Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: A systematic review and meta-analysis

Abstract

Objective: To assess the efficacy and safety of FDA-approved KRAS^G12C inhibitors in patients with KRAS^G12C-mutated solid tumors.

Methods: We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest.

Results: 18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRAS^G12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77).

Conclusions: This study provided a comprehensive understanding of the efficacy and safety of KRAS^G12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRAS^G12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRAS^G12C inhibitor treatment.

Keywords: Adagrasib; Efficacy; KRAS(G12C); Meta-analysis; Safety; Sotorasib.