The U.S. Food and Drug Administration (FDA) has granted accelerated approval to adagrasib (Krazati; Mirati Therapeutics, Inc.) in combination with cetuximab for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC). This approval is specifically for patients who have previously undergone treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The approval was granted on June 21, 2024.
The approval was based on data from the KRYSTAL-1 trial, a multicenter, single-arm expansion cohort study. Patients eligible for the trial had locally advanced or metastatic KRAS G12C-mutated CRC and had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as a VEGF inhibitor if eligible. Patients received adagrasib 600 mg twice daily in combination with cetuximab, administered either biweekly (500 mg/m2 every two weeks) or weekly (400 mg/m2 initial dose followed by 250 mg/m2 weekly). Tumor assessments were conducted every 6 weeks.
The primary efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DoR) according to RECIST v1.1, as assessed by blinded independent central review. The study enrolled 94 patients, and the ORR was 34% (95% confidence interval [CI]: 25%, 45%). All responses were partial responses. The median DoR was 5.8 months (95% CI: 4.2, 7.6). Among the responding patients, 31% experienced a DoR of at least 6 months.
The most common adverse reactions (≥20%) observed in patients treated with adagrasib and cetuximab included rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, cough, dizziness, constipation, and peripheral neuropathy. The recommended dose of adagrasib is 600 mg orally twice daily until disease progression or unacceptable toxicity. Cetuximab dosage information should be consulted in its prescribing information.
This application was granted priority review and breakthrough therapy designation, reflecting the unmet need in this patient population. Healthcare professionals are encouraged to report any serious adverse events suspected to be associated with the use of adagrasib or cetuximab to the FDA’s MedWatch Reporting System.
