Can pemetrexed plus platinum (with or without bevacizumab) be considered as an initial chemotherapy treatment option in patients who have received first-line immunotherapy?

Pemetrexed Plus Platinum With or Without Bevacizumab After First-Line Immunotherapy

In patients who have received first-line immunotherapy, pemetrexed plus platinum with or without bevacizumab should be offered as an initial chemotherapy treatment option. 1

Evidence-Based Rationale

The 2025 ASCO guideline for treatment of pleural mesothelioma provides clear direction for patients who have progressed on first-line immunotherapy. While there are no randomized trials specifically addressing the optimal systemic treatment after first-line immunotherapy, the guideline makes a conditional recommendation based on available evidence.

Key Considerations:

1. First-line Immunotherapy Followed by Chemotherapy

   • The CheckMate 743 trial demonstrated that 43.2% of patients in the immunotherapy arm (nivolumab/ipilimumab) received subsequent chemotherapy, with 40% of those receiving pemetrexed-based regimens 1
   • This suggests clinical benefit of pemetrexed-platinum regimens after immunotherapy progression

2. Bevacizumab Consideration

   • The addition of bevacizumab to pemetrexed-platinum is an option but should be carefully evaluated
   • Bevacizumab is contraindicated in patients with:
     • Poor performance status (PS ≥2)
     • Substantial cardiovascular comorbidity
     • Uncontrolled hypertension
     • Age >75 years
     • Bleeding or clotting risk 1

3. Efficacy of Pemetrexed-Platinum Regimens

   • The EMPHACIS trial demonstrated superior overall survival with pemetrexed plus cisplatin compared to single-agent cisplatin (HR 0.77) 1
   • While this trial was conducted in chemotherapy-naïve patients, it establishes the efficacy of this regimen

Treatment Algorithm

1. Assess patient eligibility for pemetrexed plus platinum after immunotherapy progression:

   • Confirm disease progression on first-line immunotherapy
   • Evaluate performance status (ECOG 0-2 preferred)
   • Review organ function (particularly renal function for pemetrexed)

2. Determine bevacizumab eligibility:

   • If patient has no contraindications to bevacizumab (good PS, age ≤75, no significant cardiovascular disease, no bleeding risk), consider adding bevacizumab
   • If contraindications exist, proceed with pemetrexed plus platinum alone

3. Treatment regimen:

   • Pemetrexed 500 mg/m² plus either cisplatin 75 mg/m² or carboplatin AUC 5-6
   • If adding bevacizumab: 15 mg/kg
   • Administer every 3 weeks for 4-6 cycles

4. Maintenance considerations:

   • Pemetrexed maintenance is not recommended after pemetrexed-platinum chemotherapy 1
   • If bevacizumab was included in the initial regimen, maintenance bevacizumab alone may be considered

Important Caveats

1. Limited direct evidence:

   • There are no randomized trials specifically addressing the sequence of immunotherapy followed by chemotherapy
   • Recommendations are based on lower quality evidence (Evidence quality: Low; Strength of recommendation: Conditional) 1

2. Maintenance therapy considerations:

   • The ECOG-ACRIN 5508 study showed that maintenance with pemetrexed plus bevacizumab combination has higher toxicity without survival benefit compared to either agent alone 2
   • Avoid combination maintenance therapy due to increased toxicity without proven survival benefit

3. Histology considerations:

   • Pemetrexed is particularly effective in non-squamous histology
   • The efficacy may vary based on the specific histologic subtype of mesothelioma (epithelioid vs. non-epithelioid)

By following this evidence-based approach, clinicians can provide appropriate second-line therapy for patients who have progressed on first-line immunotherapy, potentially extending survival while maintaining quality of life.