On 15 December 2023, Bristol Myers Squibb (BMS) announced the discontinuation of the Phase III RELATIVITY-123 trial evaluating the efficacy and safety of Opdualag as a treatment for previously treated, microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) patients.

Based on a planned analysis conducted by an independent data committee, the trial was terminated due to futility as it was unlikely for the immune checkpoint inhibitor (ICI) combination to meet the trial’s primary endpoints, which are overall survival (OS) in PD-L1 positive patients and OS in the intent-to-treat population.

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This termination is BMS’ first recent setback in CRC and it adds a layer of uncertainty about the future of LAG-3 inhibitors. Opdualag’s competition, MSD and Keytruda, are now the latest leaders in the immunotherapy race towards gaining approval as a treatment for the vast MSS mCRC patient population.

BMS has recently been making progress in expanding its market penetration into the mCRC market despite the fact that the landscape will remain challenging in the near future.

In 2018, BMS first entered the CRC space with its ICI combination of Opdivo and Yervoy, securing a second-line label in the population of microsatellite instability-high (MSI-H) patients, which only makes up approximately 15% of all mCRC patients.

Through recent external acquisitions and in-house clinical development, BMS is reshaping the CRC treatment landscape.

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Through this year’s acquisition of Mirati Therapeutics and 2022’s acquisition of Turning Point Therapeutics, BMS is extending its reach to non-MSI-H patients with Krazati and Augtyro, targeting mCRC patients carrying KRAS G12C mutations or NTRK gene fusions.

However, the size of such an addressable patient population is limited compared to other pharmaceuticals in mCRC due to the rare prevalence of such mutations.

Building on the strong physician recognition for Opdivo and Yervoy, BMS is pursuing a label expansion for the combination into the first line for MSI-H/mismatch repair-deficient patients in the Phase III CheckMate-8HW trial.

As it has another experimental arm with Opdivo alone, the pivotal trial could be the first to provide a head-to-head clinical comparison between the combination and a PD-1 monotherapy.

Since it has already met its primary progression-free survival endpoint, the combination is on its track to become the next heavyweight competitor to Keytruda, despite the community’s concern about its safety profile.

According to GlobalData’s Pharmaceutical Intelligence Center, there are nine LAG-3 inhibitor candidates in clinical development from Phase I to III in the CRC space.

Apart from monotherapies and combination therapies of relatlimab and favezelimab, the candidates are being developed by well-established Western biopharmaceuticals and emerging Chinese players.

The Phase II candidates are in the middle of the pack: Boehringer Ingelheim’s miptenalimab, Incyte’s INCAGN2385, and Beigene’s LBL-007. Novartis‘ ieramilimab, Akeso’s AK-129, and Innovent Biologics’ IBI-323 are Phase I followers in the LAG-3 inhibitor race.

The failure of the leading benchmark Opdualag is going to impact the market’s confidence in developing LAG-3 inhibitors as a whole, shifting developers’ attention away from CRC, which the World Health Organization notes is the third most common cancer in the world.

The pivotal trials from BMS and MSD have largely similar structures, except that Opdualag’s trial is more selective with enrolled patients and exclusively onboards PD-L1-positive patients.

The unfortunate outcome of the RELATIVITY-123 trial highlights the need for further investigation into potential prognostic biomarkers for LAG-3 inhibitors. If MSD’s favezelimab and Keytruda combination fail its pivotal trial, a market-wide reaction will likely occur, disrupting further developments in the checkpoint inhibitor class.

The result would be similar to the fallout of Gilead’s recent discontinuation of the Phase III trials of the anti-CD47 antibody magrolimab in high-risk myelodysplastic syndromes and acute myeloid leukemia.

Only time will tell if LAG-3 inhibitors are going to succeed in the CRC space.

The estimated primary completion date of the favezelimab combination’s Phase III trial, MK-4280A-007, is set in February 2024.

As disclosed by MSD in November’s UBS BioPharma Conference, the management is eagerly expecting a topline CRC data readout in 2024.