Is sotoracib (AMG510) a treatment for KRAS G12C mutations?

KRAS gene mutations are the most common gain-of-function mutations in lung adenocarcinoma. The most common mutation, KRAS G12C, is present in 13% of lung adenocarcinomas. Sotoracib (AMG510) is an irreversible small molecule inhibitor targeting KRAS G12C. Treatment with sotorasiib resulted in regression of KRAS G12C mutant tumors in preclinical studies and demonstrated clinical efficacy in clinical trials in non-small cell lung cancer.

In May 2021, sotorasiib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations, and these patients have received at least one previous systemic therapy. Sotorasiib is an irreversible small molecule tyrosine kinase inhibitor targeting KRAS G12C. The molecule binds to the inactive GDP-bound conformation, trapping KRAS G12C in a dormant state and inhibiting KRAS oncogenic signaling. In a Phase 2 clinical trial (CodeBreaK 100), sotoraxib was shown to have clinical efficacy in previously treated KRAS G12C mutant non-small cell lung cancer. In long-term follow-up, the 1-year survival rate of sotorasib treatment was 50.8%, the 2-year survival rate was 32.5%, and the median overall survival was 12.5 months.

Sotoracib is therefore an FDA-approved therapy for the treatment of previously treated KRAS G12C mutated non-small cell lung cancer. Sotorasiib can inhibit the activity of this mutant, thereby inhibiting the growth and spread of tumor cells. In this setting, the clinical potential of sotorasib as first-line treatment was demonstrated. After more than 6 months of treatment, the patient demonstrated a sustained complete response and was able to tolerate the treatment without significant toxicity.