The European Medicine Agency (EMA)’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 for the first-line treatment of adult patients with unresectable non-epithelioid malignant pleural mesothelioma (MPM) within the European Union. This decision follows the FDA's approval of the same regimen in September 2024, marking a significant step forward for patients with this difficult-to-treat cancer. The recommendation is based on data from the phase 2/3 KEYNOTE-483 trial, which demonstrated a statistically significant improvement in overall survival (OS) with the pembrolizumab combination.
KEYNOTE-483 Trial Results
The CHMP's positive opinion is supported by data from the phase 2/3 IND.227/KEYNOTE-483 trial (NCT02784171). The study evaluated pembrolizumab in combination with chemotherapy versus chemotherapy alone in patients with previously untreated unresectable advanced or metastatic MPM. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), and duration of response.
The data showed a median OS of 17.3 months (95% CI, 14.4-21.3) with pembrolizumab/chemotherapy compared to 16.1 months (95% CI, 13.1-18.2) with chemotherapy alone (HR, 0.79; 95% CI, 0.64-0.98; P = .0162). The median PFS was 7.1 months (95% CI, 6.9-8.1) in the pembrolizumab/chemotherapy arm and 7.1 months (95% CI, 6.8-7.7) in the chemotherapy alone arm (HR, 0.80; 95% CI, 0.65-0.99; P = .0194).
Objective response rate (ORR) was significantly higher in the pembrolizumab plus chemotherapy arm at 52% (95% CI, 45.5%-59.0%) compared to 29% (95% CI, 23.0%-35.4%) in the chemotherapy alone arm (P <.00001).
Study Design and Patient Population
The phase 3 component of the open-label, multi-center KEYNOTE-483 trial enrolled 440 patients with previously untreated unresectable advanced or metastatic MPM of any PD-L1 status. Patients were randomized 1:1 to receive either pembrolizumab at 200 mg or placebo in combination with pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin AUC 5 or 6 on day 1 of each 21-day cycle for a maximum of 6 cycles. Treatment continued until disease progression, unacceptable toxicity, or a maximum of 24 months.
Eligible patients were 18 years or older with histologically confirmed MPM, no contraindications to standard chemotherapy, unresectable advanced and/or metastatic disease, radiologically documented disease, availability of a cellular tumor block, and an ECOG performance status of 0 or 1. Patients with autoimmune disease requiring systemic therapy within 3 years or medical conditions requiring immunosuppression were excluded.
Implications for Mesothelioma Treatment
“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. “The positive CHMP opinion moves us closer to offering a new first-line treatment option with a proven overall survival [OS] benefit for certain patients in the European Union with this difficult-to-treat cancer.”
The European Commission is now reviewing the CHMP’s recommendation and is expected to issue a final decision on approving the pembrolizumab combination in the fourth quarter of 2024. If approved, this regimen will provide a valuable new treatment option for patients with non-epithelioid MPM, addressing a significant unmet need in this patient population.
