Clinical Summary: 

• Design/Population: The phase 3 KRYSTAL-10 trial compared adagrasib plus cetuximab with standard second-line chemotherapy with or without VEGF/VEGFR inhibition in patients with previously treated KRAS G12C–mutated metastatic colorectal cancer (mCRC).
• Key Outcomes: Although adagrasib plus cetuximab produced higher response rates than chemotherapy, it did not significantly improve progression-free survival or overall survival. The combination demonstrated a manageable safety profile.
• Clinical Relevance: These findings support the antitumor activity of chemotherapy-free KRAS G12C-targeted therapy but do not establish superiority over standard second-line chemotherapy.

The phase 3 KRYSTAL-10 trial did not meet its dual primary end points of progression-free or overall survival for adagrasib plus cetuximab versus standard chemotherapy in previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC), although the chemotherapy-free regimen produced substantially higher response rates.

These results were presented by Josep Tabernero, MD, PhD, Vall d'Hebron University Hospital, Barcelona, Spain, at the ESMO Gastrointestinal Cancers Congress in Munich, Germany. 

In this open-label trial, 461 patients whose disease had progressed after first-line fluoropyrimidine-based doublet chemotherapy were randomized 1:1 to receive either 600 mg of adagrasib twice daily plus 500 mg/m² of cetuximab (n = 231) or investigator's choice of FOLFIRI or mFOLFOX6 with or without VEGF/VEGFR inhibitors (n = 230). The dual primary end points were PFS and OS. Key secondary end points included objective response rate (ORR) and safety.

The study did not demonstrate significant improvements in either primary end point. Median PFS was 7.5 months with adagrasib plus cetuximab versus 8.1 months with chemotherapy (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.71 to 1.13; P = .32). Median OS was 21.6 months and 21.7 months, respectively (HR, 0.83; 95% CI, 0.67 to 1.03; P = .09).

No new safety signals were identified. Treatment-related adverse events of any grade occurred in 98% of patients receiving adagrasib plus cetuximab and 96% of those receiving chemotherapy, while grade ≥3 treatment-related adverse events occurred in 46% and 55% of patients, respectively. Serious treatment-related adverse events were reported in 9% and 12% of patients, respectively. Treatment discontinuation because of treatment-related adverse events occurred in 6 patients receiving adagrasib plus cetuximab and 4 receiving chemotherapy.

“While KRYSTAL-10 did not meet its dual primary end points vs chemo, these results demonstrated clinical activity as a chemo-free targeted regimen in previously treated pts with KRAS G12C-mutated mCRC,” concluded Dr Tabernero et al. 

Source: 

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 ESMO GI. July 1-4, 2026; Munich, Germany, LBA1.