CRBPPEME+PEMB

¹Dosing based on NDFP funding criteria. Alternative pembrolizumab dosing schedule is 4 mg/kg IV (max 400 mg) q6 weeks.

²Give pembrolizumab before chemotherapy when given on the same day.

*Adjust Carboplatin dose to AUC target (using Calvert formula) as outlined in "Other Notes" section.

REPEAT EVERY 21 DAYS

For up to 6 cycles^, unless disease progression or unacceptable toxicity

Refer to PEMB(MNT) for the maintenance phase of treatment.

^If chemotherapy is discontinued after at least 1 cycle due to intolerance, pembrolizumab may be continued as single agent: PEMB(MNT)

Refer to NDFP form for funding criteria in retreatment.

• Also refer to CCO Antiemetic Recommendations.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline. 

Premedications:

Pemetrexed:

• Starting ≥ 1 week prior to pemetrexed administration, and continued until 3 weeks after the last dose:
  • Vitamin B₁₂ 1000 mcg IM every 9 weeks
  • Folic acid 0.4 - 1 mg PO daily
• Dexamethasone 4 mg PO BID for 3 days starting day before chemotherapy (suggested for rash prophylaxis).

Carboplatin (prophylaxis for infusion reactions):

• There is insufficient evidence that routine prophylaxis with pre-medications reduce infusion reaction (IR) rates.
• Corticosteroids and H1-receptor antagonists ± H2-receptor antagonists may reduce IR rates for some patients (e.g. gynecological patients with a PFI >12 months or a history of drug allergy who are receiving carboplatin starting from the 7^th cycle) but no optimal pre-medication regimen has been established.

Pembrolizumab (prophylaxis for infusion reactions):

• Routine pre-medication is not recommended.
• May consider antipyretic and H1-receptor antagonist in patients who experienced a grade 1-2 infusion reaction.

Other Supportive Care:

• Avoid the use of corticosteroids or immunosuppressants before starting pembrolizumab treatment. Corticosteroids may be used as premedication (e.g. antiemetic) when given with chemotherapy.

• Note: NSAIDs should be held for 2-5 days prior and 2 days after pemetrexed (refer to pemetrexed drug monograph)

Doses should be modified according to the protocol by which the patient is being treated.

No dose reductions for pembrolizumab. Doses are either delayed or discontinued with toxicity. Dose modifications for pemetrexed and carboplatin are described below.

Carboplatin & Pemetrexed:

_{^a  If toxicity Grade ≥ 3 recurs a 3rd time, discontinue.}

_{^b Do not start next cycle until ANC ≥ 1.5 x 10⁹/L, platelets ≥ 100 x 10⁹/L and related organ/non-hematologic toxicity ≤ Grade 1 or baseline.}

Pembrolizumab:

Healthcare professionals should also consult the most recent pembrolizumab product monograph for additional information.

Summary of Principles of Management or immune-related adverse effects (iRAEs)

• Immune-related adverse effects (irAEs) are different in their presentation, onset and duration compared to conventional chemotherapy. Patient and provider education is essential.

• Initial irAE presentation can occur months after completion of treatment and affect multiple organs.

• Dose escalation or reduction is not recommended.

• If no other cause can be identified (such as infection), any new symptom should be considered immune-related and prompt treatment initiated.

• Organ-specific system-based toxicity management is recommended.
   

Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions of Immune-related toxicities and their management.

Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Carboplatin:

There is insufficient evidence that routine prophylaxis with extended infusion reduces IR rates.

* Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2-receptor antagonist)

Pembrolizumab:

Use pemetrexed with caution as exposure is increased with renal impairment.  

Refer to CCO's Immune Checkpoint Inhibitor Toxicity Management Guideline for detailed descriptions for immune-related nephritis management with pembrolizumab. 

*_{Exercise caution with co-administration of NSAIDs for patients with CrCl 45-79mL/min.} 

_{^Patients were excluded from clinical trials if CrCl was < 50 mL/min. (Gandhi 218, Chu 2023)}

Carboplatin: caution should be exercised and dose reduction considered as elderly patients may have more severe myelosuppression and neuropathy.

Pemetrexed: no dosage adjustments are needed, but elderly patients should be monitored closely as more myelosuppression, renal and severe GI effects were noted.

Pembrolizumab: No dosage adjustment is required. 

Refer to pembrolizumab, pemetrexed, CARBOplatin drug monograph(s) for additional details of adverse effects.

Adverse effects listed below were reported in the KEYNOTE-189 clinical trial. Additional adverse effects, including rare, severe or life-threatening adverse effects, from other clinical trials or post-marketing are also included.   

Refer to pembrolizumab, pemetrexed, CARBOplatin drug monograph(s) for additional details.

• Nephrotoxic drugs (e.g. aminoglycosides) may increase the toxicity of pemetrexed and exacerbate nephro- and ototoxicity; caution and monitor closely if used together.

• NSAIDs may increase the toxicity of pemetrexed. Hold NSAIDs with shorter half-lives (e.g. ibuprofen) at least 2 days before to 2 days after pemetrexed. Hold NSAIDs with long half-lives (e.g. piroxicam) 5 days before to 2 days after pemetrexed.

• Phenytoin levels may be altered by carboplatin. Monitor levels and adjust the phenytoin dose as required.

• Use with warfarin may increase INR and the risk of bleeding. Monitor INR and adjust the warfarin dose as required.

Refer to pembrolizumab, pemetrexed, CARBOplatin drug monograph(s) for additional details.

Administration

Pembrolizumab:

• Dilute in 0.9% sodium chloride or D5W to final concentration of 1 to 10 mg/mL; mix by gentle inversion.

• Administer over 30 minutes using sterile, non-pyrogenic, low protein-binding 0.2 to 5 micron in-line or add-on filter.

• If given with chemotherapy on the same day, administer pembrolizumab before chemotherapy. 

• Do not co-administer other drugs through the same infusion line.

• Unopened vials should be stored under refrigeration (2 to 8^oC). Protect from light. Do not freeze.

Pemetrexed:

• Reconstitute as directed with Normal Saline.

• Dilute to a total volume of 100mL (Normal Saline only); Infuse IV over 10 minutes.

• Incompatible with calcium-containing solutions.

• Do not co-administer with other drugs and diluents.

• Keep unopened vials at room temperature.  Pemetrexed is not light sensitive.

Carboplatin:

• Mix in 100mL to 250mL bag (5% Dextrose or Normal Saline).

• Administer over 30 minutes, starting 30 minutes after the end of Pemetrexed.

• Incompatible with sets, needles or syringes containing aluminum – leads to precipitation and loss of potency.

• Protect from light.

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Contraindications

• Patients who have a hypersensitivity to these drugs, any of their components, or other platinum-containing compounds

• Patients with severe renal impairment, severe myelosuppression or bleeding tumours

• Concomitant use of yellow fever vaccine.

Warnings/ Precautions
 

• Patients with abnormal renal function or who are receiving concomitant nephrotoxic drugs

• Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age

• Patients with cardiovascular risk factors

• Avoid the use of live or live-attenuated vaccines. Reduced immunogenicity may occur with the use of inactivated vaccines.

• Pembrolizumab may cause serious immune-mediated reactions affecting multiple organ systems, including GI, hepatic, renal, respiratory, endocrine and others. Use with caution and monitor closely in patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders, such as hypo or hyperthyroidism or diabetes mellitus.

Pregnancy and Lactation:

• This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
   
• Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).
   
• Fertility effects:
  • Pemetrexed: Yes (may be irreversible; Sperm preservation should be considered prior to starting treatment)
  • Carboplatin: Documented in animal studies. Fertility preservation should be considered before treatment.
  • Pembrolizumab: Unknown

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Suggested Clinical Monitoring

Carboplatin drug monograph. Ontario Health  (Cancer Care Ontario).

CDA reimbursement review: pembrolizumab. Canadian Journal of Technologies 2025;5(7).

Chu Q, Perrone F, Greillier L, et al. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet 2023;402(10419):2295-306. doi: 10.1016/S0140-6736(23)01613-6.

Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018 May 31;378(22):2078-92.

Pembrolizumab drug monograph. Ontario Health (Cancer Care Ontario).

Pemetrexed drug monograph. Ontario Health (Cancer Care Ontario).

Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med 2023 Aug 10;389(6):491-503.

Zukin M, Barrios CH, Pereira JR, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol 2013 Aug 10;31(23):2849-53.