Adagrasib Plus Cetuximab Under Review for KRAS^G12C-Mutated Advanced Colorectal CA

The Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) for adagrasib, in combination with cetuximab, for the treatment of patients with previously treated KRAS^G12C-mutated locally advanced or metastatic colorectal cancer (CRC).

Adagrasib is a highly selective, potent oral small molecule inhibitor of KRAS^G12C designed to sustain target inhibition by irreversibly locking the mutant protein in its inactive state. The application is supported by data from the multicohort phase 2 KRYSTAL-1 study (ClinicalTrials.gov Identifier: NCT03785249), which evaluated adagrasib in heavily pretreated patients with KRAS^G12C-mutated advanced CRC.

Study participants received either adagrasib 600mg orally twice daily as monotherapy (n=44) or in combination with cetuximab administered intravenously once or twice weekly (n=32); median follow-up was 20.1 months and 17.5 months, respectively. The primary endpoint was the objective response rate (ORR). 

Among 28 evaluable patients in the adagrasib plus cetuximab arm, the ORR was 46% (95% CI, 28-66). Median duration of response (DOR) was 7.6 months (95% CI, 5.7-not estimable) and median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.1).

Among 43 evaluable patients in the adagrasib monotherapy arm, the ORR was 19% (95% CI, 8-33). Median DOR was 4.3 months (95% CI, 2.3-8.3) and median PFS was 5.6 months (95% CI, 4.1-8.3). 

The safety profile of adagrasib plus cetuximab was well tolerated. The incidence of Grade 3 or 4 treatment-related adverse events was 34% in the monotherapy arm and 16% in the combination arm. There were no Grade 5 adverse events observed. 

A Prescription Drug User Fee Act target date of June 21, 2024 has been set for this application.

“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, senior vice president, head of late clinical development, Hematology, Oncology, Cell Therapy (HOCT) at Bristol Myers Squibb. “It [sNDA acceptance] reinforces our commitment to developing potentially transformative targeted cancer therapies for patients for whom few treatment options exist.”

Adagrasib is currently marketed under the trade name Krazati^® and is approved for the treatment of adults with KRAS^G12C-mutated locally advanced or metastatic NSCLC, who have received at least 1 prior systemic therapy.