FDA Grants Priority Review to Adagrasib, Cetuximab Combo for KRAS G12C-Mutated CRC

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental New Drug Application (sNDA) for adagrasib (Krazati, Bristol Myers Squibb) in combination with cetuximab for the treatment of patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC).

The Prescription Drug User Fee Act goal date is set at June 21, 2024.

The sNDA is based on results of the multicohort, phase 1b/2 KRYSTAL-1 study, which evaluated adagrasib alone or in combination with other anticancer therapies in patients with advanced solid tumors harboring a KRAS G12C mutation. Results showed that adagrasib alone or with other anticancer therapies was well tolerated and provided promising clinical activity in pretreated patients with locally advanced or metastatic CRC. After a median follow-up of 17.5 months, 28 patients experienced an objective response rate of 46% with adagrasib plus cetuximab. All responses were partial, and the remaining 54% of patients had stable disease.

The median duration of response was 7.6 months (95% CI, 5.7-not estimable).

Additionally, the safety profile of adagrasib plus cetuximab was deemed manageable and consistent with previously reported data.

“Pretreated KRAS G12C-mutated CRC is associated with poor outcomes, and the current standard of care offers limited clinical benefit for patients,” said Anne Kerber, a senior vice president at Bristol Myers Squibb, in a press release. “The acceptance of this filing for Krazati in combination with cetuximab is a positive step toward providing a potential new option for patients and their physicians.”

Adagrasib is an oral small-molecule inhibitor of KRAS G12C; these mutations are oncogenic drivers, occurring in between 3% and 4% of patients with CRC. In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer based on findings from KRYSTAL-1.

Results from KRYSTAL-1 also led to the FDA breakthrough therapy designation for the combination treatment in patients with KRAS G12C-mutated advanced CRC following prior treatment with chemotherapy and anti-VEGF therapy.