Cycle length: 21 days for pembrolizumab and 28 days for paclitaxel.
Duration of therapy: Up to 35 cycles, disease progression, or unacceptable toxicities.* |
| Drug | Dose and route | Administration | Given on days |
| Pembrolizumab | 200 mg IV | 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 |
| Paclitaxel | 90 mg/m2 IV | Dilute in NS or D5W¶ to a final concentration of 0.3 to 1.2 mg/mL and administer over 1 to 3 hours via 0.22 micron in-line filter; use non-PVC container and tubing set. | Days 1, 8, and 15 |
| Pretreatment considerations: |
| Emesis risk | - LOW.
- 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 infusion reactions | - Premedicate with dexamethasone plus both an H1 and an H2 receptor antagonist prior to paclitaxel administration.[1,2] There is no standard premedication for pembrolizumab.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Paclitaxel can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - Per the clinical trial, the rate of neutropenia was 41% (30% was grade 3 or higher).[1] The rate of febrile neutropenia was not reported. The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to current 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 kidney dysfunction | - A lower starting dose of paclitaxel may be needed in patients with liver impairment.[2]
- Refer to UpToDate topics on dosing of anticancer agents in adults; chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
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| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of therapy. Per the clinical trial, thyroid function tests were then assessed every 2 cycles thereafter.[1]
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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 pembrolizumab.
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| Monitoring parameters: |
- CBC with differential and platelet count before each treatment cycle.
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- Electrolytes, renal, and liver function before each cycle of therapy.
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- Assess changes in neurologic function prior to each treatment cycle.
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- Assess line site periodically during infusion of chemotherapy for signs and symptoms of extravasation with each paclitaxel dose.
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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.
- 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.[3]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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| Suggested dose modifications for toxicity:Δ |
| Myelotoxicity | - Repeat cycles should not begin until the ANC count is greater than 1500 cells/microL and platelets are greater than 100,000/microL. Reduce paclitaxel by 20% for grade 3 or 4 neutropenic fever or grade 4 thrombocytopenia. If patients have an episode of febrile neutropenia or persistent neutropenia that prevents treatment on schedule, secondary prevention with support-CSF is suggested in addition to a reduction in paclitaxel dose by 20%.
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| Peripheral neuropathy | - For patients who develop severe neuropathy (grade 3 or 4) for a week or longer, then the dose of paclitaxel should be reduced by 20% for subsequent courses.[2]
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| Immune-related toxicities | - All patients should be closely monitored and evaluated for immune-mediated adverse effects at least every 3 weeks during therapy.
- No dosage reductions of pembrolizumab 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). 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]
- Most pembrolizumab-associated rashes can be managed with topical corticosteroid creams.[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 MASCC,[5] from NCCN,[6] and from 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. |
