Treating KRAS G12C lung cancer: therapeutic potential of investigation drugs in early clinical study.

Abstract

Introduction: The KRAS (Kirsten rat sarcoma viral oncogene homolog) gene is recognized as the most frequently mutated oncogene in advanced non-small cell lung cancer (NSCLC). The most prevalent mutation within this gene is G12C, formally known as KRAS G12C, which leads to the substitution of glycine with cysteine at position 12 of the KRAS protein.

Areas covered: Recent advancements in research have developed effective therapies designed to inhibit activated KRAS signaling. As a result, the first two accelerated FDA-approved KRAS inhibitors, sotorasib, and adagrasib have been successfully introduced to the market for locally advanced or metastatic KRAS G12C mutated NSCLC who progressed after prior therapy. A second generation of KRAS inhibitors is currently being tested in clinical trials, and in combination with immunotherapy and chemotherapy.

Expert opinion: Future research is crucial to determine the optimal timing for treatment with KRAS G12C inhibitors. Additional studies are needed to identify biomarkers that predict which patients will benefit most. This review discusses and analyzes both completed and ongoing clinical trials of first and second-generation KRAS inhibitors. It also addresses mechanisms of resistance to KRAS inhibition, potential therapeutic strategies to overcome this resistance, biomarkers, side effects, and its role in central nervous system metastatic disease.