Accelerated approval was always a gamble on a single surrogate endpoint, and Krazati just lost that bet in colorectal cancer. Bristol Myers Squibb confirmed that the confirmatory trial for adagrasib in second-line KRAS G12C-mutant colorectal cancer failed to meet its primary endpoint — the precise condition the FDA set when granting accelerated approval. That mechanism exists specifically to be revoked when post-marketing data don’t hold up, and there is no ambiguity here about what comes next.
The failure is clinically significant because KRAS G12C colorectal cancer is biologically distinct from the lung cancer setting where adagrasib earned its regular approval. Colorectal tumors exhibit feedback reactivation of the MAPK pathway through EGFR signaling, which blunts single-agent KRAS inhibition far more aggressively than in NSCLC. The original accelerated approval in colorectal cancer rested on response rate data from KRYSTAL-1, a cohort that showed modest but real activity. The confirmatory trial — designed around a harder endpoint, almost certainly overall survival or progression-free survival in a randomized comparison — exposed what response rate data obscured: durable benefit is not following the same trajectory.
This outcome sharpens scrutiny on the entire combination strategy that BMS and others have pursued in KRAS G12C-mutant colorectal cancer. Pairing adagrasib with cetuximab was the leading hypothesis for overcoming EGFR-mediated resistance, and that combination has generated its own clinical program. The confirmatory trial failure applies to single-agent adagrasib, not the combination, but it reframes how aggressively regulators and investigators will interpret combination response data before committing to another accelerated pathway. The FDA’s willingness to extend the same benefit-of-the-doubt to early combination signals in this tumor type just contracted.
BMS now faces a formal withdrawal or FDA-initiated removal of the colorectal indication, which strips a reimbursable use case from the label even as the lung approval remains intact. The one number to watch is the response rate and PFS data from the adagrasib-plus-cetuximab cohort in KRYSTAL-1 and related studies — if the combination cannot demonstrate a statistically and clinically convincing separation from chemotherapy in a randomized readout, KRAS G12C colorectal cancer becomes a target class without a validated treatment option, not a rescued one.
Source link: https://endpoints.news/krazati-fails-confirmatory-trial-in-colorectal-cancer-putting-approval-at-risk/
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
