The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the approval of Keytruda (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with pemetrexed and platinum chemotherapy, as a first-line treatment for adult patients with unresectable non-epithelioid malignant pleural mesothelioma (MPM). This decision follows the demonstration of a statistically significant improvement in overall survival (OS) in the pivotal Phase 2/3 IND.227/KEYNOTE-483 trial.
Clinical Trial Data
The CHMP's recommendation is based on data from the KEYNOTE-483 trial, where Keytruda plus chemotherapy showed a statistically significant improvement in OS compared to chemotherapy alone. The trial's pre-specified final analysis revealed a 21% reduction in the risk of death (HR=0.79 [95% CI, 0.64-0.98]; p=0.0162) with the Keytruda combination. Median OS was 17.3 months (95% CI, 14.4-21.3) for the Keytruda arm versus 16.1 months (95% CI, 13.1-18.2) for chemotherapy alone. Progression-free survival (PFS) also significantly improved with the Keytruda combination (HR=0.80 [95% CI, 0.65-0.99], p=0.0194; median PFS 7.1 months [95% CI, 6.9-8.1] versus 7.1 months [95% CI, 6.8-7.7], respectively).
Overall response rate (ORR) was significantly higher in the Keytruda plus chemotherapy arm compared to chemotherapy alone (52% [95% CI, 45.5-59.0] versus 29% [95% CI, 23.0-35.4], respectively; p<0.00001).
Impact on 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 Dr. Gregory Lubiniecki, vice president, oncology clinical research, Merck Research Laboratories. He added, "The positive CHMP opinion moves us closer to offering a new first-line treatment option with a proven overall survival benefit for certain patients in the European Union with this difficult-to-treat cancer."
Malignant Pleural Mesothelioma
Malignant mesothelioma is a cancer that originates in the linings of the chest, abdomen, heart, and testicles. Pleural mesothelioma, affecting the lung lining, is the most common form, accounting for approximately 75% of cases. In 2022, there were an estimated 14,700 new cases and over 12,200 deaths from mesothelioma in Europe. Non-epithelioid MPM accounts for about 31% of all MPM cases and is associated with poorer survival outcomes compared to the epithelioid subtype.
Keytruda Mechanism of Action
Keytruda is an anti-programmed death receptor-1 (PD-1) therapy designed to enhance the immune system's ability to detect and combat tumor cells. It functions as a humanized monoclonal antibody, blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes against tumor cells.
Next Steps
The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union (EU), with a final decision anticipated in the fourth quarter of 2024. This decision could provide a new therapeutic option for patients with non-epithelioid MPM, addressing a significant unmet medical need.
