The Food and Drug Administration (FDA) has granted accelerated approval for the combination of adagrasib (Krazati; Mirati Therapeutics, Inc.) and cetuximab for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC). This approval applies to patients who have previously been treated with chemotherapy regimens based on fluoropyrimidine, oxaliplatin, and irinotecan, and is contingent upon the use of an FDA-approved test to confirm the KRAS G12C mutation.
Image Source: Vinoth Khandelwal
Adagrasib plus cetuximab has been granted accelerated approval by the FDA, a status that allows for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint. This combination therapy also received priority review and breakthrough therapy designation, highlighting its potential to significantly improve treatment outcomes for patients with this specific genetic mutation.
Adagrasib is administered orally at a dose of 600 mg twice daily. Cetuximab is given either biweekly at 500 mg/m² or weekly starting with an initial dose of 400 mg/m² followed by 250 mg/m² weekly. This combination targets the KRAS G12C mutation, a specific genetic alteration in some colorectal cancer tumors, which is associated with poor prognosis and limited treatment options.
The efficacy of the combination was evaluated in the KRYSTAL-1 trial, a multicenter, single-arm expansion cohort study. This trial included patients with KRAS G12C-mutated CRC who had previously received chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan, as well as a VEGF inhibitor if eligible. In the trial, patients received the combination of adagrasib and cetuximab with tumor assessments conducted every six weeks.
The primary efficacy outcomes measured were the confirmed overall response rate (ORR) and the duration of response (DOR) as per RECIST v1.1 criteria, assessed by a blinded independent central review. Among the 94 enrolled patients, the ORR was 34%, with all responses being partial. The median DOR was 5.8 months, with 31% of responding patients maintaining their response for at least six months.
Colorectal cancer is a significant health burden, and the KRAS G12C mutation occurs in a subset of patients, presenting challenges in treatment due to its association with resistance to standard therapies. The availability of targeted treatments like adagrasib and cetuximab offers a new therapeutic avenue for these patients, aiming to improve their prognosis and quality of life.
The accelerated approval of adagrasib in combination with cetuximab marks a critical advancement in the treatment of KRAS G12C-mutated colorectal cancer. By targeting a specific genetic mutation, this therapy provides a new hope for patients who have exhausted other treatment options. Ongoing studies and real-world data will further elucidate the long-term benefits and safety profile of this promising treatment regimen.
Dr. Vinoth Khandelwal, Ph.D.
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