Cycle length: In adults, every 3 weeks, OR every 6 weeks.* In pediatric patients, every 3 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 |
| Adult dosing |
| Pembrolizumab | 200 mg IV | Dilute in NS or D5W¶ to a final concentration between 1 and 10 mg/mL and infuse over 30 minutes through an 0.2- to 5-micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. | Day 1, every 3 weeks |
| OR* |
| Pembrolizumab | 400 mg IV | Dilute in NS or D5W¶ to a final concentration between 1 and 10 mg/mL and infuse over 30 minutes through an 0.2- to 5-micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. | Day 1, every 6 weeks |
| Pediatric dosing (ages 12 years and older) |
| Pembrolizumab | 2 mg/kg (up to 200 mg) IV | Dilute in NS or D5W¶ to a final concentration between 1 and 10 mg/mL and infuse over 30 minutes through an 0.2- to 5-micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. | Day 1, every 3 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 pembrolizumab in patients with an underlying autoimmune disorder.[1] Pembrolizumab 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 of either drug.
- 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 pembrolizumab.
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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 and renal tests prior to each new cycle of treatment. Assess thyroid function tests prior to initiation of therapy and every 1 to 2 cycles during treatment, and/or as clinically indicated.
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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 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 pembrolizumab, adverse reactions, including infusion-related reactions, may also develop weeks to months after therapy discontinuation; continued monitoring may be necessary.
- 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 at least prior to each new cycle of treatment. Early recognition and management of adverse effects may mitigate severe toxicity.
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- No dose reductions of pembrolizumab 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 grade 2 to 3 diarrhea/colitis, grade 2 elevation in ALT/AST or total bilirubin, new-onset type I diabetes mellitus or grade 3 or worse hyperglycemia associated with beta cell failure, grade ≥2 hypophysitis, grade ≥3 hyperthyroidism, grade 2 pneumonitis, grade 2 or 3 renal failure or nephritis, or any other grade 3 or severe drug-related toxicity that does not warrant treatment discontinuation (refer below).
- In general, treatment can be restarted after toxicity resolves to grade 0 or 1, except hyperglycemia (resume when patients are clinically and metabolically stable), hypophysitis, and hypothyroidism (therapy can be continued while hormone therapy is instituted). Missed doses are typically omitted from the treatment course.
- Discontinue pembrolizumab permanently for any grade 4 or recurrent grade 3 immune-mediated adverse event or one that is life threatening, grade 3 pneumonitis, grade 3 or 4 increase in AST/ALT or total bilirubin, grade ≥2 myocarditis, grade 3 neurologic toxicity, suspected exfoliative dermatologic condition, severe (grade 3) or life-threatening (grade 4) infusion reactions, toxicity (including intolerable or persistent grade 2 toxicity) that does not resolve within 12 weeks of last dose, 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.[1,3] For ocular toxicity, discontinue pembrolizumab permanently for grade 2 or 3 uveitis or iritis if symptoms persist despite treatment with topical immunosuppressive therapy.[3]
- Most pembrolizumab-associated rashes ≤grade 2 can be managed with topical corticosteroid creams.
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- Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for pembrolizumab,[1] 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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