Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer

Adagrasib, an irreversible, selective KRAS(G12C) inhibitor, may be an effective treatment in KRAS(G12C)-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRAS(G12C)-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 KRAS(G12C)-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRAS(G12C) mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897 Significance: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRAS(G12C)-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRAS(G12C) mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897