Adagrasib Plus Cetuximab Granted Accelerated Approval for KRAS G12CL–Mutated Colorectal Cancer

The FDA has granted accelerated approval to adagrasib (Krazati®, Mirati Therapeutics, Inc.) plus cetuximab for adult patients 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.

Why it matters: “Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer,” wrote Rona Yaeger, MD, Associate Professor of Medicine at Memorial Sloan Kettering Cancer Center, and colleagues, in their published results of the KRYSTAL-1 study (NCT03785249), on which accelerated approval was based. “Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.”

What they studied: Efficacy was studied in the phase 1/2, single-arm, multicenter trial which enrolled 94 eligible patients with locally advanced or metastatic KRAS G12C–mutated CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and a vascular endothelial growth factor (VEGF) inhibitor. Patients received 600 mg of adagrasib twice daily plus cetuximab either biweekly at 500 mg/m2 or weekly at 400 mg/m2 followed by 250 mg/m2. Every six weeks, tumor assessments were performed. Discontinuation of adagrasib treatment subsequently required cetuximab discontinuation; however, if cetuximab was discontinued, patients were permitted to continue adagrasib.

The primary efficacy outcomes measured were confirmed overall response rate and duration of response as assessed by Blinded Independent Central Review (BICR) via RECIST v1.1.

What they found: In those being treated with adagrasib plus cetuximab, the overall response rate was 34% with all responses being partial responses. The median duration of response was 5.8 months with 31% of responding patients having a duration of response of at least six months.

Adverse events: The most common adverse events experienced by ≥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.

Conclusion: “Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab,” concluded Dr. Yaeger and colleagues.

Instructions: The recommended dosage of adagrasib is 600 mg orally, twice daily until disease progression or unacceptable toxicity. Please refer to the cetuximab prescribing information for cetuximab dosage information.

For More Information

Yaeger R, Weiss J, Pelster MS, et al (2023). Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med, 388(1):44-54. DOI:10.1056/NEJMoa2212419

Krazati® (adagrasib) prescribing information (2024). Mirati Therapeutics. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216340s005lbl.pdf

Clinicaltrials.gov (2024). Phase 1/​2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. NLM identifier: NCT03785249.

US Food and Drug Administration (2024). FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer

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