KRAS Inhibitor Regimen Approved for Colorectal Cancer
The FDA issued its first approval for the use of A KRAS G12C inhibitor in a tumor type other than lung.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to adagrasib (Krazati) plus cetuximab (Erbitux) for the treatment of adult patients with locally advanced or metastatic colorectal cancer that harbors a KRAS G12C mutation and has been previously treated with a chemotherapy regimen containing fluoropyrimidine, oxaliplatin, and irinotecan.
Adagrasib and cetuximab are both targeted therapies. Adagrasib inhibits KRAS G12C, a mutated form of the protein KRAS that promotes the growth of many cancer types. Sometimes, tumors can develop resistance to adagrasib by relying on another growth-promoting protein called EGFR. Cetuximab blocks EGFR signaling, making it harder for the tumor to develop treatment resistance.
Adagrasib was previously granted accelerated approval to treat non-small cell lung cancers (NSCLC) harboring a KRAS G12C mutation. This is the first approval of a KRAS G12C inhibitor for a cancer other than NSCLC and the first approval for an adagrasib combination therapy.
The approval was based on results from the multicenter, single-arm, phase I/II KRYSTAL-1 expansion cohort trial, which were presented at the AACR Annual Meeting 2024 and simultaneously published in the AACR journal Cancer Discovery. The trial enrolled 94 patients with locally advanced or metastatic KRAS G12C-mutated colorectal cancer who had previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and, if eligible, a VEGF inhibitor. Patients were treated with adagrasib plus cetuximab.
The overall response rate was 34%, and responses lasted for a median of 5.8 months. Thirty-one percent of patients whose tumors responded experienced a response lasting at least 6 months.
The recommended dose of adagrasib is 600 mg twice a day until disease progression or unacceptable toxicity. The recommended dose of cetuximab is an initial 400 mg/m2 infusion followed by 250 mg/m2 weekly.
The prescribing information for cetuximab includes a boxed warning for potentially fatal infusion reactions and cardiopulmonary arrest.
Colorectal cancer is a cancer of the large intestine, and 3% to 4% of colorectal cancers harbor a KRAS G12C mutation. According to federal statistics, it was estimated that 152,810 individuals would be diagnosed with colorectal cancer and 53,010 patients would die of the disease in the United States in 2024.
The FDA rendered its decision on June 21, 2024. Accelerated approval means that continued approval may be contingent upon a confirmatory trial.
