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

PURPOSE: With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced KRAS G12C -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. MATERIALS AND METHODS: 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. RESULTS: Among 105 patients with advanced KRAS G12C -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. KEAP1 comutations were associated with shorter rwPFS and OS (rwPFS hazard ratio [HR], 3.19; P =.004; OS HR, 4.10; P =.003); no significant differences in rwPFS or OS were observed across TP53 (rwPFS HR, 1.10; P =.731; OS HR, 1.19; P =.631) or STK11 (rwPFS HR, 1.66; P =.098; OS HR, 1.73; P =.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 (P <.001) and TRAE-related sotorasib discontinuation (P =.014). Twenty-eight percent of patients with recent anti–PD-(L)1 therapy exposure experienced G3+ TRAEs, most commonly hepatotoxicity. CONCLUSION: Among patients treated with sotorasib in routine practice, KEAP1 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. Real-world analysis by @rohit_thum @RielyMD @KCArbourMD identifies KEAP1 mutations associated with resistance and recent anti–PD-(L)1 therapy exposure associated with toxicity among patients receiving sotorasib for advanced KRAS G12C+ NSCLC. [ABSTRACT FROM AUTHOR]