The combination of adagrasib and cetuximab did not significantly improve progression-free survival (PFS) or overall survival (OS) compared with standard chemotherapy in patients with previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC), according to results from the Phase III KRYSTAL-10 trial presented as a late-breaking abstract at the 2026 ESMO Gastrointestinal Cancers Congress.
KRAS G12C mutations occur in approximately 3–4% of colorectal cancers and have emerged as an important therapeutic target. While adagrasib plus cetuximab has demonstrated promising activity in earlier studies and is already approved in some settings, KRYSTAL-10 is the first Phase III trial to evaluate the combination against standard second-line chemotherapy.
The global, open-label study enrolled 461 patients with KRAS G12C-mutated metastatic colorectal cancer whose disease had progressed following first-line fluoropyrimidine-based doublet chemotherapy containing oxaliplatin or irinotecan. Participants were randomised to receive adagrasib plus cetuximab or investigator’s choice of FOLFIRI or modified FOLFOX6 chemotherapy, with or without a VEGF/VEGFR inhibitor.The study did not meet either of its dual primary endpoints.
Median PFS, as assessed by blinded independent central review, was 7.5 months with adagrasib plus cetuximab compared with 8.1 months with chemotherapy (hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.71–1.13; p=0.32).
At the time of the final OS analysis, with a minimum follow-up of 26.4 months, median OS was 21.6 months in the adagrasib plus cetuximab arm and 21.7 months in the chemotherapy arm (HR 0.83; 95% CI 0.67–1.03; p=0.09).
Despite the lack of improvement in the primary endpoints, the targeted combination achieved a substantially higher objective response rate than chemotherapy (47% vs 16%), including complete responses in 7% of patients compared with less than 1% in the chemotherapy group.
No new safety signals were observed.
The findings contrast with the earlier Phase I/II KRYSTAL-1 trial, in which adagrasib plus cetuximab demonstrated promising efficacy with manageable safety in heavily pretreated patients with KRAS G12C-mutated metastatic colorectal cancer.
Although KRYSTAL-10 did not meet its dual primary endpoints, the higher objective response rate and manageable safety profile demonstrated clinical activity for adagrasib plus cetuximab as a chemotherapy-free targeted regimen in previously treated patients with KRAS G12C-mutated metastatic colorectal cancer. Further analyses may help clarify whether specific patient subgroups derive greater benefit or define the optimal sequencing of KRAS-targeted therapies within the treatment pathway.
Abstract: Tabernero J, et al. Second-line adagrasib plus cetuximab versus chemotherapy in patients with KRAS G12C-mutated metastatic colorectal cancer: Results from the Phase III KRYSTAL-10 trial. Presented at the ESMO Gastrointestinal Cancers Congress 2026. Late-breaking Abstract LBA1. Access online here.
