Cycle length: Every 21 days. Duration of therapy: Maximum of four cycles, followed by maintenance therapy with pembrolizumab (with or without pemetrexed) every three weeks.* |
Drug | Dose and route | Administration | Given on days |
Pembrolizumab | 200 mg | Dilute in NS or D5W¶ to a final concentration between 1 to 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 |
Pemetrexed | 500 mg/m2 IV | Dilute with 100 mL NS¶ and administer over 10 minutes. Do not administer with calcium-containing IV fluids such as lactated Ringer's solution. | Day 1 |
Carboplatin | AUCΔ = 5 mg/mL per min IV | Dilute in 250 mL NS or D5W¶ and administer over 30 minutes, beginning 30 minutes after pemetrexed. | Day 1 |
Pretreatment considerations: |
Emesis risk | - MODERATE;◊ (LOW when pembrolizumab [with or without pemetrexed] is given as maintenance).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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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. Pembrolizumab should be used with extreme caution in such individuals.
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Prophylaxis for skin rashes | - Premedication with dexamethasone (4 mg orally twice daily for three days starting the day before pemetrexed administration with each cycle of therapy) is recommended to reduce cutaneous toxicity.[2]
- Refer to UpToDate topics on cutaneous complications of conventional chemotherapy agents.
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Vesicant/irritant properties | - Carboplatin is an irritant.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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Infection prophylaxis | - The incidence of grade 3 through 5 neutropenia was approximately 16% in the pembrolizumab arm (various chemotherapy backbones).[1] The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to existing guidelines.
- Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
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Dose adjustment for baseline liver or renal dysfunction | - Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula.Δ Avoid use of pemetrexed if CrCl is <45 mL/min.[2] There are recommendations for avoidance of NSAIDs in the days prior to and immediately following each dose of pemetrexed in patients with mild to moderate renal dysfunction (CrCl 45 to 79 mL/min) because of the potential for decreased clearance of pemetrexed.[2]
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents and dosing of anticancer agents in adults.
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Vitamin supplementation | - Vitamin supplementation with folic acid and B12 is recommended prior to administration of pemetrexed and during treatment to reduce both hematologic and nonhematologic side effects.[2]
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Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) every one to two cycles.
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Regulatory issues | - An FDA-approved patient medication guide, which is available with the US Prescribing Information,[3] must be dispensed with pembrolizumab.
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Monitoring parameters: |
- CBC with differential and platelet count before each treatment.
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- Assess electrolytes (including glucose), liver, and renal tests every three weeks prior to each new cycle of treatment. Thyroid function prior to initiation of therapy and every one to two cycles during treatment, and/or as clinically indicated.
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- Monitor for infusion reactions, 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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- While immune-mediated toxicities generally occur during treatment with pembrolizumab, 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:§ |
Myelotoxicity | - After recovery to ≤grade 1, reduce subsequent doses of both carboplatin and pemetrexed by 25% for nadir platelet count ≥50,000/microL and ANC <500/microL OR fever with ANC <1000/microL, OR platelet count nadir <50,000/microL without bleeding, regardless of ANC. Reduce subsequent doses of both carboplatin and pemetrexed by 50% for platelet count nadir <50,000/microL with grade 2 or worse bleeding. Dose reductions should be maintained for subsequent cycles.[1]
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Nonhematologic toxicity | - After recovery to ≤grade 1, reduce subsequent dose of pemetrexed by 25% for any grade 3 or 4 diarrhea, neurotoxicity, grade 3 transaminase elevation, or other nonhematologic toxicity except nausea and vomiting. Reduce subsequent pemetrexed dose by 50% for grade 3 or 4 mucositis. Discontinue pemetrexed for grade 4 transaminase elevation. Reduce subsequent carboplatin dose by 25% for grade 3 or 4 neurotoxicity, grade 3 transaminase elevation, or other grade 3 or 4 toxicities except nausea and vomiting, diarrhea, or mucositis. Discontinue carboplatin for grade 4 transaminase elevation. Dose reductions should be maintained for subsequent cycles.[1]
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Pembrolizumab immune-related toxicity | - No dosage reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities.[1,3,4]
- All patients should be closely monitored and evaluated for immune-mediated adverse effects at least every three weeks during therapy.
- 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). Discontinue pembrolizumab permanently for any grade 4 or recurrent grade 3 immune-mediated adverse event or one that is life threatening, grade 3 pneumonitis, AST/ALT elevation >8 times ULN, total bilirubin elevation >3 times ULN in patients with no hepatic tumor involvement, AST/ALT elevation to >10 times ULN for hepatitis with hepatic tumor involvement, 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.[3]
- Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for pembrolizumab,[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. |