Clinical and Genomic Features of Response and Toxicity to Sotorasib in a Real-World Cohort of Patients With Advanced <i>KRAS G12C</i>-Mutant Non-Small Cell Lung Cancer.

Abstract

With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced <i>KRAS G12C</i>-mutant non-small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice. We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity. Among 105 patients with advanced <i>KRAS G12C</i>-mutant NSCLC treated with sotorasib, treatment led to a 5.3-month median rwPFS, 12.6-month median OS, and 28% real-world response rate. <i>KEAP1</i> comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; <i>P</i> = .004; OS HR, 4.10; <i>P</i> = .003); no significant differences in rwPFS or OS were observed across <i>TP53</i> (rwPFS HR, 1.10; <i>P</i> = .731; OS HR, 1.19; <i>P</i> = .631) or <i>STK11</i> (rwPFS HR, 1.66; <i>P</i> = .098; OS HR, 1.73; <i>P</i> = .168) comutation status. Notably, almost all patients who developed grade 3 or higher treatment-related adverse events (G3+ TRAEs) had previously been treated with anti-PD-(L)1 therapy. Among these patients, anti-PD-(L)1 therapy exposure within 12 weeks of sotorasib was strongly associated with G3+ TRAEs (<i>P</i> < .001) and TRAE-related sotorasib discontinuation (<i>P</i> = .014). Twenty-eight percent of patients with recent anti-PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity. Among patients treated with sotorasib in routine practice, <i>KEAP1</i> comutations were associated with resistance and recent anti-PD-(L)1 therapy exposure was associated with toxicity. These observations may help guide use of sotorasib in the clinic and may help inform the next generation of KRAS G12C-targeted clinical trials.