On June 21, 2024, the Food and Drug Administration granted accelerated approval to adagrasib (Krazati; Mirati Therapeutics, Inc., a Bristol Myers Squibb company) plus cetuximab for adults with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
Full prescribing information for Krazati will be posted on Drugs@FDA.
Efficacy and Safety
Efficacy was evaluated in KRYSTAL-1, a multicenter, single-arm expansion cohort trial. Eligible patients were required to have locally advanced or metastatic KRAS G12C-mutated CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and a VEGF inhibitor, if eligible. Patients were treated with adagrasib 600 mg twice daily plus 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 performed every 6 weeks. Adagrasib discontinuation required cetuximab discontinuation, however patients could continue adagrasib if cetuximab was discontinued.
The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 assessed by blinded independent central review. In the 94 enrolled patients, ORR was 34% (95% CI: 25%, 45%), all responses were partial responses, and median DOR was 5.8 months (95% CI: 4.2, 7.6). Thirty-one percent of responding patients had a DOR of at least 6 months.
The most common adverse reactions (≥20%) 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. Refer to the cetuximab prescribing information for cetuximab dosage information.
Expedited Programs
This application was granted priority review and breakthrough therapy designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.
Follow the Oncology Center of Excellence on X @FDAOncology.
