Merck's Phase 3 KEYFORM-007 trial, investigating the fixed-dose combination of favezelimab and pembrolizumab, has failed to meet its primary endpoint of overall survival (OS) in patients with previously treated PD-L1 positive microsatellite stable (MSS) metastatic colorectal cancer (mCRC). The trial's results highlight the ongoing challenges in treating MSS mCRC, a subtype known for its limited response to immunotherapies. The full data will be presented at an upcoming medical meeting.
Trial Details and Results
The KEYFORM-007 trial was a randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of the favezelimab/pembrolizumab combination compared to standard of care (regorafenib or TAS-102) in patients with MSS mCRC who had progressed on prior therapies. The trial enrolled 441 patients, randomized 1:1 to receive either:
- Favezelimab 800 mg and pembrolizumab 200 mg intravenously every three weeks (Q3W) for 35 cycles, or
- Investigator's choice of regorafenib orally once daily (days 1-12 of each 28-day cycle) or TAS-102 orally twice daily (days 1-5 and days 8-12 of each 28-day cycle).
The primary endpoint was overall survival (OS), with key secondary endpoints including progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), safety, and quality of life.
At the final pre-specified analysis, the favezelimab and pembrolizumab combination did not demonstrate a statistically significant improvement in OS compared to standard of care. The safety profile of the combination was consistent with previous reports for favezelimab and pembrolizumab, with no new safety signals identified.
Colorectal Cancer Landscape
Colorectal cancer remains a significant global health challenge, being the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. In 2022, there were nearly 1.9 million new cases and over 900,000 deaths globally. In the United States, projections for 2024 estimate approximately 107,000 new cases of colon cancer and 46,000 new cases of rectal cancer, leading to over 53,000 deaths.
The five-year relative survival rates for metastatic colon and rectal cancer (stage IV) in the U.S. are approximately 13% and 18%, respectively, underscoring the need for more effective treatments.
Favezelimab and Pembrolizumab
Favezelimab (MK-4280) is an investigational anti-LAG-3 antibody designed to restore T cell effector function by preventing LAG-3 from binding to MHC class II molecules. Pembrolizumab (KEYTRUDA) is an anti-PD-1 therapy that enhances the immune system's ability to detect and fight tumor cells.
The combination of favezelimab and pembrolizumab is being explored in various hematologic malignancies and solid tumors. Ongoing studies include KEYFORM-008, a Phase 3 trial evaluating the combination in relapsed or refractory classical Hodgkin lymphoma patients who have progressed following prior anti-PD-1 therapy.
Future Directions
"Metastatic colorectal cancer continues to be a challenging disease to treat, especially for the majority of patients who have microsatellite stable disease, which has had limited response to immunotherapies," said Dr. M. Catherine Pietanza, vice president, global clinical development, Merck Research Laboratories. "We are grateful to the patients and investigators for their participation in this study, and we will continue to advance our clinical development program to evaluate KEYTRUDA-based combinations and novel candidates for patients with colorectal cancer in need of new options."
