2ND PLACE, LITERATURE REVIEW TRACK: Reassessing the Undruggable: A Systematic Review and Meta-Analysis of KRAS G12C Inhibitor Efficacy in 2,031 Cancer Patients

The “death star” gene KRAS has long been considered “undruggable” due to its smooth protein surface and picomolar affinity for guanosine nucleotides, which preclude conventional small-molecule binding. The glycine-to-cysteine substitution at codon 12 (G12C) is a recurrent oncogenic driver in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Recently developed covalent inhibitors irreversibly bind the GDP-bound inactive form of KRAS G12C and have shown clinical promise. We conducted a systematic review following PRISMA 2020 guidelines. Eighteen manuscripts representing nine clinical trials were identified, with data stratified by cancer type. In NSCLC, G12C inhibitors demonstrated consistent nontherapeutic efficacy, with objective response rates (ORRs) of 28.1-57.1% and median progression-free survival (PFS) of 5.6-9.7 months. IBI351 and Glecirasib exhibited favorable profiles in early-phase trials, and the CodeBreaK 200 Phase III trial confirmed Sotorasib’s superiority over Docetaxel. In CRC, monotherapy yielded ORRs of 23-32.2%, while combination with EGFR inhibitors such as Cetuximab or Panitumumab increased ORRs up to 62.5% and extended PFS to 8.1 months. In PDAC, efficacy was limited; one eligible cohort reported an ORR of 19% and PFS of 4 months. Adverse events were primarily low-grade. Grade ≥3 toxicities occurred in 9-34% of patients, most commonly diarrhea, fatigue, rash, and elevated liver enzymes. EGFR-based combinations were associated with increased gastrointestinal toxicity, though discontinuation rates remained low. G12C inhibitors were most effective in NSCLC, required EGFR co-inhibition in CRC, and had limited activity in PDAC. These insights inform strategies to optimize efficacy and design future combination regimens.