Cycle length: Every 2 weeks for 8 doses, then every 4 weeks.
Duration of therapy: Until disease recurrence or unacceptable toxicity, for up to 1 year. |
| Drug | Dose and route | Administration | Given on days |
| Nivolumab | 240 mg | Dilute with either NS or D5W* to a final concentration between 1 and 10 mg/mL; total infusion volume should not exceed 160 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 for 16 weeks (8 doses) |
| Then |
| Nivolumab | 480 mg | Dilute with either NS or D5W* to a final concentration between 1 and 10 mg/mL; total infusion volume should not exceed 160 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 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 in patients with an underlying autoimmune disorder.[1] Nivolumab should be used with extreme caution 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.
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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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| Dose adjustment for baseline liver or renal dysfunction | |
| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of therapy.
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| Regulatory issues | - An FDA-approved patient medication guide, which is available with the United States Prescribing Information,[2] must be dispensed with this medication.
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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, 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, and skin rash. 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 infusion and permanently discontinue for severe or life-threatening infusion-related reactions, as indicated in the United States Prescribing Information.[2]
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- While immune-mediated toxicities generally occur during treatment with nivolumab, adverse reactions, including infusion-related 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: |
| General issues | - All patients should be closely monitored and evaluated for immune-mediated adverse effects prior to each dose.
- No dose reductions of nivolumab are recommended; treatment is withheld or discontinued to manage toxicities.
- In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. 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). Most nivolumab-associated rashes can be managed with topical corticosteroid creams rather than systemic glucocorticoids.
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| Indications for discontinuation | - Discontinue nivolumab permanently for any grade 4 toxicity (except neutropenia ≤7 days, lymphopenia, asymptomatic amylase or lipase elevation, isolated electrolyte imbalances that are corrected with supplementation within 72 hours of onset, or endocrinopathy controlled with physiologic hormone replacement), grade 3 pneumonitis, grade 3 ocular toxicity, grade 2 ocular toxicity that does not respond to topical therapy and does not improve to grade 1 severity within the retreatment period or requires systemic treatment, AST/ALT elevation >10 × ULN or 5 to 10 × ULN for 2 weeks, total bilirubin elevation >5 × ULN, or concurrent AST or ALT >3 × ULN plus total bilirubin >2 × ULN, grade ≥2 myocarditis, grade 3 neurologic toxicity, suspected exfoliative dermatologic condition, severe (grade 3) or life-threatening (grade 4) infusion reactions, or if there is an inability to reduce glucocorticoid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating glucocorticoids.
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| Indications for dose delay | - Delay nivolumab for any ≥grade 2 non-skin drug-related event, except fatigue or laboratory abnormalities; any grade 3 skin drug-related adverse event or laboratory abnormality except for grade 3 lymphopenia, leukopenia, or asymptomatic amylase or lipase abnormalities; which do not require dose delay.[1] If baseline AST/ALT or total bilirubin are within normal limits, delay dosing for drug-related ≥grade 2 toxicity. For baseline AST/ALT or total bilirubin within the grade 1 toxicity range, delay dosing for drug-related ≥grade 3 toxicity.
- Treatment may be resumed when treatment-related adverse effects resolve to ≤grade 1 or baseline value except fatigue, skin toxicity, or drug-related endocrinopathies adequately controlled with physiologic hormone replacement. If baseline liver function tests are within grade 1 levels, and dose delay is required for reason other than a 2-grade shift in AST/ALT or total bilirubin, treatment may resume in the presence of grade 2 AST/ALT OR total bilirubin. If patients with combined grade 2 AST/ALT AND total bilirubin parameters meet discontinuation parameters, discontinue therapy permanently.
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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] from ASCO,[3] from the MASCC,[4] from the NCCN,[5] and from the SITC.[6]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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