The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of pembrolizumab (Keytruda) in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for adult patients with unresectable non-epithelioid malignant pleural mesothelioma.
The recommendation stems from data derived from the phase 2/3 KEYNOTE-483 trial (NCT02784171), which demonstrated a statistically significant improvement in overall survival (OS) with the pembrolizumab combination compared to chemotherapy alone. The trial reported a hazard ratio (HR) of 0.79 (95% CI, 0.64-0.98; P = .0162).
KEYNOTE-483 Trial Results
The KEYNOTE-483 trial revealed that patients in the pembrolizumab arm (n = 222) experienced a median OS of 17.3 months (95% CI, 14.4-21.3), compared to 16.1 months (95% CI, 13.1-18.2) for those receiving chemotherapy alone (n = 218). Furthermore, the pembrolizumab plus chemotherapy regimen yielded a median progression-free survival (PFS) of 7.1 months (95% CI, 6.9-8.1) versus 7.1 months (95% CI, 6.8-7.7) for chemotherapy alone (HR, 0.80; 95% CI, 0.65-0.99; P = .0194). The overall response rate (ORR) was 52% (95% CI, 45.5%-59.0%) for the pembrolizumab regimen compared to 29% (95% CI, 23.0%-35.4%) for chemotherapy alone (P < .00001).
Expert Commentary
“The CHMP’s positive opinion marks an important milestone for patients in Europe with non-epithelioid mesothelioma, who experience worse survival outcomes than patients with epithelioid mesothelioma,” said Gregory Lubiniecki, MD, vice president of Oncology Clinical Research at Merck Research Laboratories, in a news release. “The positive CHMP opinion moves us closer to offering a new first-line treatment option with a proven OS benefit for certain patients in the European Union with this difficult-to-treat cancer.”
Regulatory Context
In September 2024, the FDA approved pembrolizumab plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with unresectable advanced or metastatic malignant pleural mesothelioma, based on data from KEYNOTE-483.
Trial Design
The phase 3 portion of the study included adult patients with advanced pleural mesothelioma that was unsuitable for surgery. Prior systemic therapy for advanced disease was not allowed, although neoadjuvant/adjuvant chemotherapy was permitted if completed more than 1 year prior to study treatment. Other key inclusion criteria consisted of an ECOG performance status of 0 or 1; and measurable disease per RECIST 1.1 or modified RECIST criteria for use in pleural mesothelioma.
Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg once every 3 weeks for up to 2 years in combination with pemetrexed and platinum-based chemotherapy; or chemotherapy alone. In both arms, 500 mg/m2 of pemetrexed plus either 75 mg/m2 of cisplatin or area under the curve 5 to 6 mg/mL per minute were given once every 3 weeks for up to 6 cycles. Treatment continued until disease progression, unacceptable toxicity, withdrawal, or the completion of planned therapy.
OS served as the trial’s primary end point. Secondary end points included PFS, ORR, quality of life, and health economics.
Safety Profile
Safety data showed that adverse effects in patients with malignant pleural mesothelioma treated with pembrolizumab plus pemetrexed and platinum-based chemotherapy were consistent with the known safety profile of the agents in other patients treated with the regimen. Overall, 27% of patients in the pembrolizumab arm had adverse effects (AEs) related to study treatment vs 15% of those in the chemotherapy alone arm. Eighteen percent of patients in the pembrolizumab arm were admitted to the hospital for serious AEs related to 1 or more study drugs vs 6% of those in the chemotherapy alone arm. Grade 5 AEs related to at least 1 study drug occurred in 2 and 1 patients in these respective arms.
