S303 Comparative Efficacy and Safety of KRAS G12C-Targeted Therapies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-Analysis

Introduction: KRAS G12C mutations, found in 3%-5% of metastatic colorectal cancer cases, drive aggressive disease with limited treatment options. Recent advances in covalent inhibitors have enabled selective targeting of KRAS G12C, marking a significant shift in precision oncology and offering new treatment options for these patients. Methods: A systematic search of 5 databases identified relevant Phase I to Phase III trials, with Screening performed using Covidence. Network meta-analysis was conducted using the Netmeta package in R, and forest plots and additional analyses were generated in Stata 18.0. Risk of bias was assessed with the RoB-ME tool. Results: A total of 1,923 records were identified, and after removing duplicates and screening, 14 studies met the inclusion criteria for analysis. A total of 574 patients were included across multiple treatment arms, comprising sotorasib 960 mg (62), sotorasib 960 mg + panitumumab (93), adagrasib 1200 mg (44), divarasib + cetuximab (29), olomarasib + cetuximab (49), sotorasib 960 mg + panitumumab + FOLFIRI (31), adagrasib 1200 mg + cetuximab (94), sotorasib alone (42), sotorasib + panitumumab (39), adagrasib alone (4), divarasib alone (55), and olomarasib alone (32) treatment cohorts. The highest mean ORR was observed in the sotorasib 960 mg + panitumumab + FOLFIRI group (58.1%, 95% confidence interval [CI]: 51.7%–64.5%), while the lowest mean ORR was consistently seen in the placebo groups (1%, 95% CI: not estimable due to sample size). According to SUCRA, the treatment regimen of sotorasib 960 mg combined with panitumumab and FOLFIRI demonstrated the highest ranking in efficacy, while adagrasib 1,200 mg in combination with cetuximab was ranked lowest among the evaluated interventions. This enhanced efficacy, however, corresponded with an increased risk of treatment-related adverse events (TRAE), reflected by a risk ratio (RR) of 1.13 (95% CI: 0.95 to 1.73), with diarrhea and nausea exhibiting notably elevated risks—RRs of 3.42 (95% CI: 2.25 to 4.59) and 3.01 (95% CI: 2.04 to 3.99), respectively. Quality of life (QOL) was significantly improved in patients, and risk of bias assessment using the ROB-ME tool indicated a moderate to low risk of bias across the included studies. Conclusion: This analysis highlights the superior efficacy of sotorasib 960 mg with panitumumab and FOLFIRI in metastatic colorectal cancer, despite increased risks of diarrhea and nausea. Significant QOL improvements and a moderate to low risk of bias support the regimen's therapeutic potential.