Adagrasib in the treatment of colorectal cancer

KRASG12C mutations occur in 3-4% of metastatic colorectal cancer (mCRC) cases and confer a poor prognosis. Adagrasib is an oral, small molecule that selectively and irreversibly inhibits KRASG12C. The phase I/Ib KRYSTAL-1 study established 600 mg twice daily as a recommended phase II dose. Adagrasib monotherapy showed efficacy in heavily pretreated patients with KRASG12C-mutated mCRC. When combined with cetuximab, an anti-EGFR monoclonal antibody, efficacy was further improved with an ORR of 34% and median OS of 15.9 months, leading to the accelerated approval of the combination by the Food and Drug Administration (FDA) in USA in 2024, but it is not yet approved in the European Union. Adagrasib is a well-tolerated drug as monotherapy and in combination with cetuximab and represents a novel treatment for KRASG12C-mutated mCRC.