The US FDA grants priority review to Merck’s sBLA for Keytruda with chemo for metastatic malignant pleural mesothelioma.
The US FDA grants priority review to Merck’s sBLA for Keytruda with chemo for metastatic malignant pleural mesothelioma. Merck, referred to as MSD outside the United States and Canada, has announced that the U.S. Food and Drug Administration (FDA) has accepted a new supplemental Biologics License Application (sBLA) for priority review. This application seeks approval for Keytruda, Merck’s anti-PD-1 therapy, in combination with chemotherapy, for the initial treatment of patients with unresectable advanced or metastatic malignant pleural mesothelioma. The FDA has established September 25, 2024, as the target action date under the Prescription Drug User Fee Act (PDUFA).
The supplemental Biologics License Application: sBLA
The supplemental Biologics License Application (sBLA) relies on data from the critical phase 2/3 IND.227/KEYNOTE-483 trial. Findings from the final analysis, which were shared at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, indicated that Keytruda combined with chemotherapy led to a statistically significant enhancement in overall survival (OS). This combination reduced the risk of death by 21% (HR=0.79 [95% CI, 0.64-0.98]; two-sided p value=0.0324), with 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 chemotherapy alone. Additionally, Keytruda with chemotherapy showed a notable improvement in progression-free survival (PFS) (HR=0.80 [95% CI, 0.65-0.99], two-sided p value=0.0372; median PFS 7.13 months versus 7.16 months, respectively) and objective response rate (ORR) when compared to chemotherapy alone. After 12 months, the estimated PFS rate was 26% for the Keytruda combination versus 17% for chemotherapy alone. The ORR was significantly higher with Keytruda and chemotherapy (62% versus 38%, p<0.0001). The safety profile of Keytruda with chemotherapy in this study was consistent with previous reports.
“Malignant pleural mesothelioma is often identified at advanced stages when curative surgery is not viable and the disease progresses rapidly,” explained Dr. Gregory Lubiniecki, vice president of oncology clinical research at Merck Research Laboratories. “We are continuously exploring Keytruda for new and challenging tumors and anticipate collaborating with the FDA to offer Keytruda as a potential treatment option for patients with advanced malignant pleural mesothelioma.”
IND.227/KEYNOTE-483, a phase 2/3 trial registered as ClinicalTrials.gov NCT02784171, is led by the Canadian Cancer Trials Group (CCTG) in collaboration with the National Cancer Institute of Naples (NCIN) and the Intergroupe Francophone de Cancérologie Thoracique (IFCT). Merck has provided Keytruda and support for this trial. The study aims to compare the efficacy of Keytruda in combination with chemotherapy versus chemotherapy alone for treating patients with unresected advanced pleural mesothelioma. The primary endpoint is overall survival (OS), with secondary endpoints including progression-free survival (PFS) and objective response rate (ORR) as evaluated by blinded independent central review (BICR) following Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) modified for mesothelioma, along with assessments of safety and quality of life. In the phase 3 segment, 440 patients were enrolled and randomized to receive either:
- Keytruda (200 mg intravenously [IV] every three weeks [Q3W] for up to 35 cycles) plus pemetrexed (500 mg/m2 Q3W for six cycles) and cisplatin (75 mg/m2 Q3W for six cycles; carboplatin substitution [AUC 5-6 Q3W for six cycles] was permitted), or
- Pemetrexed and cisplatin (carboplatin substitution was permitted) alone.
Malignant mesothelioma is a form of cancer originating in the linings of various bodily structures such as the chest, abdomen, heart, and testicles. In 2022, there were over 30,000 newly diagnosed cases of mesothelioma worldwide, with more than 25,000 fatalities attributed to the disease. While the incidence of this cancer has seen a gradual decrease in the United States, global rates continue to rise due to ongoing exposure to asbestos. Pleural mesothelioma, affecting the lining of the lungs, constitutes approximately 75% of all cases. It typically progresses swiftly, with a mere 12% survival rate over five years.
Keytruda functions as an anti-programmed death receptor-1 (PD-1) therapy, bolstering the body’s immune system to identify and combat tumor cells more effectively. It’s a humanized monoclonal antibody that disrupts the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes. This activation can potentially influence both tumor cells and healthy cells.
Merck boasts the industry’s most extensive immuno-oncology clinical research initiative. With over 1,600 trials underway, Keytruda is being investigated across a diverse array of cancers and treatment scenarios. The clinical program for Keytruda aims to elucidate its role across various cancers and identify factors that could predict a patient’s likelihood of responding favorably to Keytruda treatment, including the exploration of different biomarkers.