Adagrasib Plus Cetuximab Falls Short in KRAS G12C–Mutated Colorectal Cancer

Adagrasib (Krazati) plus cetuximab (Erbitux) did not achieve statistical significance on its dual primary end points of progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with previously treated KRAS G12C–mutated metastatic colorectal cancer (mCRC), although the chemotherapy-free targeted regimen demonstrated antitumor activity with a substantially higher response rate, according to final results from the phase 3 KRYSTAL-10 trial (NCT04793958) presented at the 2026 ESMO GI Cancers Congress.¹

Among 461 enrolled patients, median PFS by blinded independent central review (BICR) was 7.5 months (95% CI, 6.3-9.2) with adagrasib plus cetuximab vs 8.1 months (95% CI, 7.3-9.2) with chemotherapy (HR, 0.89; 95% CI, 0.71-1.13; P =.32). Median overall survival (OS) at the later data cutoff was 21.6 months (95% CI, 18.4-25.5) with adagrasib plus cetuximab vs 21.7 months (95% CI, 18.0-24.8) with chemotherapy (HR, 0.83; 95% CI, 0.67-1.03; P =.09), at a minimum follow-up of 26.4 months. Neither primary end point reached statistical significance.

The objective response rate (ORR) was numerically higher with adagrasib plus cetuximab than with chemotherapy: 47% (95% CI, 40-53) vs 16% (95% CI, 11-21), respectively. Complete responses occurred in 7% of patients in the adagrasib plus cetuximab arm vs less than 1% in the chemotherapy arm.

Regulatory Implications

There were high expectations for the KRYSTAL-10 trial following the success of the single-arm phase 1/2 KRYSTAL-1 trial. In that earlier study, adagrasib plus cetuximab produced an ORR of 46% (95% CI, 28-66) in 28 evaluable patients with heavily pretreated KRAS G12C-mutated metastatic colorectal cancer, with a median duration of response of 7.6 months and median PFS of 6.9 months.²

The KRYSTAL-1 data supported the 2024 FDA accelerated approval of adagrasib plus cetuximab for adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.³

Following the approval, long-term data from KRYSTAL-1 showing sustained efficacy with adagrasib plus cetuximab were shared at the 2025 ASCO GI Cancers Symposium.⁴ “These longer follow-up results further support the FDA approval of adagrasib/cetuximab as a standard of care in patients with previously treated KRAS G12C–mutated advanced mCRC,” presenting author Rona Yaeger, MD, associate attending physician and gastrointestinal medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, said at the time.

Accelerated approvals, however, are contingent upon verification of clinical benefit in a confirmatory trial. As KRYSTAL-10 was the designated confirmatory trial, the accelerated approval of adagrasib plus cetuximab is now at risk of being withdrawn by the FDA.

Safety Results From KRYSTAL-10

The safety profile of adagrasib plus cetuximab in the KRYSTAL-10 trial was consistent with the known profiles of each agent. Any-grade treatment-emergent adverse events (TEAEs) occurred in 98% of patients in the adagrasib plus cetuximab arm (n = 230) and 96% of patients in the chemotherapy arm (n = 206), with grade 3 to 5 events in 46% and 55% of patients, respectively. Serious TEAEs occurred in 9% of adagrasib plus cetuximab patients vs 12% of chemotherapy patients. TEAEs leading to discontinuation of the regimen occurred in 3% vs 2% of patients, respectively. One treatment-related death occurred in the chemotherapy arm. No new safety signals were observed.¹

KRYSTAL-10 Study Design and Patient Population

KRYSTAL-10 is a global, open-label, randomized, phase 3 trial evaluating adagrasib 600 mg twice daily plus cetuximab 500 mg/m2 every 2 weeks vs investigator's choice of chemotherapy, consisting of FOLFIRI or mFOLFOX6, with or without VEGF/VEGFR inhibitors, in patients with KRAS G12C-mutated metastatic colorectal cancer who had progressed on first-line fluoropyrimidine-based doublet chemotherapy with oxaliplatin or irinotecan.1 A total of 461 patients were randomized 1:1 to adagrasib plus cetuximab (n = 231) or chemotherapy (n = 230). Dual primary endpoints were BICR-assessed PFS (database lock April 15, 2025) and OS (database lock February 23, 2026). Key secondary end points included ORR and safety.¹

REFERENCES

1. 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. Presented at: 2026 ESMO Gastrointestinal Cancers Congress; July 1-4, 2026; Munich, Germany. Abstract LBA1.

2. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;388(1):44-54. doi:10.1056/NEJMoa2212419

3. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. News release. US Food and Drug Administration. June 21, 2024. Accessed July 7, 2026. https://tinyurl.com/4rdmn95e

4. Yaeger R, Uboha NV, Klempner SJ, et al. Adagrasib + cetuximab for KRAS G12C–mutated metastatic colorectal cancer: longer follow-up analysis from KRYSTAL-1. J Clin Oncol. 2025;43(suppl 4):131. doi:10.1200/JCO.2025.43.4_suppl.131