Merck's Keytruda (pembrolizumab), in combination with the investigational anti-LAG-3 antibody favezelimab, failed to demonstrate a statistically significant improvement in overall survival (OS) compared to standard of care in the Phase III KEYFORM-007 study for patients with metastatic colorectal cancer (mCRC). The announcement was made by Merck on Wednesday, revealing the trial's outcome at its final pre-specified analysis.
Despite the disappointing efficacy results, the KEYFORM-007 trial confirmed the individual safety profiles of both Keytruda and favezelimab, with no new safety signals of concern identified. Merck indicated that it will continue to analyze the full dataset from KEYFORM-007 and intends to share the findings with the scientific community in the future.
Trial Details and Patient Population
The KEYFORM-007 trial was a randomized, open-label study that enrolled over 440 patients with microsatellite stable (MSS) mCRC who were positive for PD-L1 expression and had progressed after prior lines of standard treatment. Patients received a fixed-dose combination of favezelimab (800 mg) and Keytruda (200 mg), compared against standard of care, which consisted of investigator's choice of regorafenib or trifluridine and tipiracil hydrochloride.
The primary endpoint of the study was overall survival. Secondary endpoints included progression-free survival, objective response rate, duration of response, safety, and quality of life.
Implications for Colorectal Cancer Treatment
Catherine Pietanza, vice president of global clinical development at Merck Research Laboratories, stated that the company remains committed to advancing its clinical development program to evaluate Keytruda-based combinations and novel candidates for colorectal cancer patients, despite this setback.
Keytruda, a humanized IgG4 monoclonal antibody, functions by targeting the PD-1 receptor, preventing its interaction with ligands and thereby enabling the body's anti-tumor immune response. It has become a cornerstone of cancer therapy since its initial approval in 2014 for advanced melanoma. Keytruda is already approved for use in colorectal cancer specifically for unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors, gaining this approval in June 2020.
The failure of the Keytruda-favezelimab combination in KEYFORM-007 represents a setback in the effort to expand Keytruda's utility in the more challenging MSS colorectal cancer setting. This therapeutic area has proven difficult to penetrate, as highlighted by Bristol Myers Squibb's discontinuation of the Phase III RELATIVITY-123 study in December 2023, which evaluated Opdualag (nivolumab and relatlimab), another PD-1/LAG-3 combination, in the same indication due to the unlikelihood of improving overall survival.
