FDA Withdraws Adagrasib/Cetuximab Approval in KRAS G12C-Mutated CRC

The FDA has withdrawn the accelerated approval of adagrasib (Krazati) in combination with cetuximab (Erbitux) for adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, according to the agency's list of withdrawn cancer accelerated approvals.¹ The withdrawal is also reflected on adagrasib’s prescribing information under the “Recent Major Changes” section.² The withdrawal took effect September 1, 2026. The accelerated approval indication was previously granted in June 2024.³

The decision follows final results from the phase 3 KRYSTAL-10 trial (NCT04793958), the confirmatory study required to verify the combination's clinical benefit, which failed to demonstrate a statistically significant improvement in either progression-free survival (PFS) or overall survival (OS) compared with chemotherapy.⁴ These results were shared at the European Society of Medical Oncology (ESMO) Gastrointestinal Cancers Congress 2026.

What did the KRYSTAL-10 trial show?

KRYSTAL-10 randomly assigned 461 patients with KRAS G12C-mutated metastatic CRC whose disease had progressed after first-line chemotherapy to receive adagrasib plus cetuximab or investigator's choice chemotherapy.⁴ The median PFS by blinded independent central review (BICR) was 7.5 months (95% CI, 6.3-9.2) with the adagrasib combination vs 8.1 months with chemotherapy (95% CI, 7.3-9.2; HR, 0.89; 95% CI, 0.71-1.13; P = .3241). The median OS was 21.6 months (95% CI, 18.4-25.5) vs 21.7 months (95% CI, 18.0-24.8), respectively (HR, 0.83; 95% CI, 0.67-1.03; P = .0938). Neither the PFS nor OS difference reached statistical significance. The overall response rate (ORR) was 47% (95% CI, 40%-53%) in the adagrasib arm vs 16% (95% CI, 11%-21%) in the control arm.

Among all treated patients, grade 3 or higher treatment-related adverse effects occurred in 46% of patients who received adagrasib plus cetuximab vs 55% of those who received chemotherapy. Any-grade serious treatment-related treatment-emergent adverse events (TEAEs) occurred in 9% vs 12%, respectively, and led to discontinuation of therapy in 3% and 2%.

How was the KRYSTAL-10 trial designed?

KRYSTAL-10 is a global, open-label, randomized trial evaluating adagrasib at 600 mg twice daily plus cetuximab at 500 mg/m² against investigator's choice of FOLFIRI (leucovorin, fluorouracil, and irinotecan) or mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) in the second-line setting.⁵ Eligible patients had KRAS G12C-mutated locally advanced or metastatic CRC with radiographic progression on or after a first-line fluoropyrimidine-based regimen containing oxaliplatin or irinotecan, and no prior anti-EGFR antibody or KRAS G12C-targeted therapy.

The trial's dual primary end points were PFS and OS, with secondary end points including ORR, duration of response, and patient-reported outcomes.

What is adagrasib's regulatory history in colorectal cancer?

The FDA granted accelerated approval to adagrasib plus cetuximab in June 2024 for adults with previously treated KRAS G12C-mutated advanced CRC based on response data from the phase 1/2 KRYSTAL-1 trial (NCT03785249). As with other accelerated approvals, continued marketing of the combination in CRC was contingent on a confirmatory trial verifying clinical benefit; KRYSTAL-10 was designated to serve that role. Adagrasib's separate accelerated approval as a single agent in KRAS G12C-mutated non–small cell lung cancer, granted in December 2022, is not affected by this withdrawal.⁶

What does the withdrawal mean for patients with CRC?

The withdrawal applies specifically to the CRC indication for adagrasib plus cetuximab; adagrasib retains its indication in KRAS G12C-mutated NSCLC. For patients with KRAS G12C-mutated CRC, the combination is no longer an FDA-approved treatment option following the withdrawal.

References

1. Withdrawn | Cancer Accelerated Approvals - Krazati (Adagrasib). US Food and Drug Administration. Updated September 2, 2026. Accessed September 8, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-cancer-accelerated-approvals
2. Krazati (adagrasib) tablets, for oral use. Prescribing information. Bristol Myers Squibb. 2022, Accessed September 8, 2026. https://tinyurl.com/mv3ynux2
3. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. News release. FDA. June 21, 2024. Accessed September 8, 2026. https://tinyurl.com/2app6ahp
4. Tabernero J, Kopetz S, Lee J, et al. Second-line adagrasib plus cetuximab vs chemotherapy in patients with KRASG12C-mutated metastatic colorectal cancer: Results from the KRYSTAL-10 trial. Ann Oncology. 2026;37(suppl_1):S1-S76. doi:10.1016/annonc/annonc2111
5. Phase 3 study of MRTX849 with Cetuximab vs chemotherapy in patients with advanced colorectal cancer with KRAS G12C mutation (KRYSTAL-10). ClinicalTrials.gov. Updated July 23, 2026. Accessed September 8, 2026. https://tinyurl.com/2sbke9wm
6. FDA grants accelerated approval to adagrasib KRAS G12C-mutated NSCLC. News release. ASCO. December 13, 2022. Accessed September 8, 2026. https://tinyurl.com/4fran7ue