What is the clinical efficacy of adagrasib in the treatment of colorectal cancer?

In June 2024, the U.S. FDA granted accelerated approval to adagrasiib in combination with cetuximab for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (as determined by a U.S. FDA-approved test) who have previously received fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent on verification and description of clinical benefit in confirmatory trials.

Accelerated approval is based on KRYSTAL-1, a multicenter, single-arm expansion cohort trial. Eligible patients must have locally advanced or metastatic KRAS G12C mutant CRC and have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and, if eligible, a VEGF inhibitor. Patients received adagrasiib 600 mg twice daily plus cetuximab biweekly (500 mg/m2 every two weeks) or weekly (initial dose 400 mg/m2, followed by 250 mg/m2 weekly). Tumor assessments were performed every 6 weeks. Discontinuation of adagrasiib requires discontinuation of cetuximab, but patients can continue adagrasiib treatment if cetuximab is discontinued.

The primary efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as determined by blinded independent central review RECIST v1.1. Among the 94 enrolled patients, the ORR was 34%, all responses were partial, and the median DOR was 5.8 months. Thirty-one percent of responding patients had a DOR of at least 6 months.

In summary, adagrasib has demonstrated significant clinical efficacy in the treatment of colorectal cancer, especially when combined with cetuximab. However, each patient's response may vary, so in practice, individualized treatment plans need to be developed based on the patient's specific circumstances.