Ipilimumab

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.

1 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 as a single agent or in combination with nivolumab. (1.1) • Adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2) Renal Cell Carcinoma (RCC) • Treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3) Colorectal Cancer • Treatment of adults and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with nivolumab. (1.4) Hepatocellular Carcinoma • adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) as first-line treatment in combination with nivolumab. ( 1.5 ) • in combination with nivolumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. (1.5) Non-Small Cell Lung Cancer (NSCLC) • Treatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab. (1.6) • Treatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy. (1.6) Malignant Pleural Mesothelioma • Treatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab. (1.7) Esophageal Cancer • Treatment of adult patients with unresectable advanc

2 DOSAGE AND ADMINISTRATION • Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2) • Unresectable or Metastatic Melanoma : ∘ YERVOY 3 mg/kg every 3 weeks for a maximum of 4 doses. (2.2) ∘ YERVOY 3 mg/kg immediately following nivolumab 1 mg/kg on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in the Full Prescribing Information for nivolumab. (2.2) • Adjuvant Treatment of Melanoma : YERVOY 3 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg every 12 weeks for up to 4 additional doses. (2.2) • Advanced Renal Cell Carcinoma : YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2) • Treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in combination with nivolumab : ∘ Adult and pediatric patients weighing 40 kg or greater: YERVOY 1 mg/kg immediately following nivolumab 240 mg on the same day every 3 weeks for a maximum of 4 doses. After completing the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2) ∘ Pediatric patients weighing less than 40 kg: YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day every 3 weeks for a maximum of 4 doses. After completing the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. ( 2.2 ) • Hepatocellular Carcinoma : YERVOY 3 mg/kg intravenously over 30 minutes immediately following nivolumab 1 mg/kg intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses. After completing up to 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2) • Metastatic non-small cell lung cancer : ∘ YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks. (2.2) ∘ YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2) • Malignant pleural mesothelioma : YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks. (2.2) • Esophageal squamous cell carcinoma: YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks. (2.2) • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Patient Selection Information on FDA-approved tests for patient selection is available at: https://www.fda.gov/CompanionDiagnostics Non-Small Cell Lung Cancer • Select patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.6) ] . Esophageal Cancer • Select patients with unresectable or advanced or metastatic ESCC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.8) ] . • An FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. 2.2 Recommended Dosage The recommended dosages of YERVOY as a single agent are presented in Table 1. Administer YERVOY as a 30-minute intravenous infusion [see Preparation and Administration (2.4) ] . Table 1: Recommended Dosages for YERVOY as a Single Agent Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks Maximum of 4 doses Adjuvant treatment of melanoma 3 mg/kg every 3 weeks followed by 3 mg/kg every 12 weeks Every 3 weeks up to a maximum of 4 doses Every 12 weeks for up to 4 additional doses The recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2. Administer YERVOY on the same day as other therapeutic agents. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate. Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents* * Refer to the Prescribing Information for the agents administered in combination with YERVOY for recommended dosing information, as appropriate. † Refer to the Prescribing Information for nivolumab for dosage information after completing use in combination with YERVOY. Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks with nivolumab 1 mg/kg In combination with nivolumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.† Advanced renal cell carcinoma 1 mg/kg every 3

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) ] . Most common adverse reactions (≥20%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache. (6.1) Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. (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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described in the Warnings and Precautions section reflect exposure to YERVOY 3 mg/kg as a single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY 1 mg/kg administered with nivolumab 3 mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA. Unresectable or Metastatic Melanoma The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20 [see Clinical Studies (14.1) ] . Study MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients received YERVOY 3 mg/kg by intravenous infusion for 4 doses as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (n=380), or gp100 peptide vaccine as a single agent (n=132). Patients in the trial received a median of 4 doses (range: 1 to 4 doses). The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% White, and baseline ECOG performance status 0 (56%). YERVOY was discontinued for adverse reactions in 10% of patients. Table 4 presents adverse reactions from Study MDX010-20. Table 4: Selected Adverse Reactions (≥5%) in Patients Receiving YERVOY with a Difference Between Arms of >5% for All Grades and >1% for Grades 3 to 5 Compared to gp100 Peptide Vaccine in Study MDX010-20 Adverse Reactions YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg and gp100 n=380 gp100 n=132 All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%) General and Administration-Site Conditions Fatigue 41 7 34 5 31 3 Gastrointestinal Diarrhea 32 5 37 4 20 1 Colitis 8 5 5 3 2 0 Dermatologic Pruritus 31 0 21 <1 11 0 Rash 29 2 25 2 8 0 Unresectable or Metastatic Melanoma: In Combination with Nivolumab The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1) ]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV. Patients were randomized to receive: • YERVOY 3 mg/kg by intravenous infusion over 90 minutes with nivolumab 1 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (YERVOY and nivolumab arm; n=313), or • Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm; n=313), or • YERVOY 3 mg/kg by intravenous infusion over 90 minutes every 3 weeks for up to 4 doses (YERVOY arm; n=311). The median duration of exposure to nivolumab was 2.8 months (range: 1 day to 36.4 months) for the YERVOY and nivolumab arm. In the YERVOY and nivolumab arm, 39% were exposed to nivolumab for ≥6 months and 30% exposed for >1 year. Serious adverse reactions (74%), adverse reactions leading to permanent discontinuation (47%) or to dosing delays (58%), and Grade 3 or 4