Targeting KRASG12C in non-small cell lung cancer: evidence from randomized clinical trials and future therapeutic strategies.

BACKGROUND: The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation is no longer an "elusive" target, having become an important therapeutic target in non-small cell lung cancer (NSCLC). The approvals of sotorasib and adagrasib have significantly altered the second-line treatment algorithm. This systematic review critically evaluates and compares data from Phase III clinical trials and the mechanisms of resistance associated with these two inhibitors. METHODS: The systematic review was registered in the PROSPERO database and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, Scopus, and ClinicalTrials.gov were searched for phase III randomized controlled trials (RCTs) conducted between 2023 and 2026. The analysis included the CodeBreaK 200 and KRYSTAL-12 registration programs (including subanalyses), which evaluated monotherapy with sotorasib or adagrasib compared with docetaxel in patients with advanced NSCLC harboring the KRASG12C mutation. The risk of bias was assessed using the Cochrane RoB 2.0 tool. RESULTS: Both inhibitors significantly prolonged the median progression-free survival (PFS) and increased the objective response rate (ORR) compared with chemotherapy. Adagrasib demonstrated promising intracranial efficacy but was associated with greater gastrointestinal toxicity and frequent dose reductions. Sotorasib was characterized by a better safety profile and more favorable quality-of-life outcomes for patients, although the assessment of its impact on overall survival (OS) was confounded by a high crossover rate in the registration trial. However, the rapid development of secondary mutations and bypass resistance mechanisms remains the main clinical limitation of both drugs when used as monotherapy. CONCLUSION: Sotorasib and adagrasib provide clinical benefit in advanced NSCLC with the KRASG12C mutation, demonstrated improved clinical outcomes compared with docetaxel monotherapy. However, to overcome the barrier of inevitable biological resistance, it is crucial to seek new therapeutic approaches and intensively develop combination strategies based on these molecules, which supports the ongoing development of combination strategies in personalized oncology. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420261427962.