FDA Withdraws Indication for Adagrasib Plus Cetuximab in Previously Treated, KRAS G12C–Mutated mCRC

On September 1, 2026, the FDA removed the accelerated approval indication for adagrasib (Krazati) plus cetuximab (Erbitux) for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic colorectal cancer (CRC) who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.^1,2

This regulatory decision follows the final data readout from the phase 3 KRYSTAL-10 trial (NCT04793958), which were presented at the 2026 ESMO Gastrointestinal Cancers Annual Congress.³ The findings showed that the trial did not meet either of its dual primary end points of statistically significant overall survival (OS) or progression-free survival (PFS) benefits with the use of adagrasib plus cetuximab vs chemotherapy in patients with KRAS G12C–mutated metastatic CRC (mCRC) whose disease had progressed on first-line fluoropyrimidine-based therapy.

What was the design of KRYSTAL-10?

This global, randomized, open-label study enrolled patients with histologically confirmed mCRC with a KRAS G12C mutation who had disease progression during frontline therapy with a fluoropyrimidine-based oxaliplatin- or irinotecan-containing regimen. Patients also needed to have an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive twice-daily adagrasib at 600 mg in combination with cetuximab at 500 mg/m² every 2 weeks or investigator’s choice of FOLFIRI (leucovorin, fluorouracil, and irinotecan) or modified FOLFOX (leucovorin, fluorouracil, and oxaliplatin), with or without a VEGF/VEGFR inhibitor.

Key secondary end points included overall response rate (ORR), duration of response (DOR), 1-year OS rate, and safety.

What were the key efficacy data from KRYSTAL-10?

At a minimum follow-up of 26.4 months, the median OS with adagrasib plus cetuximab (n = 231) was 21.6 months (95% CI, 18.4-25.5) compared with 21.7 months (95% CI, 18.0-24.8) with chemotherapy (n = 230; HR, 0.83; 95% CI, 0.67-1.03; P = .0938). The respective 12-, 30-, and 36-month OS rates among patients who received adagrasib plus cetuximab were 73.4%, 38.0%, and 27.1%. These rates were 70.1%, 27.3%, and 22.5%, respectively, among patients who received chemotherapy.

At a minimum follow-up of 16.4 months, the median PFS was 7.5 months (95% CI, 6.3-9.2) with adagrasib plus cetuximab compared with 8.1 months with chemotherapy (95% CI, 7.3-9.2; HR, 0.89; 95% CI, 0.71-1.13; P = .3241). The respective 12-month PFS rates in these arms were 30.2% and 24.4%. The 18-month PFS rates were 20.0% and 15.4%, respectively.

The ORR with adagrasib plus cetuximab was 47% (95% CI, 40%-53%) compared with 16% (95% CI, 11%-21%) in the chemotherapy arm (difference, 31%; 95% CI, 23%-39%). The median DOR was 9.2 months (95% CI, 7.4-11.1) with adagrasib plus cetuximab vs 9.4 months (95% CI, 5.6-11.8) with chemotherapy.

What safety data were seen in KRYSTAL-10?

Any-grade treatment-related treatment-emergent adverse effects (TEAEs) were reported in 98% of safety-evaluable patients in the adagrasib/cetuximab arm (n = 230) vs 96% of those in the chemotherapy arm (n = 206). Grade 3 to 5 treatment-related TEAEs were observed in 46% and 55% of patients, respectively. Serious treatment-related TEAEs were seen in in 9% and 12% of patients, respectively. Treatment-related TEAEs that led to treatment discontinuation were seen in 3% and 2% of patients, respectively. One treatment-related death (due to sepsis) was reported in the chemotherapy arm.

What is the regulatory history of adagrasib plus cetuximab in KRAS G12C–Mutated mCRC?

On June 21, 2024, the FDA granted accelerated approval to the combination for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.⁴ This regulatory decision was backed by data from the phase 1/2 KRYSTAL-1 trial (NCT03785249), in which the confirmed ORR was 34% (95% CI, 25%-45%), consisting of all partial responses, among patients who received adagrasib plus cetuximab in the single-arm trial. Additionally, the median DOR was 5.8 months (95% CI, 4.2-7.6).

References

1. Withdrawn | cancer accelerated approvals. FDA. Updated September 2, 2026. Accessed September 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-cancer-accelerated-approvals
2. Krazati. Prescribing information. Bristol Myers Squibb; updated August 2026. Accessed September 14, 2026. https://packageinserts.bms.com/pi/pi_krazati.pdf
3. 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 Oncol. 2026;37(suppl 1):S1-S2. doi:10.1016/j.annonc.2026.09.005
4. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. FDA. June 21, 2024. Accessed September 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer