FDA Approves Adagrasib for Use in Previously Treated CRC

The FDA announced on June 21, 2024, that it had approved¹ adagrasib (Krazati; Mirati Therapeutics, Inc., a Bristol Myers Squibb company) for use in adult patients with previously treated KRAS G12C–mutated locally advanced or metastatic colorectal cancer. The treatment can be used in combination with cetuximab to treat these patients. The news comes after the FDA agreed to priority review on February 20, 2024.²

Adagrasib is an oral small-molecule inhibitor of KRAS G12C, which could help in treating patients with cancers due to KRAS G12C mutations. This includes 14% of non–small cell lung cancer (NSCLC) cases and 3% to 4% of CRC cases. CRC is the third most commonly diagnosed cancer in the world, making new treatments vital. Adagrasib was previously granted breakthrough therapy designation by the FDA in 2022 for KRAS G12C-mutated advanced CRC whose cancer had progressed after other treatments.

The FDA approval is based on the results of the KRYSTAL-1 phase 1/2 trial (NCT03785249) conducted as an open-label, multicenter, multiple expansion cohort study. The trial aimed to determine the safety and efficacy of adagrasib for patients with advanced solid tumors with the mutation. The objective response rate was the primary end point of the trial with duration of response (DOR), progression-free survival (PFS), and safety acting as the secondary end points.

The results of the clinical trial through June 2022 were published in The New England Journal of Medicine in 2023.³ There were 44 patients who received adagrasib and 32 who received adagrasib with cetuximab; the groups had follow-ups of 20.1 months and 17.5 months, respectively. A response was reported in 19% of patients who received adagrasib by itself (95% CI, 8%-33%) with a median DOR of 4.3 months (95% CI, 2.3-8.3) and a PFS of 5.6 months (95% CI, 4.1-8.3). In contrast, the response rate to the combination of adagrasib and cetuximab was 46% (95% CI, 28%-66%), with a median DPR of 7.6 months (95% CI, 5.7-not estimable). The median PFS was 6.9 months (95% CI, 5.4-8.1).

A total of 34% of the patients who only took adagrasib had a grade 3 or 4 adverse event related to treatment compared with 16% in the combination group. The most common adverse events included nausea, diarrhea, vomiting, musculoskeletal pain, fatigue, renal impairement, haptotoxicity, dyspnea, edema, and decreased appetite.

References

1. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. News Release. FDA; June 21, 2024. Accessed June 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer?utm_medium=email&utm_source=govdelivery
2. U.S. Food and Drug Administration (FDA) accepts supplemental new drug application for KRAZATI (adagrasib) in combination with cetuximab as a targeted treatment option for patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) for priority review. News release. Bristol Myers Squibb. February 20, 2024. Accessed June 19, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-KRAZATI-adagrasib-in-Combination-with-Cetuximab-as-a-Targeted-Treatment-Option-for-Patients-with-Previously-Treated-KRAS-G12C-Mutated-Locally-Advanced-or/default.aspx
3. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;388(1):44-54. doi:10.1056/NEJMoa2212419