Cycle length: Combination nivolumab and ipilimumab every 3 weeks for 4 doses, then nivolumab monotherapy every 2 or 4 weeks.
Duration of therapy: Maintenance nivolumab monotherapy is continued until disease progression, unacceptable toxicity, or patient withdrawal. |
| Drug | Dose and route | Administration | Given on days |
| Nivolumab | 1 mg/kg IV | Dilute with either NS or D5W¶ to a final concentration between 1 and 10 mg/mL. Infuse over 30 minutes through an IV line containing a sterile, nonpyrogenic, low-protein binding inline filter (pore size of 0.2 to 1.2 micrometer).Δ | Day 1 |
| Ipilimumab | 3 mg/kg IV | Dilute with either NS or D5W¶ to a final concentration between 1 and 2 mg/mL. Infuse over 30 minutes through an IV line containing a sterile, nonpyrogenic, low-protein binding inline filter. Administer 30 minutes AFTER completion of nivolumab infusion.◊ | Day 1 |
| Followed by |
| Nivolumab | 240 mg IV | Dilute with either NS or D5W¶ to a final concentration between 1 and 10 mg/mL. Infuse over 30 minutes through an IV line containing a sterile, nonpyrogenic, low-protein binding inline filter (pore size of 0.2 to 1.2 micrometer).Δ | Day 1, every 2 weeks |
| OR§ |
| Nivolumab | 480 mg IV | Dilute with either NS or D5W¶ to a final concentration between 1 and 10 mg/mL. Infuse over 30 minutes through an IV line containing a sterile, nonpyrogenic, low-protein binding inline filter (pore size of 0.2 to 1.2 micrometer).Δ | Day 1, every 4 weeks |
| Pretreatment considerations: |
| Immune status | - Anti-PD-1 and anti-CTLA4 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. There are only limited data on the safety and efficacy of checkpoint inhibitors such as nivolumab and ipilimumab in patients with underlying autoimmune disorders or those who are on chronic immunosuppressive therapy, especially after a solid organ transplant. Nivolumab and ipilimumab should be used with extreme caution or avoided altogether in such individuals.
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| Emesis risk | - MINIMAL.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - There is no standard premedication regimen for nivolumab or ipilimumab.
- Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not indicated (estimated risk of febrile neutropenia is <5%).
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| Laboratory tests | - Assess baseline thyroid function tests (TSH, FT4), electrolytes, and liver function tests prior to initiation of therapy.
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| Regulatory issues | - FDA-approved patient medication guides, which are available with the United States Prescribing Information for both ipilimumab and nivolumab,[2,3] must be dispensed with these medications.
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| Monitoring parameters: |
- CBC with differential and platelet count prior to each new cycle of treatment.
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- Assess electrolytes (including glucose), ACTH, and liver, renal, and thyroid function tests every 2 or 4 weeks or prior to each new cycle of treatment.
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- Monitor for fatigue, colitis, hepatotoxicity, hypophysitis, adrenal insufficiency, hypo- or hyperthyroidism, nephrotoxicity, pneumonitis, hyperglycemia, skin rash, myositis, and uveitis.
- Many other clinically relevant immune-mediated toxicities have been observed, which may involve any organ system or tissue, and may be severe or fatal.
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- Monitor for infusion reactions during treatment. Interrupt or slow infusion for mild to moderate infusion-related reactions. Interrupt infusion and permanently discontinue for severe or life-threatening infusion-related reactions, as indicated in the United States Prescribing Information.[2,3]
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- While immune-mediated toxicities generally occur during treatment with nivolumab and ipilimumab, adverse reactions may also develop weeks to months after therapy discontinuation.
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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| Suggested dose modifications for toxicity:[1-3] |
| General issues | - All patients should be closely monitored and evaluated for immune-mediated adverse effects prior to each dose.
- In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. Most mild to moderate immune-mediated rashes can be managed with topical corticosteroid creams. Based on the type and severity of the reaction, withhold treatment and administer systemic glucocorticoids. Upon resolution to ≤grade 1, initiate glucocorticoid taper. Immune-mediated adverse reactions that do not resolve with systemic glucocorticoids may be managed with other systemic immunosuppressants (based on limited data).
- No dose reductions of nivolumab or ipilimumab are recommended; treatment is withheld or discontinued to manage toxicities. The assessment for discontinuation of ipilimumab should be made separately from the assessment for discontinuation of nivolumab.[1] Although there is some overlap, if discontinuation criteria are met for ipilimumab and not for nivolumab, treatment with nivolumab may continue if ipilimumab is discontinued.
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| Dose delays | - Subjects requiring dose delay should be re-evaluated weekly and resume dosing when retreatment criteria are met. In general, treatment with both drugs or nivolumab alone may resume when toxicity resolves to ≤grade 1 or baseline value, excluding fatigue or skin toxicity (treatment may resume if ≤grade 2), endocrinopathies adequately controlled with physiologic hormone replacement, or hepatic function if elevated at baseline.[1]
- Refer to "Issues specific to liver function" below.
- Individuals who received systemic glucocorticoids for management of drug-related toxicity must be off glucocorticoids or tapered down to an equivalent dose of prednisone ≤10 mg/day before treatment reinitiation.
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| Indications for discontinuation | - Discontinue ipilimumab permanently for any grade 3 or 4 colitis.[3] Otherwise, discontinue ipilimumab permanently for grade 2 or worse myocarditis, any exfoliative dermatologic toxicity, grade 3 or worse neurotoxicity, grade 3 or worse infusion-related reaction, grade 2 or worse ophthalmic toxicity that does not improve to grade 1 within 2 weeks of starting topical therapy or that requires systemic treatment, severe grade 4 (excluding endocrinopathy) or recurrent grade 3 immune-mediated adverse event that requires systemic immunosuppressive therapy, or severe grade 3 reactions lasting 12 weeks or longer after the last dose (excluding endocrinopathy) or an inability to reduce glucocorticoid doses to 10 mg or less prednisone equivalent per day within 12 weeks of initiating glucocorticoids.[2,3] In such cases, the use of a glucocorticoid-sparing agent (eg, infliximab, vedolizumab, or mycophenolate) may be indicated.
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| Issues specific to liver function | - Specific guidelines for managing hepatic events in the original protocol[1] included the following:
- Discontinue ipilimumab and/or nivolumab permanently for:
- Any AST or ALT >15 × ULN irrespective of duration, and for AST/ALT >10 × ULN for >2 weeks.
- Any total bilirubin elevation >8 × ULN irrespective of duration if bilirubin levels elevated at baseline, and for levels >5 × ULN for those with normal bilirubin at baseline.
- Concurrent AST or ALT >3 × ULN and total bilirubin >5 × ULN for those with normal bilirubin at baseline, and up to 8 × ULN for those with elevated bilirubin at baseline.
- Delay dosing of nivolumab and ipilimumab for drug-related ≥grade 2 toxicity in patients with normal baseline hepatic function, and for drug-related ≥grade 3 toxicity for patients with a baseline AST/ALT in the grade 1 range. For baseline AST/ALT within the grade 2 toxicity range, delay dosing for drug-related AST/ALT increase at 2 × baseline value or when AST/ALT is 8 × ULN, whichever is lower.
- If AST/ALT levels do not improve with a dose delay of 3 to 5 days, or if levels worsen, or if AST/ALT levels are >8 × ULN, initiate therapy with glucocorticoids. If levels do not improve within 3 to 5 days, consider adding mycophenolate. Tapering of steroids can start once AST/ALT levels have declined by one CTCAE grade, and the taper should be slow, over not less than one month.
- Therapy may resume when AST/ALT levels have returned to near baseline, unless the criteria for permanent discontinuation have been met.
- Patients with baseline grade 1 elevations in AST/ALT or total bilirubin who require dose delays for reasons other than a drug-related hepatic event may resume treatment with grade 2 AST/ALT/total bilirubin elevations as long as other toxicity has resolved to ≤grade 1.
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| Guidance from expert groups | - Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for nivolumab[2] and ipilimumab,[3] from ASCO,[4] from the MASCC,[5] from the NCCN,[6] and from the SITC.[7]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
