Safety and objective response of KRAS G12C inhibitors versus docetaxel in previously treated advanced NSCLC: Meta-analysis of randomized trials.

Abstract

e20747 Background: Patients with previously treated KRAS G12C–mutated advanced non–small cell lung cancer (NSCLC) have limited standard options, with docetaxel remaining a commonly used therapy after progression on platinum-based chemotherapy and immunotherapy. KRAS G12C inhibitors have demonstrated antitumor activity in this setting, but their comparative efficacy and treatment tolerability versus docetaxel across randomized trials remain clinically relevant. We conducted a systematic review and meta-analysis to compare objective response rate (ORR) and treatment discontinuation due to treatment-related adverse events (TRAEs) between KRAS G12C inhibitors anddocetaxel. Methods: A systematic search was conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to September 2025 to identify randomized controlled trials comparing KRAS G12C inhibitors versus docetaxel in patients with previously treated advanced or metastatic KRAS G12C–mutated non–small cell lung cancer. Three study reports/datasets were included, comprising a total of 912 patients. Eligible studies reported objective response rate (ORR) and/or treatment discontinuation due to treatment-related adverse events (TRAEs). Pooled analyses were performed using random-effects models, and results were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Results: Three study reports/datasets were included. For objective response rate (ORR), KRAS G12C inhibitors were associated with significantly higher tumor response compared with docetaxel (RR 2.90; 95% CI 1.72–4.89; P < 0.0001; I² = 44%), with a total of 165 responses among 550 patients in the KRAS G12C inhibitor group versus 38 responses among 362 patients receiving docetaxel. Regarding treatment tolerability, discontinuation due to treatment-related adverse events (TRAEs) was significantly more frequent with KRAS G12C inhibitors compared with docetaxel (RR 1.78; 95% CI 1.02–3.13; P = 0.04; I² = 0%), corresponding to 45 discontinuations among 545 patients in the KRAS G12C inhibitor group versus 15 discontinuations among 327 patients in the docetaxel group. Conclusions: KRAS G12C inhibitors demonstrate significantly higher objective response rates compared with docetaxel in previously treated KRAS G12C–mutated advanced NSCLC, supporting superior antitumor activity in this setting. However, treatment discontinuation due to TRAEs was also significantly more frequent with KRAS G12C inhibitors, highlighting an important tolerability trade-off that may impact treatment delivery in clinical practice. These findings emphasize the need to balance response benefit with toxicity-related interruption, and underscore the importance of time-to-event outcomes and patient-centered endpoints to guide optimal sequencing strategies.