Sotorasib (Lumakras®): A Comprehensive Monograph on the First-in-Class KRAS G12C Inhibitor

Executive Summary

Sotorasib represents a landmark achievement in molecular oncology, emerging as the first clinically approved therapeutic agent to successfully target a mutation in the Kirsten rat sarcoma viral oncogene homolog (KRAS), a protein long considered "undruggable." Developed by Amgen under the code name AMG-510 and marketed as Lumakras® or Lumykras®, this small molecule is a highly selective, first-in-class, covalent inhibitor of the specific KRAS p.G12C mutant protein. Its mechanism of action involves irreversibly trapping the mutant protein in an inactive, GDP-bound state, thereby halting the oncogenic signaling cascades that drive tumor proliferation.

This report provides a comprehensive analysis of Sotorasib, synthesizing data on its molecular profile, pharmacology, clinical development, safety, and regulatory status. The initial accelerated approval of Sotorasib for previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) was based on the compelling efficacy data from the single-arm CodeBreaK 100 trial. The subsequent confirmatory Phase 3 CodeBreaK 200 trial demonstrated a statistically significant improvement in progression-free survival compared to standard-of-care docetaxel, though without a corresponding benefit in overall survival, a finding complicated by trial design factors such as patient crossover.

In metastatic colorectal cancer (mCRC), Sotorasib monotherapy showed limited activity, revealing tissue-specific resistance mechanisms. However, the pivotal CodeBreaK 300 trial established a new standard of care by demonstrating that Sotorasib in combination with the EGFR inhibitor panitumumab significantly improves outcomes, leading to a new regulatory approval for this indication.