Circulating tumor DNA dynamic variation predicts sotorasib efficacy in KRASp.G12C-mutated advanced non-small cell lung cancer

Background: The objective of this study was to investigate the correlation between circulating tumor DNA (ctDNA) KRAS G12C-mutation dynamic variations and treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) receiving sotorasib therapy in a real-world setting. Methods: Peripheral blood samples were prospectively collected from 32 patients at baseline, at cycle 3, and then at each radiologic assessment during sotorasib treatment. Both tissue and plasma samples were analyzed by using ultra-deep, customized next-generation sequencing (NGS) assays. Plasma samples from 27 of 32 patients also were analyzed by digital polymerase chain reaction analysis, and ctDNA dynamic variations were correlated with radiologic responses and patients' clinical outcomes. Results: A significant correlation between NGS and digital polymerase chain reaction-detected KRAS G12C variant allelic fractions (p < .001) was observed. Patients who achieved clearance of KRAS G12C-mutant ctDNA levels had a significant improvement in the objective response rate (80% vs. 8%; p < .001), median progression-free survival (7.9 vs. 2.8 months; p < .001), and median overall survival (16.8 vs. 6.4 months; p < .001) compared with those who did not achieve clearance. The clearance of ctDNA was the only prognostic factor significantly associated with both median progression-free survival (hazard ratio, 0.15; 95% confidence interval, 0.04-0.48) and median overall survival (hazard ratio, 0.09; 95% confidence interval, 0.02-0.45) in multivariable analysis. Moreover, a dynamic increase in the KRAS G12C median variant allele fraction anticipated radiologic disease progression in 70% of patients who were evaluable at the resistance time point. Conclusions: This study demonstrated that early clearance of KRAS G12C-mutant ctDNA predicted the clinical benefit of sotorasib in patients with advanced NSCLC, suggesting that dynamic monitoring of ctDNA levels also may anticipate sotorasib resistance.