Merck's Keytruda-LAG-3 combo fails in phase 3 colorectal cancer trial

Merck & Co. has faced a setback in its attempt to penetrate the microsatellite stable (MSS) metastatic colorectal cancer market. The pharmaceutical company recently revealed that a fixed-dose combination of Keytruda and an anti-LAG-3 antibody did not achieve the desired improvement in overall survival rates. This failure prolongs the search for an effective checkpoint inhibitor for this particular cancer subtype.

Previously, a study on colorectal cancer supported full FDA approval of Keytruda for patients with microsatellite instability-high solid tumors. However, MSS colorectal cancer, which is more prevalent, has proven to be a tougher challenge. Checkpoint inhibitors have demonstrated response rates below 10% when used as single agents in this setting. This lack of monotherapy efficacy has driven interest in exploring combination treatments that incorporate PD-1/L1 inhibitors with other mechanisms, such as LAG-3 blockade. Binding to LAG-3 has the potential to activate antigen-specific T lymphocytes and destroy cancer cells, potentially offering a solution for patients resistant to anti-PD-1/L1 therapy.

To test this hypothesis, Merck initiated the KEYFORM-007 trial. This open-label study compared the favezelimab-Keytruda combination against standard care options, specifically regorafenib (marketed by Bayer as Stivarga) or a combination of trifluridine and tipiracil. Unfortunately, the combination did not outperform these existing therapies in terms of survival rates, thereby closing one potential pathway for using checkpoint inhibitors in MSS colorectal cancer.

In a February earnings call, Dean Li, M.D., Ph.D., president of Merck Research Laboratories, had expressed hope that a positive outcome from the favezelimab-Keytruda trial could serve as a foundation for expanding the role of checkpoint inhibitors in MSS colorectal cancer. Although this objective was not achieved, Merck is not abandoning its efforts in this area. The company plans to continue investigating other Keytruda-based combinations for treating colorectal cancer.

Despite this setback, there are still opportunities for favezelimab to reach the market. Merck is conducting a phase 3 trial to evaluate the fixed-dose combination of favezelimab and Keytruda in patients with relapsed or refractory classical Hodgkin lymphoma, who have previously progressed on anti-PD-1 therapy. This trial is currently ongoing with an estimated primary completion date in 2027.

Merck's failure to achieve improved survival rates with the favezelimab-Keytruda combination in MSS colorectal cancer is a significant challenge. However, the company remains committed to exploring other combination therapies and advancing its LAG-3 development program, holding out hope for future successes in oncology treatments.