Sotorasib for Lung Cancers with KRAS p.G12C Mutation

Background: Sotorasib demonstrated anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a Phase 1 study, with particularly promising results in those with non-small-cell lung cancer (NSCLC).

Methods: In this single-group, Phase 2 trial, we evaluated the efficacy of sotorasib, administered orally at a daily dose of 960 mg, in patients with KRAS p.G12C-mutated advanced NSCLC who had been previously treated with standard therapies. The primary endpoint was objective response (complete or partial response) based on independent central review. Key secondary endpoints included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were also assessed for their association with response to sotorasib treatment.

Results: A total of 126 patients were enrolled, the majority of whom (81.0%) had received both platinum-based chemotherapy and PD-1/PD-L1 inhibitors prior to the study. Of the 124 patients with measurable disease at baseline, 46 (37.1%; 95% CI, 28.6 to 46.2) achieved an objective response, including 4 patients (3.2%) with a complete response and 42 (33.9%) with a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to not evaluable). Disease control was observed in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to not evaluable). Treatment-related adverse events occurred in 88 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 patient (0.8%). Responses were observed across subgroups defined by PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53.

Conclusions: This Phase 2 trial demonstrated that sotorasib provides a durable clinical benefit with a manageable safety profile in patients with previously treated KRAS p.G12C-mutated advanced NSCLC,AMG510 without introducing new safety concerns.