On June 21, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the KRAS G12C inhibitor 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.
KRYSTAL-1
Efficacy was evaluated in KRYSTAL-1 (ClinicalTrials.gov identifier NCT03785249), a multicenter, single-arm expansion cohort trial. Eligible patients were required to have locally advanced or metastatic KRAS G12C–mutated colorectal cancer and to have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and a VEGF inhibitor, if eligible. Patients received adagrasib at 600 mg twice daily plus cetuximab administered either biweekly (500 mg/m2 every 2 weeks) or weekly (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Tumor assessments were performed every 6 weeks. Adagrasib discontinuation required cetuximab discontinuation; however, patients could continue on with adagrasib if cetuximab was discontinued.
The major efficacy outcome measures of the trial were confirmed overall response rate and duration of response according to Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by blinded independent central review. In the 94 enrolled patients, the overall response rate was 34% (95% confidence interval [CI] = 25%–45%); all responses were partial responses. The median duration of response was 5.8 months (95% CI = 4.2–7.6 months); 31% of responding patients had a duration of response lasting at least 6 months.
The most common adverse reactions (occurring in ≥ 20% of patients receiving adagrasib) were 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 adagrasib dose is 600 mg orally twice daily until disease progression or unacceptable toxicity.
This application was granted Priority Review and Breakthrough Therapy designations.
