Cycle length: Combination nivolumab and 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 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).¶ | Day 1 |
| Ipilimumab | 1 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 AFTER completion of nivolumab infusion.Δ | 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).¶ | 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).¶ | 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 with extreme caution or avoided in such individuals with a history of potentially life-threatening autoimmune disorders or chronic immunosuppression for either solid organ allografts or hematopoietic cell transplantation. Patients on chronic immunosuppression for other reasons (eg, brain metastases) should be tapered off the immunosuppression (whenever possible) prior to initiation of immunotherapy to maximize its potential efficacy.
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| Emesis risk | - MINIMAL.
- Refer to UpToDate topic 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 topic "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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| 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 kidney 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) and liver, kidney, and thyroid function tests every two or four weeks or prior to each new cycle of treatment. Cortisol may be assessed as clinically indicated. CPK may be assessed if myositis or myocarditis is suspected.
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- Monitor for fatigue, colitis, hepatotoxicity, hypophysitis, adrenal insufficiency, hypo- or hyperthyroidism, nephrotoxicity, pneumonitis, hyperglycemia, skin rash, myositis, myocarditis, 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.[2,3]
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- While immune-mediated toxicities generally occur during the treatment course with nivolumab and ipilimumab, adverse reactions may also develop weeks to months after therapy discontinuation.
- Refer to UpToDate topic 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.[2,3] If treatment is withheld, both drugs must be held until treatment can resume, regardless of whether the drug-related adverse event is attributed to nivolumab or ipilimumab.[1] In general, treatment may resume (either with both drugs or, in most cases, nivolumab monotherapy) when toxicity resolves to ≤grade 1 or baseline value on a glucocorticoid dose of 10 mg or less prednisone equivalent per day, excluding fatigue and endocrinopathies.
- For patients with endocrinopathies, withhold both drugs for grade 2 toxicity until symptom improvement with hormone replacement, and resume therapy (either with both drugs or, in most cases, nivolumab monotherapy) once acute symptoms have resolved. For patients with grade ≥3 toxicity, either permanently discontinue or withhold both drugs until clinically stable, depending upon severity.
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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, such as infliximab or mycophenolate mofetil.
- Discontinue ipilimumab permanently for any grade 3 or 4 colitis or AST/ALT elevation >5 × ULN or elevated total bilirubin >3 × ULN.
- For other toxicities, discontinue ipilimumab permanently for severe grade 4 (excluding endocrinopathy) or any 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 corticosteroid-sparing immunosuppressive agent may be indicated.
- Discontinue nivolumab permanently for severe or grade 3 immune-mediated adverse event that is recurrent in the absence of concomitant ipilimumab or life-threatening.[2,3]
- Refer to UpToDate topics on "Immune checkpoint inhibitor colitis", "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", and "Toxicities associated with checkpoint inhibitor immunotherapy".
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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 topic 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. |
