Nivolumab/Relatlimab

Merck’s efforts to combine its PD-1 blockbuster Keytruda with an experimental LAG-3 inhibitor hit a stumbling block Wednesday morning. The company said a Phase 3 study testing the LAG-3 program favezelimab in combination with Keytruda did not improve overall survival figures when compared to standard of care, failing its primary endpoint. Researchers were evaluating the combo in a metastatic colorectal cancer setting where patients had previously been treated with a PD-L1 therapy and the DNA in their cells were considered “microsatellite stable.” It’s a blow for Merck, which is trying to catch Bristol Myers Squibb in developing an approved dual PD-1/LAG-3 combination therapy. But this setting has proved tricky. Bristol Myers’ treatment, called Opdualag that combines Opdivo with relatlimab, also failed a Phase 3 study in microsatellite stable metastatic colorectal cancer late last year. In addition to colorectal cancer, Merck is attempting to develop the combination in bladder cancer, melanoma, hematological malignancies and esophageal cancer, among others.

iStock, Sundry Photography Merck follows in the footsteps of Bristol Myers Squibb, which in December 2023 also failed to secure a late-stage victory for its combo regimen of a PD-1 blocker and an anti-LAG-3 antibody. Merck on Wednesday announced that its blockbuster PD-1 inhibitor Keytruda (pembrolizumab), when combined with the investigational anti-LAG-3 antibody favezelimab, failed to significantly improve survival in the Phase III KEYFORM-007 study of metastatic colorectal cancer patients. Data were sparse in Merck’s announcement. The company only revealed that at the final pre-specified analysis, the Keytruda regimen “did not demonstrate an improvement in OS [overall survival] compared to standard of care.” Despite the efficacy miss, KEYFORM-007 confirmed the individual safety pro Keytruda and favezelimab and found no new signals of concern. Catherine Pietanza, vice president of global clinical development at Merck Research Laboratories, said in a statement that despite this Phase III stumble, the pharma will “continue to advance our clinical development program to evaluate Keytruda-based combinations and novel candidates” for colorectal cancer patients. KEYFORM-007 , a randomized and open-label study, enrolled more than 440 patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) who are positive for PD-L1 expression and who had undergone prior lines of standard treatment. The investigational regimen was given at a fixed dose—800 mg for favezelimab and 200 mg for Keytruda—and was compared against standard care, which consisted of an investigator’s choice of regorafenib or trifluridine and tipiracil hydrochloride. The study’s primary outcome was overall survival. Key secondary endpoints were progression-free survival, objective response rate, duration of response and safety. KEYFORM-007 was also designed to evaluate the effect of the Keytruda combo on patients’ quality of life. Merck said it is still conducting a full review of KEYFORM-007’s data and plans to share the findings with the scientific community in the future. Keytruda , a humanized IgG4 monoclonal antibody, works by targeting the PD-1 receptor and preventing its interaction with corresponding ligands, preventing cancer cells from evading the body’s anti-tumor immune response. This mechanism of action has turned Keytruda into a cornerstone of cancer therapy since its first approval in 2014 for advanced melanoma. Last year, the blockbuster therapy brought in more than $25 billion in revenue . Keytruda is also approved for colorectal cancer, breaking into this indication in June 2020 . However, the PD-1 inhibitor is only indicated specifically for unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. Wednesday’s late-stage stumble effectively slows its push into the MSS colorectal cancer setting—a therapeutic space that has been hard to break open. In December 2023, Bristol Myers Squibb announced that it was discontinuing the Phase III RELATIVITY-123 study in the same indication after a planned analysis concluded that the company’s Opdualag (nivolumab and relatlimab)—also a combination of a PD-1 blocker and an anti-LAG-3 antibody—was unlikely to improve overall survival.