Usual Adult Dose for Melanoma - Metastatic

Unresectable or metastatic melanoma:

• As a single agent: 3 mg/kg IV every 3 weeks for up to 4 doses
• In combination with nivolumab: 3 mg/kg IV every 3 weeks for up to 4 doses or until unacceptable toxicity, whichever occurs first

Adjuvant treatment of melanoma:

• Initial dose: 10 mg/kg IV every 3 weeks for up to 4 doses
• Maintenance dose: 10 mg/kg IV every 12 weeks for up to 3 years

Comments:

• When used as a single agent:
• Unresectable or metastatic melanoma: This drug should be administered via IV infusion over 30 minutes.
• Adjuvant treatment of melanoma: This drug should be administered via IV infusion over 90 minutes.
• When used with nivolumab (1 mg/kg IV every 3 weeks):
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• After completing 4 doses of combination therapy, nivolumab should be administered as a single agent until disease progression or unacceptable toxicity.
• The manufacturer product information for nivolumab should be consulted.

Uses:

• As a single agent or in combination with nivolumab, for the treatment of unresectable or metastatic melanoma
• 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

Usual Adult Dose for Renal Cell Carcinoma

1 mg/kg IV every 3 weeks for up to 4 doses

Comments:

• To be used with nivolumab (3 mg/kg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• After completing 4 doses of combination therapy, nivolumab should be administered as a single agent until disease progression or unacceptable toxicity.
• The manufacturer product information for nivolumab should be consulted.

Use: In combination with nivolumab, for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma

Usual Adult Dose for Colorectal Cancer

1 mg/kg IV every 3 weeks for 4 doses

Comments:

• Approved under accelerated approval based on overall response rate and duration of response; continued approval may depend on verification and description of clinical benefit in confirmatory trials.
• To be used with nivolumab (3 mg/kg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• After completing 4 doses of combination therapy, nivolumab should be administered as a single agent until disease progression or unacceptable toxicity.
• The manufacturer product information for nivolumab should be consulted.

Use: In combination with nivolumab, for the treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

Usual Adult Dose for Hepatocellular Carcinoma

3 mg/kg IV every 3 weeks for 4 doses

Comments:

• Approved under accelerated approval based on overall response rate and duration of response; continued approval may depend on verification and description of clinical benefit in confirmatory trials.
• To be used with nivolumab (1 mg/kg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• After completing 4 doses of combination therapy, nivolumab should be administered as a single agent until disease progression or unacceptable toxicity.
• The manufacturer product information for nivolumab should be consulted.

Use: In combination with nivolumab, for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Usual Adult Dose for Non-Small Cell Lung Cancer

1 mg/kg IV every 6 weeks
Duration of therapy: In combination with nivolumab until disease progression or unacceptable toxicity, or up to 2 years without disease progression

Comments:

• Patients with metastatic non-small cell lung cancer (NSCLC) should be selected for therapy based on programmed cell death-ligand 1 (PD-L1) expression.
• For information on US FDA-approved tests for the determination of PD-L1 expression in NSCLC: www.fda.gov/CompanionDiagnostics
• To be used with nivolumab (360 mg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• For metastatic or recurrent NSCLC: The regimen also includes histology-based platinum-doublet chemotherapy (every 3 weeks) for 2 cycles; the manufacturer product information for each agent should be consulted.
• The manufacturer product information for nivolumab should be consulted.

Uses:

• In combination with nivolumab, for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 (at least 1%) as determined by a US FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma receptor tyrosine kinase (ALK) genomic tumor aberrations
• In combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, for the first-line treatment of patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations

Usual Adult Dose for Malignant Pleural Mesothelioma

1 mg/kg IV every 6 weeks
Duration of therapy: In combination with nivolumab until disease progression or unacceptable toxicity, or up to 2 years without disease progression

Comments:

• To be used with nivolumab (360 mg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• The manufacturer product information for nivolumab should be consulted.

Use: In combination with nivolumab, for the first-line treatment of patients with unresectable malignant pleural mesothelioma

Usual Adult Dose for Esophageal Carcinoma

1 mg/kg IV every 6 weeks
Duration of therapy: In combination with nivolumab until disease progression or unacceptable toxicity, or up to 2 years

Comments:

• To be used with nivolumab (3 mg/kg IV every 2 weeks or 360 mg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• The manufacturer product information for nivolumab should be consulted.

Use: In combination with nivolumab, for the first-line treatment of patients with unresectable advanced or metastatic esophageal squamous cell carcinoma

Usual Pediatric Dose for Melanoma - Metastatic

12 years and older:

• As a single agent: 3 mg/kg IV every 3 weeks for up to 4 doses
• In combination with nivolumab: 3 mg/kg IV every 3 weeks for up to 4 doses or until unacceptable toxicity, whichever occurs first

Comments:

• When used as a single agent: This drug should be administered via IV infusion over 30 minutes.
• When used with nivolumab (1 mg/kg IV every 3 weeks):
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• After completing 4 doses of combination therapy, nivolumab should be administered as a single agent until disease progression or unacceptable toxicity.
• The manufacturer product information for nivolumab should be consulted.

Use: As a single agent or in combination with nivolumab, for the treatment of unresectable or metastatic melanoma

Usual Pediatric Dose for Colorectal Cancer

12 years and older: 1 mg/kg IV every 3 weeks for 4 doses

Comments:

• Approved under accelerated approval based on overall response rate and duration of response; continued approval may depend on verification and description of clinical benefit in confirmatory trials.
• To be used with nivolumab (3 mg/kg IV every 3 weeks)
• Both drugs should be administered via IV infusion over 30 minutes on the same day.
• After completing 4 doses of combination therapy, nivolumab should be administered as a single agent until disease progression or unacceptable toxicity.
• The manufacturer product information for nivolumab should be consulted.

Use: In combination with nivolumab, for the treatment of patients with MSI-H or dMMR mCRC that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

Renal Dose Adjustments

Renal dysfunction: Data not available

If Nephritis with Renal Dysfunction Develops During Therapy:

• Grade 2 or 3 increased blood creatinine: This drug should be withheld.
• Complete or partial resolution (Grade 0 or 1) after corticosteroid taper: Therapy should resume.
• If no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of starting steroids: This drug should be permanently discontinued.
• Grade 4 increased blood creatinine: This drug should be permanently discontinued.

Comments:

• Renal dysfunction (GFR at least 15 mL/min/1.73 m2) had no clinically significant effect on the clearance of this drug.

Liver Dose Adjustments

Liver dysfunction: Data not available

If Hepatitis with No Tumor Involvement of The Liver OR Hepatitis with Tumor Involvement of The Liver/Non-HCC Develops During Therapy:

• AST or ALT increases to greater than 3 to 5 times the upper limit of normal (3 to 5 x ULN) or total bilirubin (TB) increases to greater than 1.5 to 3 x ULN: This drug should be withheld.
• Complete or partial resolution (Grade 0 or 1) after corticosteroid taper: Therapy should resume.
• If no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of starting steroids: This drug should be permanently discontinued.
• AST or ALT greater than 5 x ULN or TB greater than 3 x ULN: This drug should be permanently discontinued.

If Hepatitis with Tumor Involvement of The Liver/HCC Develops During Therapy:

• Baseline AST/ALT up to ULN: This drug should be withheld or permanently discontinued based on recommendations for hepatitis with no liver involvement.
• This guidance only applies to HCC patients who are being treated with this drug in combination with nivolumab.
• Baseline AST/ALT greater than 1 to 3 x ULN and increases to greater than 5 to 10 x ULN OR baseline AST/ALT greater than 3 to 5 x ULN and increases to greater than 8 to 10 x ULN: This drug should be withheld.
• Complete or partial resolution (Grade 0 or 1) after corticosteroid taper: Therapy should resume.
• If no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of starting steroids: This drug should be permanently discontinued.
• AST/ALT greater than 10 x ULN or TB increases to greater than 3 x ULN: This drug should be permanently discontinued.

Comments:

• Mild liver dysfunction (TB greater than 1 to 1.5 x ULN or AST greater than ULN) had no clinically significant effect on the clearance of this drug.
• This drug has not been studied in patients with moderate (TB greater than 1.5 to 3 x ULN and any AST) or severe (TB greater than 3 x ULN and any AST) liver dysfunction.

Dose Adjustments

No dose reduction is recommended for this drug. When this drug is administered in combination with nivolumab, both drugs should be withheld or permanently discontinued for toxicity.

General Guidelines:

• For severe (Grade 3) immune-mediated adverse reactions: This drug should be withheld.
• For life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive therapy, persistent moderate (Grade 2) or severe (Grade 3) reactions lasting at least 12 weeks after last 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 starting steroids: This drug should be permanently discontinued.

Colitis:

• Grade 2: This drug should be withheld.
• Complete or partial resolution (Grade 0 or 1) after corticosteroid taper: Therapy should resume.
• If no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of starting steroids: This drug should be permanently discontinued.
• Grade 3 or 4: This drug should be permanently discontinued.

Endocrinopathies:

• Depending on clinical severity, withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement should be considered; once acute symptoms have resolved, therapy should resume.
• Grade 3 or 4: This drug should be withheld until clinically stable or permanently discontinued depending on severity.

Exfoliative Dermatologic Conditions:

• Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS): This drug should be withheld.
• Confirmed SJS, TEN, or DRESS: This drug should be permanently discontinued.

Infusion-Related Reactions:

• Grade 1 or 2: The rate of infusion should be interrupted or slowed.
• Grade 3 or 4: This drug should be permanently discontinued.

Myocarditis:

• Grade 2, 3, or 4: This drug should be permanently discontinued.

Neurological Toxicities:

• Grade 2: This drug should be withheld.
• Complete or partial resolution (Grade 0 or 1) after corticosteroid taper: Therapy should resume.
• If no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of starting steroids: This drug should be permanently discontinued.
• Grade 3 or 4: This drug should be permanently discontinued.

Ophthalmologic:

• Grade 2, 3, or 4 that does not improve to Grade 1 within 2 weeks while receiving topical therapy OR that requires systemic therapy: This drug should be permanently discontinued.

Pneumonitis:

• Grade 2: This drug should be withheld.
• Complete or partial resolution (Grade 0 or 1) after corticosteroid taper: Therapy should resume.
• If no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of starting steroids: This drug should be permanently discontinued.
• Grade 3 or 4: This drug should be permanently discontinued.

Precautions

CONTRAINDICATIONS: None

Unresectable or metastatic melanoma or MSI-H or dMMR mCRC: Safety and efficacy have not been established in patients younger than 12 years.
Other indications: Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• For most indications, administer as a 30-minute IV infusion; when used for adjuvant treatment of melanoma, administer as a 90-minute IV infusion.
• Administer diluted solution though an IV line containing a sterile, nonpyrogenic, low-protein-binding in-line filter.
• When administered in combination with other agents:
• With nivolumab: Infuse nivolumab first followed by this drug on the same day.
• With nivolumab and platinum-doublet chemotherapy: Infuse nivolumab first followed by this drug and then platinum-doublet chemotherapy on the same day.
• Use separate infusion bags and filters for each infusion.
• Do not coadminister other drugs through the same IV line.
• Flush the IV line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.
• Consult the manufacturer product information for each therapeutic agent used in combination with this drug for recommended dosage information, as appropriate.

Storage requirements:

• Vials: Store refrigerated at 2C to 8C (36F to 46F); store in original carton until time of use to protect from light. Do not freeze or shake.
• Allow vial(s) to stand at room temperature for about 5 minutes before preparation of infusion.
• Diluted solution: Store refrigerated at 2C to 8C (36F to 46F) or at room temperature (20C to 25C [68F to 77F]) for no more than 24 hours from the time of preparation to the time of infusion.

Reconstitution/preparation techniques:

• The manufacturer product information should be consulted.

IV compatibility:

• Compatible: 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP

Monitoring:

• Endocrine: Adrenocorticotropic hormone (ACTH) level and thyroid function (at baseline and before each dose)
• Hepatic: Liver enzymes (at baseline and before each dose)
• Immunologic: For signs/symptoms of underlying immune-mediated adverse reactions
• Renal: Creatinine (at baseline and before each dose)

Patient advice:

• Read the US FDA-approved patient labeling (Medication Guide).
• Contact health care provider immediately for signs/symptoms of diarrhea, colitis, hepatitis, hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, diabetes mellitus, or nephritis.
• Contact health care provider immediately if a new rash develops.
• Contact health care provider immediately for any new/worsening symptoms of pneumonitis.
• Inform health care provider of a known/suspected pregnancy.
• Patients of childbearing potential: Use effective contraception during therapy and for 3 months after the last dose.
• If you may have been exposed to this drug during pregnancy, contact Bristol-Myers Squibb at 1-844-593-7869.
• Do not breastfeed during therapy and for 3 months after the last dose.