FDA Withdraws Approval of Krazati/Erbitux Combination in KRAS G12C Colorectal Cancer Following Phase 3 Failure
In a major post-marketing regulatory enforcement action, the U.S. Food and Drug Administration (FDA) has withdrawn its approval of the combination of Krazati (adagrasib) and Erbitux (cetuximab) for the treatment of patients with KRAS G12C-mutated colorectal cancer. The decision follows the failure of the confirmatory Phase 3 KRYSTAL-10 trial to demonstrate clinical benefit.
Confirmatory Trial Failure (KRYSTAL-10)
The combination of adagrasib and cetuximab was previously granted accelerated approval based on early-stage objective response rate (ORR) and duration of response (DOR) data. Under the accelerated approval pathway, sponsors are required to conduct randomized Phase 3 trials to verify and describe clinical benefit1 (such as progression-free survival and overall survival).
The confirmatory Phase 3 KRYSTAL-10 trial (NCT04793945) randomized 461 patients with advanced KRAS G12C-mutated colorectal cancer to receive either the Krazati/Erbitux combination or standard chemotherapy. The final results failed to show any statistically significant benefit:
- Progression-Free Survival (PFS): Median PFS was 7.5 months for the Krazati/Erbitux combination compared to 8.1 months for standard chemotherapy.
- Overall Survival (OS): Median OS was 21.6 months for the combination versus 21.7 months for chemotherapy.
Because the combination failed to improve either PFS or OS relative to standard chemotherapy, the FDA initiated the withdrawal of this specific indication.
Broader Implications
This regulatory rollback underscores the rigorous oversight of the FDA's accelerated approval program and the high risk of translating early surrogate endpoint success (tumor shrinkage) into long-term survival benefits. It also highlights the persistent challenges of targeting KRAS G12C mutations in colorectal cancer compared to non-small cell lung cancer (NSCLC), where KRAS G12C inhibitors have demonstrated more robust and durable efficacy.
"The decision follows final results from the phase 3 KRYSTAL-10 trial, the study designed to confirm the drug combination's benefit... KRYSTAL-10 (open-label, randomized; n=461) showed median PFS 7.5 vs 8.1 months and OS 21.6 vs 21.7 months for adagrasib/cetuximab versus chemotherapy, without statistical significance." — Cure Today Report (8 Sep 2026)
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An instance of Accelerated pathways shift the proof of clinical benefit from pre-market trials to post-marketing requirements. — Krazati's combination had its approval withdrawn after failing to verify survival benefit in its mandatory Phase 3 post-marketing confirmatory study. ↩︎