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FDA approves pembrolizumab combination with chemotherapy as first-line treatment for advanced malignant pleural mesothelioma: results from KEYNOTE-483

The Food and Drug Administration (FDA) recently approved the combination of pembrolizumab with pemetrexed and platinum chemotherapy as a first-line treatment for patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). This decision follows findings from the Phase II/III KEYNOTE-483 trial (NCT02784171), which demonstrated a significant survival advantage in patients treated with the pembrolizumab combination over chemotherapy alone. 1

The study enrolled 440 patients with no prior systemic therapy for advanced disease and randomized them in a 1:1 ratio to either the pembrolizumab-chemotherapy regimen (n=222) or chemotherapy alone (n=218), with treatment continuing for up to two years or until disease progression. The primary endpoint of the study was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR). 2

Results demonstrated a statistically significant OS benefit for the pembrolizumab combination. Median OS reached 17.3 months (95% CI: 14.4-21.3) in the pembrolizumab plus chemotherapy arm, compared to 16.1 months (95% CI: 13.1-18.2) in the chemotherapy-only arm, with a hazard ratio (HR) of 0.79 (95% CI: 0.64-0.98; p=0.0162), translating to a 21% reduction in the risk of death. The median PFS was also prolonged, though similar between groups, at 7.1 months (95% CI: 6.9-8.1) for pembrolizumab with chemotherapy and 7.1 months (95% CI: 6.8-7.7) for chemotherapy alone (HR 0.80; 95% CI: 0.65-0.99; p=0.0194), indicating a modest reduction in disease progression or death with the pembrolizumab combination.

Further analysis highlighted a significantly higher confirmed ORR with pembrolizumab plus chemotherapy at 52% (95% CI: 45.5-59.0) compared to 29% (95% CI: 23.0-35.4) with chemotherapy alone, underscoring the enhanced tumor response with the pembrolizumab combination. Additionally, the median DoR was comparable, with 6.9 months (95% CI: 5.8-8.3) in the pembrolizumab arm and 6.8 months (95% CI: 5.5-8.5) in the chemotherapy-alone arm, suggesting a similar duration of benefit among responders.

Adverse events (AEs) were consistent with the established safety profiles of pembrolizumab and the chemotherapy regimen. Common side effects included fatigue, nausea, and oral mucositis, with 27% of patients in the pembrolizumab arm experiencing grade 3 or higher AEs compared to 15% in the chemotherapy group. Despite a higher AE-related discontinuation rate in the pembrolizumab cohort, the safety profile aligns with prior observations in similar regimens, supporting the benefit-risk balance of this combination.

This approval under the FDA’s Project Orbis, conducted in collaboration with regulatory partners in Australia and Canada, marks an important advance for patients with MPM, offering an effective first-line combination therapy that enhances overall survival in a challenging-to-treat population.

References:

  1. FDA approves pembrolizumab with chemotherapy for unresectable advanced. U.S. Food and Drug Administration. 2024. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-unresectable-advanced-or-metastatic-malignant-pleural
  2. Clinicaltrials.gov. 2024. Available from: https://clinicaltrials.gov/study/NCT06318286