FDA Grants Accelerated Approval to Adagrasib With Cetuximab for KRAS G12C-Variant Colorectal Cancer
On June 21, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer) to adagrasib (Krazati®) plus cetuximab for adults with KRAS G12C-variant 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.
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-variant 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). Investigators performed tumor assessments every six weeks. Adagrasib discontinuation required cetuximab discontinuation; however, patients could continue adagrasib if they discontinued cetuximab.
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 reported in at least 20% of patients 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 patients experience disease progression or unacceptable toxicity. View the full prescribing information for adagrasib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216340s005lbl.pdf). Refer to the cetuximab prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125084s279lbl.pdf) for cetuximab dosage.
This application was granted priority review and breakthrough therapy designation. FDA’s expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-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 (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088.
For assistance with single-patient applications for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate (https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).