Nivolumab and Relatlimab-rmbw for Melanoma

INDICATIONS AND USAGE OPDUALAG™ is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. OPDUALAG is a combination of nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3) blocking antibody, indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. (1)

DOSAGE AND ADMINISTRATION • Adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg: 480 mg nivolumab and 160 mg relatlimab intravenously every 4 weeks. (2) • Administer OPDUALAG as an intravenous infusion over 30 minutes. (2) • See full Prescribing Information for dosage modifications for adverse reactions (2.2) and preparation and administration instructions for the injection (2.3) . 2.1 Recommended Dosage The recommended dosage of OPDUALAG for adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity occurs. The recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg has not been established [see Use in Specific Populations (8.4) ] . 2.2 Dosage Modifications No dose reduction for OPDUALAG is recommended. In general, withhold OPDUALAG for severe (Grade 3) immune-mediated adverse reactions (IMARs). Permanently discontinue OPDUALAG for life-threatening (Grade 4) IMARs, recurrent severe (Grade 3) IMARs that require systemic immunosuppressive treatment, 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 adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Dosage Modifications for Adverse Reactions * Based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal Adverse Reaction Severity* Dose Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold a Grade 4 Permanently discontinue Hepatitis AST/ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN. Withhold a AST or ALT increases to more than 8 times ULN regardless of baseline. or Total bilirubin increases to more than 3 times ULN. Permanently discontinue Endocrinopathies b Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue 2.3 Preparation and Administration OPDUALAG is a fixed-dose combination of nivolumab and relatlimab. Visually inspect the solution in the drug product vial for particulate matter and discoloration prior to administration. OPDUALAG is a clear to opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white particles. Preparation • During preparation of the infusion solution, use aseptic technique to assure sterility, as the product does not contain a preservative. • OPDUALAG can be administered diluted or undiluted and administered at a final concentration as specified in Table 2 below. • Withdraw the required volume of OPDUALAG and transfer into an intravenous container. OPDUALAG is compatible with di(2-ethylhexyl)phthalate (DEHP)-plasticized polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), and polyolefin (PO) intravenous bags. • If diluting OPDUALAG prior to administration: - Dilute OPDUALAG solution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion meeting the final concentration and maximum infusion volume parameters as specified in Table 2 below. - Then mix the diluted solution by gentle inversion. Do not shake. • Discard partially used vials or empty vials following infusion preparation. Table 2: Maximum Infusion Volumes and Concentration Ranges by Patient Group * The concentration range in each group includes 12 mg/mL nivolumab and 4 mg/mL relatlimab as the upper limit, which represents a scenario in which the drug product is infused without dilution. Patient Group Maximum Infusion Volume (mL or mL/kg) Concentration Range (mg/mL)* Adult patients who weigh at least 40 kg and pediatric patients 12 years of age or older who weigh at least 40 kg 160 mL Nivolumab: 3 mg/mL to 12 mg/mL Relatlimab: 1 mg/mL to 4 mg/mL Adult patients who weigh less than 40 kg 4 mL/kg Nivolumab: 3 mg/mL to 12 mg/mL Relatlimab: 1 mg/mL to 4 mg/mL Storage of Prepared Solution Store the prepared solution either: • at room temperature and room light for no more than 8 hours from the time of preparation to the end of the infusion. Discard the prepared solution if not used within 8 hours from the time of preparation; -or- under refrigeration at 2°C to 8°C (36°F to 46°F) with protection from light for no more than 24 hours from the time of preparation, which includes the time allowed for equilibration of the infusion bag to room temperature and the duration of the infusion. Discard the prepared solution if not used within 24 hours from the time of preparation. Do not freeze. Administration • Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) filter (pore size of 0.2 micrometer to 1.2 micrometer). • Flush the intravenous line at the end of the infusion. • Do not coadminister other drugs through the same intravenous line.

WARNINGS AND PRECAUTIONS • Immune-Mediated Adverse Reactions : (5.1) o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis with renal dysfunction, and immune-mediated myocarditis. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue based on severity and type of reaction. (2.2) • Infusion-related reactions : Interrupt, slow the rate of infusion, or permanently discontinue OPDUALAG based on severity of reaction. ( 2.2 , 5.2 ) • Complications of allogeneic HSCT : Fatal and other serious complications can occur in patient who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3) • Embryo-fetal toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions OPDUALAG potentially breaks peripheral tolerance and induces immune-mediated adverse reactions (IMARs) [see Clinical Pharmacology (12.1) ] . Important IMARs listed under Warnings and Precautions may not include all possible severe and fatal IMARs. IMARs, which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, IMARs can also manifest after discontinuation. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2) ] . In general, if OPDUALAG 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 IMARs are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis OPDUALAG can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving OPDUALAG, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDUALAG in 0.8% and withholding of OPDUALAG in 1.4% of patients. Systemic corticosteroids were required in 100% (13/13) of patients with pneumonitis. Pneumonitis resolved in 85% of the 13 patients. Of the 5 patients in whom OPDUALAG was withheld for pneumonitis, 5 reinitiated OPDUALAG after symptom improvement; of these, none had recurrence of pneumonitis. Immune-Mediated Colitis OPDUALAG can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving OPDUALAG, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of OPDUALAG in 2% and withholding of OPDUALAG in 2.8% of patients. Systemic corticosteroids were required in 100% (24/24) of patients with diarrhea or colitis. Colitis resolved in 83% of the 24 patients. Of the 10 patients in whom OPDUALAG was withheld for colitis, 9 reinitiated OPDUALAG after symptom improvement; of these, 67% had recurrence of colitis. Immune-Mediated Hepatitis OPDUALAG can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology. Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving OPDUALAG, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDUALAG in 1.7% and withholding of OPDUALAG in 2.3% of patients. Systemic corticosteroids were required in 100% (20/20) of patients with hepatitis. Hepatitis resolved in 70% of the 20 patients. Of the 8 patients in whom OPDUALAG was withheld for hepatitis, 6 reinitiated OPDUALAG after symptom improvement; of these, 50% had recurrence of hepatitis. Immune-Mediated Endocrinopathies Adrenal Insufficiency OPDUALAG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDUALAG depending on severity [see Dosage and Administration (2.2) ] . Adrenal insufficiency occurred in 4.2% (15/355) of patients receiving OPDUALAG, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDUALAG in 1.1% and withholding of OPDUALAG in 0.8% of patients. Approximately 87% (13/15) of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 87% (13/15) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 33% of the 15 patients. Of the 3 patients in whom OPDUALAG was withheld for adrenal insufficiency, all 3 reinitiated OPDUALAG after symptom improvement. Hypophysitis OPDUALAG can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2) ] . Hypophysitis occurred in 2.5% (9/355) of patients receiving OPDUALAG, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDUALAG in 0.3% and withholding of OPDUALAG in 0.6% of patients. All (9/9) of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 100% (9/9) of patients with hypophysitis. Hypophysitis resolved in 22% of the 9 patients. Of the 2 patients in whom OPDUALAG was withheld for hypophysitis, none reinitiated OPDUALAG after symptom improvement. Thyroid Disorders OPDUALAG can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2) ] . Thyroiditis Thyroiditis occurred in 2.8% (10/355) of patients receiving OPDUALAG, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent

ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling. • Severe and Fatal IMARs [see Warnings and Precautions (5.1) ] • Infusion-Related Reactions [see Warnings and Precautions (5.2) ] • Complications of Allogeneic HSCT [see Warnings and Precautions (5.3) ] The most common adverse reactions (≥20%) are musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. (6.1) The most common laboratory abnormalities (≥20%) are decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium. (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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OPDUALAG was evaluated in RELATIVITY-047, a randomized (1:1), double-blinded trial in 714 patients with previously untreated metastatic or unresectable melanoma [see Clinical Studies (14) ] . Patients received intravenous OPDUALAG (nivolumab 480 mg and relatlimab 160 mg) every 4 weeks (n=355) or nivolumab 480 mg by intravenous infusion every 4 weeks (n=359). Patients were treated with OPDUALAG or nivolumab until disease progression or unacceptable toxicity. The median duration of exposure was 6 months (range: 0 to 31 months) in OPDUALAG-treated patients and 5 months (range: 0 to 32 months) in nivolumab-treated patients. Serious adverse reactions occurred in 36% of patients treated with OPDUALAG. The most frequent serious adverse reactions reported in ≥1% of patients treated with OPDUALAG were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%). Fatal adverse reaction occurred in 3 (0.8%) patients who were treated with OPDUALAG; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. OPDUALAG was permanently discontinued due to adverse reactions in 18% of patients. Adverse reactions which resulted in permanent discontinuation of OPDUALAG in ≥1% of patients included myocarditis (1.7%) and pneumonitis (1.4%). Dosage interruptions due to an adverse reaction occurred in 43% of patients who received OPDUALAG. Adverse reactions that required dosage interruption in ≥2% of patients who received OPDUALAG were diarrhea (3.9%), troponin increased (3.9%), AST increased (2.8%), troponin T increased (2.8%), ALT increased (2.3%), arthralgia (2.3%), hypothyroidism (2.3%), anemia (2%), fatigue (2%), pneumonitis (2%), and rash (2%). The most common (≥20%) adverse reactions that occurred in patients treated with OPDUALAG were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%). The most common (≥20%) laboratory abnormalities that occurred in patients treated with OPDUALAG were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%). Tables 3 and 4 summarize both the adverse reactions and laboratory abnormalities, respectively, in RELATIVITY-047. Table 3: Adverse Reactions in ≥15% of Patients - RELATIVITY-047 Toxicity was graded per NCI CTCAE v5. a Includes multiple terms. Adverse Reaction OPDUALAG (n=355) Nivolumab (n=359) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal pain a 45 4.2 31 1.7 General Fatigue a 39 2 29 0.6 Skin and Subcutaneous Tissue Rash a 28 1.4 21 1.9 Pruritus 25 0 17 0.6 Gastrointestinal Diarrhea a 24 2 17 1.4 Nausea 17 0.6 14 0 Nervous System Headache a 18 0.3 12 0.3 Endocrine Hypothyroidism a 17 0 14 0 Metabolism and Nutrition Disorders Decreased appetite 15 0.6 7 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough a 15 0.3 11 0 Clinically relevant adverse reactions in <15% of patients who received OPDUALAG included vitiligo, adrenal insufficiency, myocarditis, and hepatitis. Table 4: Laboratory Abnormalities (≥15%) That Worsened from Baseline a in Patients Who Received OPDUALAG in RELATIVITY-047 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDUALAG group (range: 280 to 342 patients) and nivolumab group (range: 276 to 345 patients). Laboratory Abnormality OPDUALAG a Nivolumab a Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased AST 30 2.3 22 1.4 Increased ALT 26 3.2 25 2 Decreased sodium 24 1.2 21 0.6 Increased alkaline phosphatase 19 0.6 17 0.9 Increased creatinine 19 0 16 0 Hematology Decreased hemoglobin 37 2.7 31 3.5 Decreased lymphocytes 32 2.5 24 2.9