FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer

FDA accelerated approval (June 21, 2024)

The FDA granted accelerated approval to adagrasib (Krazati) plus cetuximab for adults with KRAS G12C–mutated locally advanced or metastatic colorectal cancer, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Supporting evidence: KRYSTAL-1

Efficacy was evaluated in KRYSTAL-1, a multicenter, single-arm expansion cohort. Eligible patients had KRAS G12C–mutated locally advanced or metastatic CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and a VEGF inhibitor, if eligible. Treatment was adagrasib 600 mg orally twice daily plus cetuximab (500 mg/m² every 2 weeks or 400 mg/m² loading dose then 250 mg/m² weekly). Tumor assessments occurred every 6 weeks.

Major endpoints were confirmed ORR and DOR per RECIST v1.1 by blinded independent central review. Among 94 patients, ORR was 34% (95% CI, 25%–45%); all responses were partial. Median DOR was 5.8 months (95% CI, 4.2–7.6), and 31% of responders had DOR ≥6 months.

Safety and dosing

Common adverse reactions (≥20%) included rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, and others. Recommended adagrasib dose: 600 mg twice daily until progression or unacceptable toxicity; see cetuximab prescribing information for dosing.

The application received priority review and breakthrough therapy designation. Full prescribing information will be posted on Drugs@FDA.