Cycle length: Combination nivolumab plus ipilimumab every 3 weeks for 4 doses¶, then nivolumab monotherapy.
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 | 3 mg/kg IV | Dilute with either NS or D5WΔ 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).§ | Day 1, every 3 weeks × 4 doses |
| Ipilimumab | 1 mg/kg IV | Dilute with either NS or D5WΔ 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 AFTER completion of nivolumab infusion.¥ | Day 1, every 3 weeks × 4 doses |
| Followed by |
| Nivolumab‡ | 240 mg IV | Dilute with either NS or D5WΔ 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).§ | Day 1, every 2 weeks |
| OR |
| Nivolumab‡ | 480 mg IV | Dilute with either NS or D5WΔ 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).§ | 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. Nivolumab and ipilimumab should be used either with extreme caution or avoided altogether in individuals with a history of potentially life-threatening autoimmune disorders or on chronic immunosuppression for either solid organ allografts or hematopoietic cell transplantation. Patients on chronic immunosuppressive therapy for other reasons (eg, brain metastases) should be tapered off the immunosuppression, if possible, prior to initiation of immunotherapy to maximize its potential efficacy.
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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 <5%).
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| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of therapy.
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| Dose adjustment for baseline liver or renal dysfunction | |
| 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), CPK, and liver, renal, and thyroid function tests every 2 to 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: |
- All patients should be closely monitored and evaluated for immune-mediated adverse effects prior to each dose.
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- No dose reductions of nivolumab or ipilimumab are recommended; treatment is withheld or discontinued to manage toxicities. When nivolumab administration is combined with ipilimumab, withhold or permanently discontinue both drugs for an adverse reaction meeting the dose modification guidelines for either drug, regardless of whether the drug-related adverse event is attributed to nivolumab or ipilimumab.[2,3] In general, treatment may resume when toxicity resolves to grade ≤1 or baseline value, excluding fatigue and endocrinopathies.
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- 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 corticosteroids. Upon resolution to grade ≤1, initiate corticosteroid taper. Immune-mediated adverse reactions that do not resolve with systemic corticosteroids may be managed with other systemic immunosuppressants (based on limited data).
- Discontinue ipilimumab permanently for any grade ≥3 colitis, AST/ALT elevation >5 × ULN, or total bilirubin >3 × ULN (no tumor involvement of the liver).[3] For patients with liver tumor involvement, permanently discontinue for AST/ALT elevation >10 × ULN or total bilirubin >3 × ULN. Otherwise, discontinue ipilimumab permanently for grade ≥2 myocarditis, any exfoliative dermatologic toxicity, grade ≥3 neurotoxicity, grade ≥2 ophthalmic toxicity that does not improve to grade 1 within 2 weeks of starting topical therapy or that requires systemic treatment, grade 4 (excluding endocrinopathy) or recurrent grade 3 immune-mediated adverse event that requires systemic immunosuppressive therapy, or 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 corticosteroid-sparing agent (eg, infliximab, vedolizumab, or mycophenolate) may be indicated. For most patients, single-agent nivolumab maintenance therapy may be resumed when toxicity improves to grade ≤1 on a glucocorticoid dose of 10 mg or less prednisone equivalent per day.
- During the maintenance phase, discontinue nivolumab permanently for grade ≥3 pneumonitis, grade 4 colitis, AST/ALT elevation >8 × ULN, or total bilirubin increase >3 × ULN (for no tumor involvement of the liver). For patients with liver tumor involvement, discontinue permanently for ALT/AST elevation >10 × ULN or total bilirubin increase >3 × ULN. Discontinue permanently for grade 4 nephritis with renal dysfunction, any exfoliative skin condition, grade ≥2 myocarditis, grade ≥3 neurologic toxicity, or grade ≥3 infusion-related reaction. Otherwise, discontinue permanently for any grade 4 (excluding endocrinopathy) or recurrent grade 3 immune-mediated adverse event that requires systemic immunosuppressive therapy, or 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] In such cases, the use of a corticosteroid-sparing agent (eg, infliximab, vedolizumab, or mycophenolate) may be indicated.
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- 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. |
