Scott E. Kopetz

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2–7.6). Median progression-free survival was 6.9 months (95% CI, 5.7–7.4) and median overall survival was 15.9 months (95% CI, 11.8–18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3–4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. Significance: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.