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تعداد آیتم قابل مشاهده باقیمانده : -28 مورد

Systemic therapy regimens for non-small cell lung cancer: Pembrolizumab, pemetrexed, and carboplatin[1]

Systemic therapy regimens for non-small cell lung cancer: Pembrolizumab, pemetrexed, and carboplatin[1]
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.
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.
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.
Vesicant/irritant properties
  • Carboplatin is an irritant.
  • Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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.
Dose adjustment for baseline liver or kidney dysfunction
  • Each carboplatin dose should be calculated based upon kidney 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 kidney 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 kidney insufficiency, conventional cytotoxic agents and dosing of anticancer agents in adults.
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]
Thyroid function tests
  • Assess baseline thyroid function tests (TSH, FT4) every one to two cycles.
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 kidney 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.
  • 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 topics on toxicities associated with checkpoint inhibitor immunotherapy.
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]
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]
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.
If there is a change in body weight of at least 10%, doses should be recalculated.
This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of antineoplastic therapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ALT: alanine aminotransferase; ANC: absolute neutrophil count; ASCO: American Society of Clinical Oncology; AST: aspartate aminotransferase; AUC: area under the concentration × time curve; CBC: complete blood count; CrCl: creatinine clearance; D5W: 5% dextrose in water; FDA: US Food and Drug Administration; FT4: free thyroxine; GFR: glomerular filtration rate; IV: intravenous; MASCC: Multinational Association of Supportive Care in Cancer; NCCN: National Comprehensive Cancer Network; NS: normal saline; NSAIDs: nonsteroidal anti-inflammatory drugs; PD-1: programmed cell death protein 1; SITC: Society for Immunotherapy of Cancer; TSH: thyroid-stimulating hormone; ULN: upper limit of normal.

* Patients who had radiographic disease progression but were clinically stable could continue to receive treatment at the discretion of an investigator until disease progression was confirmed by imaging performed at least 28 days after the imaging assessment that first showed disease progression.

¶ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies). There is also the option of a ready-to-use formulation of pemetrexed that requires no reconstitution, dilution, or refrigeration.[2]

Δ AUC is converted to a patient-specific carboplatin dose (in mg) according to kidney function by using the Calvert formula. The Calvert formula is total dose (mg) = (target AUC) × (GFR + 25). If using measured serum creatinine, limit the maximal GFR for the calculation to 125 mL/min (maximum dose 750 mg). Refer to UpToDate topics on dosing of anticancer agents in adults.

◊ Consensus-based guidelines from the NCCN classify higher carboplatin doses (AUC ≥4) as highly emetogenic; by contrast, the American Society of Clinical Oncology and the Multinational Association for Supportive Care in Cancer guidelines consider all carboplatin doses to be moderately emetogenic. Although many institutions classify carboplatin-containing regimens as moderately emetogenic, a benefit for adding a neurokinin 1 receptor antagonist on day 1 has been shown in many studies; additional prophylaxis beyond day 1 for delayed emesis is not needed for most patients. Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.

§ In the original protocol, treatment-related toxicity had to return to ≤grade 1 or to baseline before initiating a subsequent cycle. If toxic effects were clearly attributed to one component of the treatment, that component alone could be discontinued. Maximum of two dose modifications, if applicable, to each of the therapy components were allowed for toxicity; treatment discontinued if cycles were delayed >42 days. Subjects who required a third dose modification to any component of therapy had that component discontinued. Dose adjustments in the study may differ slightly from those recommended by the manufacturer. The manufacturer's recommendations can be found in the United States Prescribing Information.[2,3,8]
References:
  1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378:2078.
  2. Pemetrexed disodium injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on March 15, 2024).
  3. Pembrolizumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on January 8, 2019).
  4. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021; 39(36):4073.
  5. MASCC 2020 clinical practice recommendations for the management of immune-mediated adverse events from checkpoint inhibitors. (Available online at link.springer.com/journal/520/topicalCollection/AC_c9dc4afd8c5d6799b830394e9758cad9, accessed on January 26, 2021).
  6. NCCN guidelines for management of immunotherapy-related toxicities. (Available online at nccn.org, accessed on June 21, 2021).
  7. SITC cancer immunotherapy guidelines. (Available online at sitcancer.org/research/cancer-immunotherapy-guidelines, accessed on March 10, 2022).
  8. Carboplatin injection. United States Prescribing Information. US National Library of of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on January 8, 2019).
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