An attempt by Merck & Co. to unlock the microsatellite stable (MSS) metastatic colorectal cancer market has ended in failure. The drugmaker found a fixed-dose combination of Keytruda and an anti-LAG-3 antibody failed to improve overall survival, extending the wait for a checkpoint inhibitor that moves the needle in the indication.
An earlier colorectal cancer study supported full FDA approval of Keytruda in people with microsatellite instability-high solid tumors. MSS colorectal cancer, the most common form of the disease, has proven a tougher nut to crack, with checkpoint inhibitors achieving sub-10% response rates as single agents.
The lack of monotherapy efficacy in the setting has fueled interest in combining PD-1/L1 inhibition with other mechanisms of action, including blockade of LAG-3. Binding to LAG-3 could drive the activation of antigen-specific T lymphocytes and the destruction of cancer cells, potentially leading to responses in people who are resistant to anti-PD-1/L1 therapy.
Merck put that idea to the test in KEYFORM-007, an open-label trial that pitted the favezelimab-Keytruda combination against the investigator’s choice of regorafenib, which Bayer sells as Stivarga, or trifluridine plus tipiracil. The study combination failed to improve on the survival achieved by the standard of care options, closing off one avenue for bringing checkpoint inhibitors to MSS colorectal cancer.
On an earnings call in February, Dean Li, M.D., Ph.D., president of Merck Research Laboratories, said his team would use a positive signal in the favezelimab-Keytruda trial “as a beachhead to expand and extend the role of checkpoint inhibitors in MSS CRC.”
That positive signal failed to materialize, but Merck said it will continue to study other Keytruda-based combinations in colorectal cancer.
Favezelimab still has other shots at coming to market. Merck’s LAG-3 development program includes a phase 3 trial that is studying the fixed-dose combination in patients with relapsed or refractory classical Hodgkin lymphoma who have progressed on anti-PD-1 therapy. That trial, which is still enrolling, has an estimated primary completion date in 2027.