Impact of standard vs reduced dosing of sotorasib on efficacy and toxicity in KRAS G12C–mutated advanced non-small cell lung cancer: A systematic review and meta-analysis.

Abstract

8593 Background: KRAS is the most common oncogenic driver in lung adenocarcinoma. Advances in targeted therapies such as Sotorasib have improved outcomes, but optimizing dosing strategies is crucial to balance efficacy and tolerability. Sotorasib serves as an illustrative example, as it was the first drug for which the FDA requested a dose optimization strategy. The FDA’s decision to maintain 960 mg dose was influenced by CodeBreaK100 and CodeBreaK200 trials. CodeBreaK100, which demonstrated an ORR of 36%, formed the basis for accelerated approval, while CodeBreaK200 confirmed clinical benefit. A post-approval dose randomization study comparing 240 mg and 960 mg doses found no clear exposure-safety relationships, though ORR was numerically higher for 960 mg. However, tolerability remains challenging with 960 mg dose, often requiring dose reductions in clinical practice. This systematic review and meta-analysis evaluates the impact of starting at 960 mg of Sotorasib versus reduced dose on efficacy and toxicity, with implications for optimizing dosing strategies in targeted therapies. Methods: We conducted a systematic search of PubMed, EMBASE, SCOPUS, CINAHL, and Web of Science up to Oct 1,2024. Eligible studies included randomized clinical trials, prospective and retrospective studies, reporting efficacy outcomes (ORR, PFS), and treatment-related adverse events. Pooled estimates for efficacy and toxicity outcomes were calculated using random effects model. Results: Out of 4510 studies screened, 145 full-text articles were assessed for eligibility, resulting in 14 studies, of which 9 focused on Sotorasib. The pooled ORR was 32% (95%CI 28%-36%) for patients starting at 960 mg (n=889), compared to 26% (95%CI 19%-34%) for those starting at a reduced dose (n=130) with no statistically significant difference (RR 1.26, 95%CI 0.87-1.83). The pooled hazard ratio for PFS did not show a significant benefit for starting at 960 mg compared to at reduced dose (HR 0.77, 95%CI 0.56-1.05). Adverse events leading to dose reduction and discontinuation at 960 mg were 16% (95%CI 10%-23%) and 9% (95%CI 6%-13%), respectively. Limited toxicity data were available for those who started treatment at reduced dose, precluding direct comparison. Conclusions: While the standard 960 mg dose of Sotorasib showed a trend toward higher ORR compared to starting at reduced doses, it is associated with significant toxicity, resulting in frequent dose reductions and treatment discontinuation. No significant PFS benefit was observed with starting at 960 mg dose, highlighting the need to optimize dosing strategies that balance efficacy with tolerability.Future studies should include subgroup analyses of efficacy and tolerability for dose reductions to guide optimal dosing regimens, aligning with initiatives like the FDA’s Project Optimus to improve patient outcomes.