Adagrasib Shows Promise in Colorectal Cancer with KRAS G12C Mutation

KRAS mutations are ubiquitous across a broad spectrum of malignancies. Adagrasib is a novel oral agent that irreversibly binds to mutant KRAS G12C protein in its inactive, GDP-bound state. Preclinical data indicate that epidermal growth factor receptor (EGFR) inhibitors may potentiate the activity of adagrasib.

Investigators report results of a phase 1–2, industry-sponsored, nonrandomized, open-label trial of adagrasib in heavily pretreated patients with metastatic colorectal cancer harboring a KRAS G12C mutation. Patients were treated either with adagrasib alone or combined with the EGFR inhibitor cetuximab. Of the 76 patients treated, most (63%) had received three or more prior regimens, most (63%) had liver metastases, and most (68%) had p53 mutations.

Of 43 evaluable patients treated with single-agent adagrasib, 23% responded. During a median follow-up of 20.1 months, median duration of response was 4.3 months, progression-free survival (PFS) was 5.6 months, and overall survival (OS) was 19.8 months. Of 28 evaluable patients treated with adagrasib plus cetuximab, 46% responded. During a median follow-up of 17.5 months, median duration of response was 7.6 months, PFS was 6.9 months, and OS was 13.4 months. Grade 3/4 treatment-related adverse events occurred in 34% of patients treated with adagrasib alone, including anemia and diarrhea, and in 16% of those treated with combination therapy, ultimately leading to cetuximab discontinuation in 16%.