Efficacy of third-generation EGFR-TKIs in advanced NSCLC with different T790M statuses tested via ddPCR and NGS

Abstract Objective Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibiors (TKIs) is the standard strategy for T790M-positive non-small cell lung cancer (NSCLC). We hypothesize that ddPCR, with a higher sensitivity than NGS, would optimize the treatment strategies in EGFR-TKIs relapsed patients. In this study, we compared the efficacy of third-generation TKIs with various T790M statuses via these two assays. Methods NGS was performed on blood samples of patients progressed from previous EGFR-TKIs treatment for resistance mechanism. T790M-negative patients received a further liquid biopsy using ddPCR for T790M status detection. The analysis of efficacy and survival for subsequent third-generation EGFR-TKIs was carried out. Results A cohort of 40 patients were enrolled from Sept, 2020 to Dec, 2021, with 30.0% (12/40) tested T790M-positive via NGS (Group A). In another 28 T790M-negative patients by NGS, 11 (39.3%) were T790M-positive (Group B) and 17 (60.7%) were T790M-negative (Group C) via ddPCR. After a median follow-up period of 13.7 months, a relatively longer progression-free survival (PFS) was observed in group A (not reached) and group B (10.0 months, 95% CI 7.040-12.889) than in group C (7.0 months, 95%CI 0.000-15.219), with no significant difference across all three groups (P = 0.196), or between group B and Group C (P = 0.412). The detection of EGFR-sensitive comutations correlated with an inferior mPFS (P = 0.041) and objective response rate (p = 0.326), and a significantly lower disease control rate (P = 0.033) in T790M-negative patients via NGS (n = 28). Conclusion This study indicates that ddPCR may contribute as a supplement to NGS in liquid biopsies for T790M detection in EGFR-TKIs relapsed patients and help to optimize the treatment strategies, especially for those without EGFR-sensitive comutations.