More than five years after an FDA accelerated approval in a subtype of progressive colorectal cancer, Bristol Myers Squibb now has data supporting its checkpoint inhibitor doublet in newly diagnosed patients. But another approval may have to wait.

The dual immunotherapy combo of Opdivo and Yervoy cut the risk of disease progression or death by 79% compared with chemotherapy—with or without targeted therapies—in patients newly diagnosed with metastatic colorectal cancer that was microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR).

Investigators shared the results, from the CheckMate 8HW study, at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.  

After about two years of median follow-up, 72% of patients who received the anti-PD-1/CTLA-4 combo were alive without disease progression, versus 14% in the control group. 

The results “have potentially practice-changing implications” for previously untreated MSI-H/dMMR metastatic colorectal cancer, lead study author Thierry Andre, M.D., from the Sorbonne Université in Paris, said in a statement.

Further, CheckMate 8HW could help Bristol turn a 2018 FDA accelerated approval for the combo to treat post-chemo MSI-H/dMMR colorectal cancer into a full nod. But the current data may not be enough to support that conversion.

As part of the accelerated approval, the FDA asked Bristol to run a confirmatory study to prove the benefit of the immunotherapy doublet compared with Opdivo alone. That assessment remains ongoing in CheckMate 8HW, even though the trial is already technically a win given its dual primary endpoint design.

PD-1 inhibitors have supplanted chemo as the standard of care for the first-line treatment of MSI-H/dMMR colorectal cancer. Merck’s Keytruda won its full FDA approval in mid-2020 for that indication. Immuno-oncology agents are expected to work very well in MSI-H tumors because they are enriched with neoantigens that can be targeted by the immune system.

Although the Merck PD-1 single agent has set a high bar, Bristol’s PD-1/CTLA-4 combo data look strong by a cross-trial comparison. In Keynote-177, Keytruda alone cut the risk of progression or death by 40% against chemo—with or without targeted therapies—in previously untreated MSI-H/dMMR colorectal cancer. The median progression free survival result was 16.5 months and 8.2 months for the two arms, respectively.

Opdivo and Yervoy’s 72% risk reduction versus chemo came in notably higher. Besides, although the median progression-free survival readout hasn’t been reached for the combo arm, it looks to be at least 38.4 months, compared with 5.8 months for chemo in CheckMate 8HW.

Nevertheless, such cross-trial comparisons are not reliable given different patient characteristics, and the only way to know for certain whether the two-drug regimen is better than a PD-1 alone is through a head-to-head trial. CheckMate 8HW is studying an Opdivo arm to test the treatments against each other.

The study is also following patients for an overall survival readout. Back when Keytruda got its go-ahead here in 2020, overall survival data from Keynote-177 were not mature.

“It remains crucial to identify predictive factors that can aid in the clinical decision-making process when choosing between immune checkpoint inhibitor monotherapy or combination,” Andre said. “Identifying patients who would benefit from dual immunotherapy combination aligns with optimizing treatment choices to help deliver the best possible outcome for these patients.”

The positive PD-1/CTLA-4 readout in MSI-H colorectal cancer comes as Bristol’s PD-1/LAG-3 combo, Opdualag, failed to move the needle in previously treated microsatellite stable (MSS) disease in the RELATIVITY-123 trial. Only about 5% to 7% of metastatic colorectal cancer cases are MSI-H, while the rest are MSS.