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 q3Weeks for a maximum of 4 doses  

• Combination with nivolumab

  • Indicated in combination with nivolumab for unresectable or metastatic melanoma in adults
  • Ipilimumab 3 mg/kg IV q3Weeks PLUS
  • Nivolumab 1 mg/kg IV on the same day for maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier
  • After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks as a single agent until disease progression or unacceptable toxicity

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 q3Weeks for 4 doses followed by 10 mg/kg q12Weeks 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

Contraindicated (0)

Serious - Use Alternative (2)

• palifermin

  palifermin increases toxicity of ipilimumab by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

• selinexor

  selinexor, ipilimumab. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

Monitor Closely (6)

• cholera vaccine

  ipilimumab decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

• dengue vaccine

  ipilimumab decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

• efgartigimod alfa

  efgartigimod alfa will decrease the level or effect of ipilimumab by receptor binding competition. Use Caution/Monitor. Coadministration of efgartigimod with medications that bind to the human neonatal Fc receptor may lower systemic exposures and effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. If long-term use of such medications is essential, consider discontinuing efgartigimod and using alternative therapies.

• ponesimod

  ponesimod and ipilimumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• siponimod

  siponimod and ipilimumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• vemurafenib

  ipilimumab, vemurafenib. Either increases toxicity of the other by Other (see comment). Modify Therapy/Monitor Closely. Comment: Grade 3 increases in transaminases and bilirubin observed in a majority of patients when coadministered.

Minor (0)

• cholera vaccine

  Monitor Closely (1)ipilimumab decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

• dengue vaccine

  Monitor Closely (1)ipilimumab decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

• efgartigimod alfa

  Monitor Closely (1)efgartigimod alfa will decrease the level or effect of ipilimumab by receptor binding competition. Use Caution/Monitor. Coadministration of efgartigimod with medications that bind to the human neonatal Fc receptor may lower systemic exposures and effectiveness of such medications. Closely monitor for reduced effectiveness of medications that bind to the human neonatal Fc receptor. If long-term use of such medications is essential, consider discontinuing efgartigimod and using alternative therapies.

• palifermin

  Serious - Use Alternative (1)palifermin increases toxicity of ipilimumab by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

• ponesimod

  Monitor Closely (1)ponesimod and ipilimumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• selinexor

  Serious - Use Alternative (1)selinexor, ipilimumab. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

• siponimod

  Monitor Closely (1)siponimod and ipilimumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• vemurafenib

  Monitor Closely (1)ipilimumab, vemurafenib. Either increases toxicity of the other by Other (see comment). Modify Therapy/Monitor Closely. Comment: Grade 3 increases in transaminases and bilirubin observed in a majority of patients when coadministered.