a39-0800200c9a66
Version: 35
Effective Time: 20210525
 
E.R. Squibb & Sons, L.L.C.