ipilimumab (Rx)

Melanoma

Unresectable or metastatic melanoma

• Indicated for treatment of unresectable or metastatic melanoma in adults and children aged ≥12 yr
• 3 mg/kg IV q3Week for a maximum of 4 doses  

Cutaneous Melanoma

• Indicated for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy
• 10 mg/kg IV q3Week for 4 doses followed by 10 mg/kg q12Week for up to 3 yr  

Renal Cell Carcinoma

Indicated in combination with nivolumab for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma

Ipilimumab1 mg/kg IV q3Weeks following nivolumab on the same day for 4 doses  

After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression

Also see nivolumab drug monograph for dose and continuation as monotherapy

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

Indicated in combination with nivolumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan

Ipilimumab 3 mg/kg IV immediately following nivolumab 1 mg/kg IV on the same day, q3Weeks for 4 doses  

After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression

Also see nivolumab drug monograph for dose and continuation as monotherapy

Hepatocellular Carcinoma

Indicated in combination with nivolumab for hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib

Ipilimumab 3 mg/kg IV immediately following nivolumab 1 mg/kg IV on the same day, q3Weeks for 4 doses  

After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression

Also see nivolumab drug monograph for dose and continuation as monotherapy

Non-small Cell Lung Cancer

Combination with nivolumab

• Indicated in combination with nivolumab for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in adults whose tumors express PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations
• Nivolumab 3 mg/kg IV q2Weeks, plus  
• Ipilimumab 1 mg/kg IV q6Weeks
• Continue until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression

Combination with nivolumab and platinum-based chemotherapy

• Indicated in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, for first-line treatment of metastatic or recurrent NSCLC in adults with no EGFR or ALK genomic tumor aberrations
• Nivolumab 360 mg/kg IV q3Weeks, PLUS  
• Ipilimumab 1 mg/kg IV q6Weeks, PLUS
• Histology-based platinum doublet chemotherapy q3Weeks for 2 cycles
• Continue until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Malignant Pleural Mesothelioma

Indicated in combination with nivolumab for patients with unresectable malignant pleural mesothelioma, as first-line treatment

Ipilimumab 1 mg/kg IV q6Weeks, PLUS

Nivolumab 360 mg IV q3Weeks

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

Dosage Modifications

Note: No dose reduction is recommended for adverse reactions

Renal impairment

• All severities: No dosage adjustment required

Hepatic impairment

• Mild (TB >1 to 1.5x ULN or AST >ULN): No dose adjustment required
• Moderate-to-severe (TB >1.5x ULN and any AST): Not studied; caution advised

Pneumonitis

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Colitis

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Hepatitis with no tumor involvement of the liver

• AST or ALT increases to >3 and ≤8x ULN or total bilirubin increases to >1.5 and <3x ULN: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
• AST or ALT increases to >8x ULN or total bilirubin increases to >3x ULN: Permanently discontinue

Hepatitis with tumor involvement of the liver

• Withhold therapy

  • Baseline AST or ALT >1 and ≤3x ULN and increases to >5 and ≤10x ULN
  • Baseline AST or ALT >3 and ≤5x ULN and increases to >8 and ≤10x ULN
  • Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
  • Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids

• Permanently discontinue

  • AST or ALT increases to >10x ULN or total bilirubin increases to >3x ULN

Endocrinopathies

• 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 therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
• Grade 4 increased blood creatinine: Permanently discontinue

Exfoliative dermatologic conditions

• Suspected Steven Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy
• Confirmed SJS, TEN, or DRESS: Permanently discontinue
• Myocarditis H4
• Grade 2, 3, or 4: Permanently discontinue

Neurologic toxicities

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Infusion-related reactions H4

• Grade 1 or 2: Interrupt or slow infusion rate
• Grade 3 or 4: Permanently discontinue

Dosing Considerations

Patient selection

• Patients selection should be based on PD-L1 expression
• Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics

Orphan Designations

Small cell lung cancer

Orphan sponsor

• Bristol-Myers Squibb Company; 5 Research Parkway; Wallingford, Connecticut 06492

Malignant Melanoma

Indicated for treatment of unresectable or metastatic melanoma in adults and adolescents aged ≥12 yr

<12 years: Safety and efficacy not established

≥12 years: 3 mg/kg IV q3Week for a maximum of 4 doses  

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

Indicated in combination with nivolumab for patients aged ≥12 years with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan

<12 years: Safety and efficacy not established

≥12 years: 1 mg/kg IV q3Weeks following nivolumab on the same day; repeat for up to 4 doses or until intolerable toxicity or disease progression  

Also see nivolumab drug monograph for dose and continuation as monotherapy

Dosage Modifications

Renal impairment

• All severities: No dosage adjustment required

Hepatic impairment

• Mild (TB >1 to 1.5 x ULN or AST >ULN): No dose adjustment required
• Moderate-to-severe (TB >1.5 x ULN and any AST): Not studied; caution advised

Interrupt or slow rate of infusion

• Grade 1 or 2 infusion-related reactions

Withhold

• Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper

  • Grade 2 colitis or diarrhea
  • Grade 2 pneumonitis
  • Grade 2 or 3 increased blood creatinine nephritis with renal dysfunction
  • Grade 2 neurological toxicities
  • Grade 2 myocarditis

• Resume when acute symptoms have resolved

  • Grade 2 to 4 hypophysitis

• Resume when AST/ALT returns to baseline

  • Hepatitis (AST or ALT >3x to <5x ULN or total bilirubin >1.5x to <3x ULN)

Withhold until specialist assessment

• Grade 2 exfoliative or bullous dermatologic conditions

Withhold if not clinically stable

• Grade 2 to 4 endocrinopathies

Permanently discontinue

• Grade 3 or 4 colitis or diarrhea
• Hepatitis (AST or ALT >5x ULN or total bilirubin >3x ULN)
• Grade 3 or 4 exfoliative or bullous dermatologic conditions
• Grade 3 or 4 pneumonitis
• Grade 4 increased blood creatinine
• Grade 3 or 4 myocarditis
• Grade 2 to 4 ophthalmologic that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment
• Grade 3 or 4 neurological toxicities if signs of encephalitis or respiratory insufficiency due to neurological toxicity regardless of grade
• Grade 3 or 4 infusion-related reactions