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
Rohit Thummalapalli, Ezra Bernstein, Benjamin Herzberg, Bob T. Li, Afsheen N. Iqbal, Isabel R. Preeshagul, Fernando C. Santini, Juliana Eng, Marc Ladanyi, Soo‐Ryum Yang, Ronglai Shen, Piro Lito, Gregory J. Riely, Joshua K. Sabari, Kathryn C. Arbour
Abstract
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.