Cycle length: Every two weeks, OR every four weeks.
Duration of therapy: For up to 12 months, or until disease progression or unacceptable toxicity during this period. |
| Drug | Dose and route | Administration | Given on days |
| Nivolumab | 240 mg IV* | Dilute in 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 micrometers). | Day 1, every 2 weeks |
| OR |
| Nivolumab | 480 mg IV* | Dilute in 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 micrometers). | 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.[2] Nivolumab should be used with extreme caution in such individuals.
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| Emesis risk | - MINIMAL. In the original protocol, no antiemetic premedications were routinely administered prior to dosing.[1]
- 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,[3] 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.[3]
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- While immune-mediated toxicities generally occur at any point 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: |
- All patients should be closely monitored and evaluated for immune-mediated adverse effects prior to each dose. Early recognition and management of adverse effects may mitigate severe toxicity.
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- No dose reductions of nivolumab are recommended; treatment is withheld or discontinued to manage toxicities.[1,3]
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- 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).
- Dose delays for treatment-related toxicity are not allowed. Interrupt treatment for:[1]
- Any nonskin grade 2 toxicity (including endocrinopathies and LFT abnormalities if baseline normal liver function), except fatigue and other laboratory abnormalities, which do not require dose interruption.
- Any grade 3 skin toxicity or laboratory abnormality (including LFTs if baseline liver function was within grade 1 toxicity range), except lymphopenia, leukopenia, and amylase and lipase elevations, which do not require dose interruption.
- If toxicity resolves within 2 days of the planned dose, proceed with treatment; otherwise, omit that dose and resume 2 (or 4) weeks later.
- Criteria to resume therapy include:[1]
- Resume treatment without dose reduction when the toxicity has resolved to grade ≤1 or baseline value, with the following exceptions:
- Treatment may be resumed in the presence of grade 2 fatigue, skin toxicity (if there was no grade 3 skin toxicity), AST/ALT elevation, or total bilirubin elevation (if baseline LFTs were grade 1 and dose omission was performed for reason other than a 2-grade shift in ALT/AST or total bilirubin).
- For drug-related endocrinopathies adequately controlled with physiologic hormone replacement, treatment may be resumed once acute symptoms have resolved.
- Drug-related pulmonary toxicity, diarrhea/colitis, uveitis or neurologic toxicity must have resolved to baseline.
- To manage drug-related adverse events, prolonged dosing delays/omissions may be needed to allow for steroid tapers. Missed doses are typically omitted from the treatment course.
- Discontinue nivolumab permanently for any grade 4 (except asymptomatic lipase or amylase elevations) or recurrent grade 3 immune-mediated adverse event that requires systemic immunosuppressive treatment or one that is life threatening; grade 3 pneumonitis, uveitis, diarrhea/colitis, neurotoxicity, or drug-related thrombocytopenia lasting more than 7 days or associated with bleeding; AST/ALT elevation >8 times ULN; total bilirubin elevation >5 times ULN, or concurrent ALT/AST >3 × ULN and total bilirubin >2 × ULN; grade ≥2 myocarditis; suspected exfoliative skin rash; severe (grade 3) or life-threatening (grade 4) infusion reaction; or inability to reduce glucocorticoid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating glucocorticoids.[1,3]
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- Most nivolumab-associated rashes can be managed with topical corticosteroid creams.
- Refer to UpToDate topics on mucocutaneous toxicities associated with immune checkpoint inhibitors.
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- Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for nivolumab,[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 and mucocutaneous toxicities associated with immune checkpoint inhibitors.
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