Efficacy and safety of <i>KRAS</i> <i>p.G12C</i> inhibitors in advanced NSCLC: A systematic review and meta-analysis.

Abstract

e20691 Background: Advances in target therapy have improved the natural history of non-small-cell lung cancer (NSCLC). KRAS pG12C mutation, found in 10–13% of advanced non-squamous NSCLC, is a distinct subtype with a complex biology whose prognosis has been poor for decades. While KRAS p.G12C inhibitors show promise, there are many concerns regarding their clinical impact and toxicity profile. Therefore, we conducted a systematic review and meta-analysis to evaluate the safety and efficacy of KRAS p.G12C inhibitors in advanced NSCLC patients harboring this biomarker. Methods: PubMed, Embase, and Cochrane databases were searched to identify clinical trials investigating KRAS p.G12C inhibitors for advanced NSCLC in the second-line and subsequent treatment settings. Pooled analyses were conducted to assess treatment-related adverse events (TRAEs) and objective response rate (ORR), with their corresponding 95% confidence intervals (CIs). Median values for progression-free survival (PFS), overall survival (OS), and duration of response (DOR) were extracted and reported alongside their ranges across the included studies. All statistical analyses were carried out using R software version 4.3.1. Results: From an initial yield of 970 studies, four single-arm trials (Phase I and II) were included, comprising 494 patients. Median age of participants ranged from 64 to 66 years (25-89), with 56% of the cohort being male. The KRAS p.G12C inhibitors evaluated were sotorasib, adagrasib, divarasib, and garsorasib. The pooled incidence of all-grade TRAEs was 92% (95% CI: 77–98), with 33% of patients experiencing grade 3/4 TRAEs (95% CI: 18–52). The most common TRAEs included diarrhea, nausea, and elevated alanine aminotransferase levels. The pooled ORR was 47% (95% CI: 40–54). Median PFS varied from 6.3 to 13.8 months, while median OS ranged from 12.5 to 14.1 months. Median DOR ranged from 12.3 to 18 months. Conclusions: This meta-analysis underscores the favorable safety and efficacy profiles of KRAS p.G12C inhibitors after first-line progression in advanced NSCLC, despite the frequent adverse events, which were considered manageable. Further randomized controlled trials are expected to confirm these results and refine their role in subgroup populations, including STK1 and KEAP1 co-mutations, that confer even poor prognosis.