Efficacy and safety of KRAS -G12C inhibitors in colorectal cancer: a systematic review of clinical trials

Abstract

Patients with colorectal cancer (CRC) who have KRAS mutations often see poor results with standard treatments, leaving them with fewer viable options. Over the past few years, new KRAS G12C inhibitors have emerged as a targeted approach for a specific subset of these mutations, though their effectiveness and safety in advanced CRC remain areas of ongoing research. In this systematic review, we identified nine clinical trials including a total of 668 patients, by searching PubMed, Web of Science, CENTRAL, and Embase through October 2024. When sotorasib was used alone, the objective response rate (ORR) ranged from 7.1 to 9.7%, with disease control (DC) rates of 73.8 to 82.3% and a median progression-free survival (PFS) spanning 4-5.6 months. Combining sotorasib with panitumumab, especially at higher doses, raised its ORR to 26.4%. Meanwhile, pairing adagrasib with cetuximab led to a 42% ORR and a median PFS of 6.9 months, surpassing the 19% ORR observed with adagrasib alone. Divarasib monotherapy produced a 36% ORR and an 85.5% DC rate, with a PFS of 5.6 months; in tandem with cetuximab, those numbers climbed to a 62.5% ORR and a PFS of 8.1 months. Common side effects across these trials included diarrhea, nausea, fatigue, and various skin reactions. Overall, KRAS G12C inhibitors appear to offer meaningful benefits for CRC patients, particularly when used alongside EGFR inhibitors like cetuximab or panitumumab. However, further large-scale, randomized trials are needed to refine dosing strategies and gain a clearer picture of both efficacy and potential risks.

Keywords: Adagrasib; KRAS G12-C inhibitors; KRAS mutation; Metastatic colorectal cancer; Sotorasib.