Cycle length: Every 21 days.
Duration of therapy: Maximum of four cycles, followed by maintenance therapy with pembrolizumab alone 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 |
| NabpaclitaxelΔ | 100 mg/m2 IV | Administer undiluted over 30 minutes. | Day 1, 8, and 15 |
| Carboplatin | AUC◊ = 6 mg/mL per min IV | Dilute in 250 mL NS or D5W¶ and administer over 30 minutes. The carboplatin should be given immediately after the nabpaclitaxel. | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (30 to 90%) on day 1;§
LOW (10 to 30%) on days 8 and 15.[2] - MINIMAL with pembrolizumab monotherapy.
- Refer to UpToDate topic on "Prevention and treatment 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 | - Premedication to prevent hypersensitivity reactions is generally not needed. Premedication may be needed in patients who have had a prior hypersensitivity reaction to nabpaclitaxel. There is no standard premedication for pembrolizumab.
- Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".
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| Vesicant/irritant properties | - Nabpaclitaxel can cause significant tissue damage; avoid extravasation. Carboplatin is an irritant.
- Refer to UpToDate topic 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 34% in the pembrolizumab-plus-nabpaclitaxel arm versus 35% in the nabpaclitaxel-containing chemotherapy-only arm.[1] The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to existing guidelines.
- Refer to UpToDate topic 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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| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of pembrolizumab.
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| Dose adjustment for baseline liver or renal dysfunction | - A lower starting dose for nabpaclitaxel may be needed for patients with impairment.[4] Do not administer nabpaclitaxel if AST is >10 times ULN or bilirubin is >5 times ULN. Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula.◊
- Refer to UpToDate topics on "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" and "Dosing of anticancer agents in adults".
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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.
|
| Monitoring parameters: |
- CBC with differential and platelet count before each treatment.
|
- 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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- Assess changes in neurologic function prior to each treatment cycle.
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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.
- Refer to UpToDate topic on "Toxicities associated with checkpoint inhibitor immunotherapy".
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Do not administer carboplatin and nabpaclitaxel on day 1 of each new cycle unless ANC is ≥1500/microL and platelet count is ≥100,000/microL.[4] For patients who develop neutropenic fever OR ANC <500/microL for >7 days or delay of next cycle by >7 days for thrombocytopenia (<50,000/microL), withhold treatment until counts recover to an ANC of at least 1500/microL and platelet count of at least 100,000/microL on day 1, or to an ANC of at least 500/microL and platelet count of at least 50,000/microL on days 8 or 15 of the cycle.[4] Upon resumption of therapy, reduce nabpaclitaxel and carboplatin by 25% upon the first occurrence, an additional 25% on the second recurrence, and discontinue treatment for a third occurrence.
|
| Renal/hepatic toxicity | - Alterations in renal function during therapy may require a recalculation of the carboplatin dose.
- Refer to UpToDate topics on "Dosing of anticancer agents in adults" and "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".
|
| Peripheral neuropathy | - Patients should have less than grade 2 peripheral neuropathy prior to beginning therapy, per the original trial of nabpaclitaxel and carboplatin without pembrolizumab.[5] Withhold nabpaclitaxel for grade 3 or 4 neuropathy during treatment. Resume nabpaclitaxel and carboplatin at reduced doses when peripheral neuropathy improves to grade 1 or completely resolves. Upon resumption of therapy, reduce nabpaclitaxel and carboplatin AUC by 25% for the first occurrence of grade 3 or 4 peripheral neuropathy, and an additional 25% for the second occurrence.[4] Discontinue treatment for a third occurrence.[2,4]
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| Hepatotoxicity | - Reduced starting doses of nabpaclitaxel are recommended for individuals with pre-existing moderate to severe hepatic impairment; the need for further dose adjustments in subsequent courses based upon ongoing hepatotoxicity should be based on individual tolerance and clinician judgment.[4]
- Refer to UpToDate topic on "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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| Pembrolizumab immune-related toxicity | - No dosage reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities.[1,3,6]
- 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,[6] from the MASCC,[7] from the NCCN,[8] and from the SITC.[9]
- Refer to UpToDate topic 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. |
