FDA approves pembrolizumab with chemotherapy for unresectable advanced or metastatic malignant pleural mesothelioma

Regulatory approval: On Sep 17, 2024, the FDA approved pembrolizumab (Keytruda) with pemetrexed and platinum chemotherapy as first-line treatment for unresectable advanced or metastatic malignant pleural mesothelioma. Approval was supported by the randomized open-label KEYNOTE-483 trial, which showed a statistically significant overall survival benefit versus chemotherapy alone (median OS 17.3 vs 16.1 months; HR 0.79; p=0.0162).

FDA approval (Sep 17, 2024)

The FDA approved pembrolizumab (Keytruda; Merck) in combination with pemetrexed and platinum chemotherapy as first-line treatment for unresectable advanced or metastatic malignant pleural mesothelioma (MPM).

Supporting evidence: KEYNOTE-483 (NCT02784171)

KEYNOTE-483 was a randomized, open-label trial in patients with unresectable advanced or metastatic MPM and no prior systemic therapy for advanced/metastatic disease. Patients were randomized 1:1 to:

  • Pembrolizumab (up to 2 years) + pemetrexed + platinum chemotherapy (up to 6 cycles) (n=222), or
  • Pemetrexed + platinum chemotherapy (up to 6 cycles) (n=218).

Efficacy outcomes

Primary endpoint: overall survival (OS).

  • Median OS: 17.3 months (95% CI, 14.4–21.3) vs 16.1 months (95% CI, 13.1–18.2); HR 0.79 (95% CI, 0.64–0.98); p=0.0162.

Key secondary endpoints (blinded independent central review; modified RECIST 1.1 for mesothelioma):

  • Median PFS: 7.1 vs 7.1 months; HR 0.80 (95% CI, 0.65–0.99); p=0.0194.
  • Confirmed ORR: 52% vs 29%.
  • Median DoR: 6.9 vs 6.8 months.

Safety and dosing

Adverse reactions in MPM were reported as similar to those seen with pembrolizumab plus pemetrexed/platinum chemotherapy. Recommended pembrolizumab dose: 200 mg Q3W or 400 mg Q6W until progression or unacceptable toxicity, up to 2 years.

Regulatory context

The review was conducted under Project Orbis with collaboration from Australia’s TGA and Health Canada; reviews at other agencies were ongoing at the time of the announcement. The application received priority review.

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