Colorectal Cancer: FDA Approves Adagrasib for KRAS G12C-Mutated CRC

Colorectal cancer patients with KRAS G12C mutations have received a new treatment option as the US Food and Drug Administration (FDA) has granted accelerated approval to adagrasib (Krazati, Mirati Therapeutics, Inc.) in combination with cetuximab. This highly selective and potent small-molecule KRAS G12C inhibitor is now indicated for patients with locally advanced or metastatic KRAS G12C–mutated CRC who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and, if eligible, a vascular endothelial growth factor inhibitor. The mutation must be identified using an FDA-approved test, as stated in an FDA press release.

Adagrasib represents the first KRAS inhibitor approved for CRC, following its previous accelerated approval for KRAS G12C–mutated non–small cell lung cancer based on findings from the KRYSTAL-12 trial. The CRC approval was supported by results from the KRYSTAL-1 multicenter, single-arm expansion cohort trial, which demonstrated an overall response rate of 34% among 94 enrolled patients. All responses were partial, with a median duration of response of 5.8 months. Additionally, 31% of the responding patients experienced a duration of response of at least 6 months.

Colorectal Cancer Treatment Protocol: Adagrasib and Cetuximab Dosage and Administration Details from the KRYSTAL-1 Trial

Patients in the KRYSTAL-1 trial received 600 mg of adagrasib twice daily along with cetuximab administered either biweekly at a dose of 500 mg/m2 or initially at 400 mg/m2 followed by weekly doses of 250 mg/m2. If patients discontinued adagrasib, they also had to discontinue cetuximab; however, adagrasib could be continued if cetuximab was discontinued. The recommended dose of adagrasib is 600 mg taken orally twice daily until disease progression or unacceptable toxicity occurs, as per the prescribing information.

Common adverse reactions, occurring in at least 20% of treated patients, included rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, cough, dizziness, constipation, and peripheral neuropathy.

Colorectal Cancer Prognoses and Treatment: Scott Kopetz Highlights the Potential of Adagrasib for KRAS G12C-Mutated Cases

“Patients with KRAS G12C-mutated colorectal cancer have historically faced poor prognoses and remain in need of additional treatment options,” said Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston. This statement was made earlier in the year when the FDA announced its decision to accept the drug application for priority review. Kopetz emphasized the significance of the data from the KRYSTAL-1 trial, highlighting the potential benefit of adagrasib for these specific patients, a sentiment echoed by Bristol Myers Squibb, which acquired Mirati Therapeutics, Inc. in 2023.

The approval of adagrasib for CRC marks a significant advancement in the treatment landscape for patients with KRAS G12C mutations, who have historically had limited options and poor outcomes. This new therapy offers hope for improved management and outcomes for this challenging subset of colorectal cancer patients. The efficacy demonstrated in the KRYSTAL-1 trial underscores the potential of adagrasib as a viable treatment option, addressing a critical unmet need in oncology.

In summary, the accelerated approval of adagrasib in combination with cetuximab for KRAS G12C–mutated CRC is a promising development in cancer treatment. The KRYSTAL-1 trial provided robust evidence of the therapy’s efficacy, with a notable response rate and duration of response among patients who had exhausted other treatment options. This new treatment offers a significant step forward in managing KRAS G12C–mutated CRC, providing patients with a targeted therapy that can improve their prognosis and quality of life. As the medical community continues to explore and develop treatments for difficult-to-treat cancers, the approval of adagrasib highlights the importance of targeted therapies in oncology.