Label: YERVOY- ipilimumab injection

  • NDC Code(s): 0003-2327-11, 0003-2328-22
  • Packager: E.R. Squibb & Sons, L.L.C.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated June 29, 2020

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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)     5/2020

    Dosage and Administration (2)     6/2020

    Warnings and Precautions (5)     6/2020

    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)
    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, previously untreated advanced renal cell carcinoma, 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)

    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)
    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. (2.3)
    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. (2.4)
    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. (2.5)
    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. (2.6)
    Metastatic non-small cell lung cancer:
    Nivolumab 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks. (2.7)
    Nivolumab 360 mg every 3 weeks with YERVOY 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. (2.7)

    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. (2.5, 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. (2.5, 5.2)
    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: 6/2020

  • Table of Contents

    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

    2 DOSAGE AND ADMINISTRATION

    2.1 Patient Selection

    2.2 Recommended Dosage for Unresectable or Metastatic Melanoma

    2.3 Recommended Dosage for Adjuvant Treatment of Melanoma

    2.4 Recommended Dosage for Advanced Renal Cell Carcinoma

    2.5 Recommended Dosage for MSI-H or dMMR Metastatic Colorectal Cancer

    2.6 Recommended Dosage for Hepatocellular Carcinoma

    2.7 Recommended Dosing for Metastatic NSCLC

    2.8 Recommended Dosage Modifications for Adverse Reactions

    2.9 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 Allogenic 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

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

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

    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 treatment of patients with intermediate or poor risk, previously untreated 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.

  • 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 for Unresectable or Metastatic Melanoma

    The recommended dosage of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a maximum of 4 doses.

    2.3 Recommended Dosage for Adjuvant Treatment of Melanoma

    The recommended dosage of YERVOY is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years.

    2.4 Recommended Dosage for Advanced Renal Cell Carcinoma

    The recommended dosage of YERVOY is 1 mg/kg administered intravenously over 30 minutes, immediately following nivolumab 3 mg/kg administered intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses or until intolerable toxicity or disease progression. After completing 4 doses of the combination, administer nivolumab as a single agent. Review the Prescribing Information for nivolumab for dosage information.

    2.5 Recommended Dosage for MSI-H or dMMR Metastatic Colorectal Cancer

    The recommended dosage of YERVOY is 1 mg/kg administered intravenously over 30 minutes, immediately following nivolumab 3 mg/kg administered intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses or until intolerable toxicity or disease progression. After completing 4 doses of the combination, administer nivolumab as a single agent. Review the Prescribing Information for nivolumab for dosage information.

    2.6 Recommended Dosage for Hepatocellular Carcinoma

    The recommended dosage of YERVOY is 3 mg/kg administered intravenously over 30 minutes, immediately following nivolumab 1 mg/kg administered intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses or until intolerable toxicity or disease progression. After completing 4 doses of the combination, administer nivolumab as a single agent. Review the Prescribing Information for nivolumab for dosage information.

    2.7 Recommended Dosing for Metastatic NSCLC

    The recommended dose of YERVOY in combination with nivolumab is nivolumab 3 mg/kg administered as an intravenous infusion over 30 minutes every 2 weeks and YERVOY 1 mg/kg administered as an intravenous infusion over 30 minutes every 6 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression [see Clinical Studies (14.6)]. Review the Prescribing Information for nivolumab for recommended dosing information.

    The recommended dose of YERVOY in combination with nivolumab and platinum-doublet chemotherapy is nivolumab 360 mg administered as an intravenous infusion over 30 minutes every 3 weeks and YERVOY 1 mg/kg administered as an intravenous infusion over 30 minutes every 6 weeks and histology-based platinum-doublet chemotherapy every 3 weeks for 2 cycles until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression [see Clinical Studies (14.6)]. Review the Prescribing Information for nivolumab and platinum-based chemotherapy for recommended dosing information.

    2.8 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 for adverse reactions that require management different from these general guidelines are summarized in Table 1.

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

    Table 1: Recommended Dosage Modifications for Adverse Reactions
    ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
    * Graded per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4).
    a Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper.
    b Resume YERVOY when AST/ALT returns to baseline.
    c Permanently discontinue YERVOY if signs of encephalitis or respiratory insufficiency due to neurological toxicity regardless of grade.
    d Signs of mass effect, including headache, photophobia, or visual field cuts.
    e Resume YERVOY when acute symptoms have resolved.

    Adverse Reaction

    Severity*

    YERVOY Dosage Modifications

    Immune-Mediated Adverse Reactions[See Warnings and Precautions (5.1)]

    Colitis/diarrhea

    Grade 2

    Withholda

    Grade 3 or 4

    Permanently discontinue

    Hepatitisb

    AST or ALT more than 3 times and up to 5 times the ULN

    or

    Total bilirubin 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

    Exfoliative or Bullous Dermatologic Conditions

    Grade 2

    Withhold until specialist assessment

    Grade 3 or 4

    Permanently discontinue

    Endocrinopathies

    Grades 2, 3, or 4

    Withhold if not clinically stable

    Hypophysitisd

    Grade 2, 3, or 4

    Withholde

    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 Toxicitiesc

    Grade 2

    Withholda

    Grade 3 or 4

    Permanently discontinue

    Myocarditis

    Grade 2

    Withholda

    Grade 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 [Warnings and Precautions (5.2)]

    Grade 1 or 2

    Interrupt or slow the rate of infusion

    Grade 3 or 4

    Permanently discontinue

    2.9 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 (2.8)]. 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 reaction is not controlled with corticosteroid therapy. Institute hormone replacement therapy for endocrinopathies as warranted.

    Immune-Mediated Diarrhea or Colitis

    YERVOY can cause immune-mediated diarrhea/colitis, which may be fatal. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated diarrhea/colitis. In cases of corticosteroid-refractory diarrhea/colitis, consider repeating infectious workup to exclude alternative etiologies. If other causes are excluded, consider addition of an alternative immunosuppressive agent to the corticosteroid therapy or replacement of the corticosteroid therapy in corticosteroid-refractory immune-mediated colitis.

    YERVOY 3 mg/kg as a Single Agent

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

    YERVOY 10 mg/kg as a Single Agent

    Immune-mediated diarrhea/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%). Diarrhea/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 diarrhea/colitis.

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

    YERVOY 1 mg/kg with Nivolumab

    Immune-mediated diarrhea/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%). Diarrhea/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 diarrhea/colitis. Systemic corticosteroids were therefore required in 100% (60/60) of patients with immune-mediated diarrhea/colitis. Approximately 23% of patients required coadministration of another immunosuppressant with corticosteroids. Diarrhea/colitis resolved in 95% of the 60 patients. Of the 18 patients in whom YERVOY or nivolumab was withheld for diarrhea/colitis, 16 received additional treatment after symptom improvement; of these, 10 had recurrence of diarrhea/colitis.

    YERVOY 3 mg/kg with Nivolumab

    Immune-mediated colitis occurred in 10% (5/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 2 months (range: 1.1 to 19 months). Immune-mediated colitis led to permanent discontinuation or withholding of treatment in 4.1% and 4.1% of patients, respectively. Sixty percent (60%) of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 15 days (range: 9 days to 1.1 months). Complete resolution occurred in 80% of patients. Of the 2 patients in whom YERVOY or nivolumab was withheld for colitis, 2 received additional treatment after symptom improvement, and 2 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 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 Nivolumab

    Immune-mediated hepatitis occurred in 20% (10/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 1.3 months (range: 22 days to 4.1 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of treatment in 6.1% and 12% of patients, respectively. Seventy percent (70%) of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 3 days to 34 months). Complete resolution occurred in 70% of patients. Of the 6 patients in whom YERVOY or nivolumab was withheld for hepatitis, 4 received additional treatment after symptom improvement, and 3 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 and toxic epidermal necrolysis (TEN). 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 (2.8)].

    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 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 Nivolumab

    Immune-mediated rash occurred in 35% (17/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 15 days (range: 6 days to 3.1 months). Immune-mediated rash led to withholding of treatment in 6% of patients. Twelve percent (12%) of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 8 days (range: 1 to 15 days). Complete resolution occurred in 65% of patients. Of the 3 patients in whom YERVOY or nivolumab was withheld for rash, 2 received additional treatment after symptom improvement, and none 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 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 (2.8)].

    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 Nivolumab

    Hypophysitis:

    Hypophysitis occurred in 4% (2/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 3.7 months (range: 3 to 4.3 months). Hypophysitis led to withholding of treatment in 2% of patients. One patient with hypophysitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for 6 days.

    Adrenal Insufficiency:

    Adrenal insufficiency occurred in 18% (9/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 2.8 months (range: 1.4 to 8 months). Adrenal insufficiency led to withholding of treatment in 4.1% of patients. One patient with adrenal insufficiency received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for 1.2 months. Complete resolution occurred in 22% of patients.

    Hypothyroidism:

    Hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (11/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 3.3 months (range: 1.4 to 16.2 months). Complete resolution occurred in 46% of patients.

    Hyperthyroidism:

    Hyperthyroidism occurred in 10% (5/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 1.4 months (range: 1.4 to 2.8 months). Complete resolution occurred in 80% of patients.

    Immune-Mediated Pneumonitis

    YERVOY 1 mg/kg with 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.

    The incidence and severity of immune-mediated pneumonitis in patients with NSCLC treated with YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and 2 cycles of platinum-doublet chemotherapy were comparable to treatment with YERVOY in combination with nivolumab only.

    YERVOY 3 mg/kg with Nivolumab

    Immune-mediated pneumonitis occurred in 10% (5/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Median time to onset was 8.3 months (range: 1.2 to 17.5 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of treatment in 6.1% and 4.1% of patients, respectively. All patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 23 days (range: 12 days to 1.4 months). Complete resolution occurred in 60% of patients. Of the 2 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 2 received additional treatment after symptom improvement, and 1 had recurrence of pneumonitis.

    Immune-Mediated Nephritis with Renal Dysfunction

    YERVOY 1 mg/kg with 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

    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 (2.8)]. 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.

    5.3 Complications of Allogenic Hematopoietic Stem Cell Transplant after YERVOY

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

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

    5.4 Embryo-Fetal Toxicity

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

    5.5 Risks Associated When Administered in Combination with Nivolumab

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

  • 6 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 1,062 patients in CHECKMATE-214, CHECKMATE-142, and CHECKMATE-227; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 49 patients in CHECKMATE-040; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, an open-label, multicenter, randomized trial in adult patients with previously untreated metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations.

    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 2 presents adverse reactions from Study MDX010-20.

    Table 2: 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

    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 3 presents selected adverse reactions from Study CA184-029.

    Table 3: 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 4 presents selected laboratory abnormalities from Study CA184-029.

    Table 4: 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

    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 5 summarizes adverse reactions in CHECKMATE-214.

    Table 5: Adverse Reactions (>15%) in Patients Receiving YERVOY with 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 with 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 6 summarizes the laboratory abnormalities in CHECKMATE-214.

    Table 6: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY with 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 with 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

    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 7 summarizes adverse reactions in CHECKMATE-142.

    Table 7: 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.

    YERVOY plus Nivolumab MSI-H/dMMR Cohort

    (n=119)

    Percentage (%) of Patients

    Adverse Reaction

    All Grades

    Grades 3-4

    General Disorders and Administration Site Conditions

         Fatiguea

    49

    6

         Pyrexia

    36

    0

         Edemab

    7

    0

    Gastrointestinal Disorders

         Diarrhea

    45

    3.4

         Abdominal painc

    30

    5

         Nausea

    26

    0.8

         Vomiting

    20

    1.7

         Constipation

    15

    0

    Musculoskeletal and Connective Tissue Disorders

         Musculoskeletal paind

    36

    3.4

         Arthralgia

    14

    0.8

    Skin and Subcutaneous Tissue Disorders

         Pruritus

    28

    1.7

         Rashe

    25

    4.2

         Dry Skin

    11

    0

    Infections and Infestations

         Upper respiratory tract infectionf

    9

    0

    Metabolism and Nutrition Disorders

         Decreased appetite

    20

    1.7

    Respiratory, Thoracic, and Mediastinal Disorders

         Cough

    19

    0.8

         Dyspnea

    13

    1.7

    Nervous System Disorders

         Headache

    17

    1.7

         Dizziness

    11

    0

    Endocrine Disorders

         Hyperglycemia

    6

    1

         Hypothyroidism

    14

    0.8

         Hyperthyroidism

    12

    0

    Investigations

         Weight decreased

    10

    0

    Psychiatric Disorders

         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 8 summarizes laboratory abnormalities in CHECKMATE-142.

    Table 8: Laboratory Abnormalities Worsening from Baseline 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

    Percentage of Patients with Worsening Laboratory Test from Baselinea

    YERVOY plus 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

    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 9 summarizes the adverse reactions and Table 10 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040.

    Table 9: 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 10: 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 11 and 12 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

    Table 11: 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 12: 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 13 and 14 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

    Table 13: 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 14: 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

    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.

    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.

    Immune System: graft-versus-host disease

    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.

    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.

  • 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 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 15 and Figure 1.

    Table 15: 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

    Figure 1

    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 16 and Figure 2.

    Table 16: 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 2: Kaplan-Meier Curves for Overall Survival in Study CA184-029

    Figure 2

    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 17 and Figure 3. 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 17: 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 with 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 3: Kaplan-Meier Curves for Overall Survival (Intermediate/Poor Risk Population) in CHECKMATE-214

    Figure 3

    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 independent radiographic review committee (IRRC) 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 18.

    Table 18: Efficacy Results in MSI-H/dMMR Cohort of CHECKMATE-142
    a Estimated using the Clopper-Pearson method.
    b In the monotherapy cohort, 55% of the 20 patients with ongoing responses were followed for less than 12 months from the date of onset of response. In the combination cohort, 78% of the 51 patients with ongoing responses were followed for less than 12 months from the date of onset of response.

    YERVOY plus Nivolumab
    MSI-H/dMMR Cohort

    All Patients
    (n=119)

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

    IRRC Overall Response Rate; n (%)

    58 (49%)

    38 (46%)

          (95% CI)a

    (39, 58)

    (35, 58)

          Complete Response (%)

    5 (4.2%)

    3 (3.7%)

          Partial Response (%)

    53 (45%)

    35 (43%)

    Duration of Response

          Proportion with ≥6
          months response duration

    83%

    89%

          Proportion with ≥12b
          months response duration

    19%

    21%

    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 19.

    Table 19: 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 20 and Figure 4.

    Table 20: 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 4: Overall Survival (PD-L1 ≥1%) - CHECKMATE-227

    ipilimumab-figure4.jpg

    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/mg2, 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 21.

    Table 21: 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 5).

    Figure 5: Overall Survival - CHECKMATE-9LA

    ipilimumab-figure5
  • 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

    [print code]

  • MEDICATION GUIDE

    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, 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 can cause serious side effects in many parts of your body which can lead to death. These problems may happen anytime during treatment with YERVOY or after you have completed treatment. Some of these problems may happen more often when YERVOY is used in combination with nivolumab.

    Call your healthcare provider right away if you develop any of these signs or symptoms or they get worse. Do not try to treat symptoms yourself.

    Intestinal problems (colitis) that can cause tears or holes (perforation) in the intestines. Signs and symptoms of colitis may include:

    diarrhea (loose stools) or more bowel movements than usual
    mucus or blood in your stools
    dark, tarry, sticky stools
    stomach pain (abdominal pain) or tenderness
    you may or may not have fever

    Liver problems (hepatitis) that can lead to liver failure. Signs and symptoms of hepatitis may include:

    yellowing of your skin or the whites of your eyes
    dark urine (tea colored)
    nausea or vomiting
    pain on the right side of your stomach
    bleeding or bruise more easily than normal
    decreased energy

    Skin problems that can lead to severe skin reaction. Signs and symptoms of severe skin reactions may include:

    skin rash with or without itching
    sores in your mouth
    your skin blisters or peels

    Nerve problems that can lead to paralysis. Symptoms of nerve problems may include:

    unusual weakness of legs, arms, or face
    numbness or tingling in hands or feet

    Hormone gland problems (especially the pituitary, adrenal, and thyroid glands). Signs and symptoms that your glands are not working properly may include:

    persistent or unusual headaches
    unusual sluggishness
    feeling cold all the time
    weight gain
    changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness
    dizziness or fainting

    Lung problems (pneumonitis). Symptoms of pneumonitis may include:

    new or worsening cough
    chest pain
    shortness of breath

    Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:

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

    Inflammation of the brain (encephalitis). Signs and symptoms of encephalitis may include:

    headache
    fever
    tiredness or weakness
    confusion
    memory problems
    sleepiness
    seeing or hearing things that are not really there (hallucinations)
    seizures
    stiff neck

    Eye problems. Symptoms may include:

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

    Getting medical treatment right away may keep the problem from becoming more serious.

    Your healthcare provider will check you for these problems during treatment with YERVOY. Your healthcare provider may treat you with corticosteroid medicines. Your healthcare provider may 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. YERVOY may be used:
    o
    in adults and children 12 years of age and older when melanoma has spread or cannot be removed by surgery
    o
    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.

    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 (autoimmune disease), such as ulcerative colitis, Crohn’s disease, lupus, or sarcoidosis
    have had an organ transplant
    have liver problems
    are pregnant or plan to become pregnant. YERVOY can harm your unborn baby.
    o
    Females who are able to become pregnant should use effective birth control during treatment with YERVOY and for 3 months after the last dose of YERVOY.
    o
    If you become pregnant or think you are pregnant, tell your healthcare provider right away. You or your healthcare provider should contact Bristol-Myers Squibb at 1-800-721-5072 as soon as you become aware of the pregnancy.
    o
    Pregnancy Safety Surveillance Study: Females who become pregnant during treatment with YERVOY are encouraged to enroll in a Pregnancy Safety Surveillance Study. The purpose of this study is to collect information about the health of you and your baby. You or your healthcare provider can enroll you in the Pregnancy Safety Surveillance Study by calling 1-844-593-7869.
    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, 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.
    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. 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.
    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.
    It is important for you to keep all appointments with your healthcare provider. Call your healthcare provider if you miss an appointment. There may be special instructions for you.

    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 reactions. Tell your doctor 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
    difficulty breathing
    o
    dizziness
    o
    fever
    o
    feeling like passing out

    Graft-versus-host disease, a complication that can happen after receiving a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic), may be severe, and can lead to death, if you receive YERVOY either before or after transplant. Your healthcare provider will monitor you for the following signs and symptoms: skin rash, liver inflammation, stomach-area (abdominal) pain, and diarrhea.

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

    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. 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

    [print code]

    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: June 2020

  • 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
  • INGREDIENTS AND APPEARANCE
    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)