Merck's Keytruda Combo Fails Phase III Colorectal Cancer Trial

Merck recently disclosed that its Phase III KEYFORM-007 study of the combination of Keytruda (pembrolizumab) and the investigational anti-LAG-3 antibody favezelimab did not achieve its primary goal of improving overall survival in patients with metastatic colorectal cancer. The announcement highlighted that the final analysis of the study showed no significant improvement in overall survival when compared to the standard care treatments.

Keytruda, Merck's blockbuster PD-1 inhibitor, is already a significant player in cancer therapy. However, this study aimed to test its efficacy in combination with favezelimab for microsatellite stable (MSS) metastatic colorectal cancer patients who also express PD-L1 and had previously undergone standard treatments. The investigational regimen was administered at fixed doses: 800 mg of favezelimab and 200 mg of Keytruda, compared against standard care options like regorafenib or a combination of trifluridine and tipiracil hydrochloride.

Despite the setback, Merck underscored the safety of Keytruda and favezelimab, noting that no new safety concerns were identified. Catherine Pietanza, Vice President of Global Clinical Development at Merck Research Laboratories, stated that the company remains committed to advancing its clinical development program for colorectal cancer. The trial, which enrolled over 440 patients, also evaluated other metrics such as progression-free survival, objective response rate, duration of response, and safety, in addition to the primary endpoint of overall survival.

Merck is still in the process of fully reviewing the data from the KEYFORM-007 study and intends to share detailed findings with the scientific community at a later date.

Keytruda, a humanized IgG4 monoclonal antibody, works by targeting the PD-1 receptor to prevent its interaction with ligands that allow cancer cells to evade the immune system. This mechanism has made Keytruda a cornerstone in cancer treatment since its first approval in 2014 for advanced melanoma. In 2022, Keytruda generated over $25 billion in revenue.

While Keytruda has already been approved for colorectal cancer since June 2020, its indication is limited to cases of unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. The recent trial's failure to show benefits in MSS colorectal cancer patients adds another layer of difficulty in expanding its use in this particular setting, which has been challenging to treat effectively.

The difficulty in treating MSS colorectal cancer is underscored by similar setbacks faced by other pharmaceutical companies. For instance, in December 2023, Bristol Myers Squibb decided to halt the Phase III RELATIVITY-123 study after concluding that their combination therapy, Opdualag (nivolumab and relatlimab), was also unlikely to improve overall survival in the same patient population.

In summary, while Merck’s attempt to expand the use of Keytruda in MSS metastatic colorectal cancer has hit a roadblock, the company remains focused on exploring further combinations and novel candidates in the hopes of finding effective treatments for this challenging cancer type. The KEYFORM-007 trial’s results will continue to undergo analysis, with a broader dissemination of findings anticipated in the near future.