Comparison of circulating tumor DNA (ctDNA) sequencing and tumor-based genotyping for the detection of EGFR mutations in non-small cell lung cancer (NSCLC).

Abstract

e20586 Background: Therapy for NSCLC is based on detection of actionable oncogenic drivers. Conventionally, targetable mutations are detected by tissue biopsy, which may be insufficient for molecular testing. Repeat biopsy is often required at the time of disease progression. Guardant360™ (G360) utilizes digital next-generation sequencing (NGS) to analyze ctDNA in plasma. Limited data exists on clinical outcomes of 3rd generation EGFR tyrosine kinase inhibitors (TKIs) against T790M-mediated resistance detected by digital NGS in ctDNA. We hypothesize that G360 has high concordance in detecting actionable oncogenic drivers and similar clinical outcomes compared with tumor-based genotyping. Methods: G360 (Guardant Health, Inc.) was performed in 20 advanced NSCLC patients (pts) with matched tumor-based genotyping by either Sanger sequencing (N = 10) or Ion Torrent ApliSeq v.2 NGS (N = 10; Life Technologies, Fisher Scientific). Matched genotypes were done at diagnosis (N = 12) or at time of acquired resistance (N = 8). Sensitivity, specificity, and response to EGFR TKIs (RECIST V1.1) were determined. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method. Objective response rates (ORR) were calculated by MedCalc(r) software. Results: Compared with tumor-based testing, G360 has high concordance for EGFR exon 19 deletion, T790M and L858R (90%, 85% and 100%, respectively) and high specificity (100%, 93.3%, and 100%, respectively). OS of pts with T790M or L858R were similar between those detected by G360 and by tumor-based testing (p > 0.99). Pts who received 3rd generation EGFR TKIs (4 osimertinib, 1 PF-06747775) after detected T790M in plasma (N = 4) had similar ORR (50% vs 25% with difference of 25%, 95% CI (-0.45 to 0.75)) and median PFS (7.5 vs 6.0 mos, p = 0.63) as those detected by tumor-based testing (N = 4). Conclusions: G360 showed high concordance for EGFR actionable mutations. Clinical outcomes of 3rd generation EGFR TKI treatment in T790M+ disease were similar between those detected by G360 and those detected by tumor testing. G360 represents a viable option for pts who are not candidates for solid tumor biopsies.