3/8/24, 3:59 PM Pembrolizumab, pemetrexed, and carboplatin for NSCLC - UpToDate

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Chemotherapy 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 Day 1

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.

Pemetrexed 500 mg/m 2 IV Dilute with 100 mL NS ¶ and administer over 10 minutes. Do Day 1
not administer with calcium-containing IV fluids such as
lactated Ringer's solution.

Carboplatin AUC Δ = 5 mg/mL per min IV Dilute in 250 mL NS or D5W ¶ and administer over 30 Day 1
minutes, beginning 30 minutes after pemetrexed.

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 Premedication with dexamethasone (4 mg orally twice daily for three days starting the day before pemetrexed
rashes administration with each cycle of therapy) is recommended to reduce cutaneous toxicity. [2]

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Refer to UpToDate topics on cutaneous complications of conventional chemotherapy agents.

Vesicant/irritant Carboplatin is an irritant.

properties 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 Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula. Δ Avoid use of
baseline liver or renal pemetrexed if CrCl is <45 mL/min. [2] There are recommendations for avoidance of NSAIDs in the days prior to and
dysfunction 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.

Vitamin Vitamin supplementation with folic acid and B12 is recommended prior to administration of pemetrexed and during
supplementation 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 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.

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 After recovery to ≤grade 1, reduce subsequent dose of pemetrexed by 25% for any grade 3 or 4 diarrhea, neurotoxicity,
toxicity 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 No dosage reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities.
immune-related toxicity [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

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(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.

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

* 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).

Δ AUC is converted to a patient-specific carboplatin dose (in mg) according to renal 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 topic 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 topic review on "Prevention and treatment 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
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3/8/24, 3:59 PM Pembrolizumab, pemetrexed, and carboplatin for NSCLC - UpToDate

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, et al. 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 January 8, 2019).
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, et al. J Clin Oncol 2021.
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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