Real world cfDNA collection in EGFR-mutant NSCLC

Abstract

Background: Plasma cell-free DNA (cfDNA) assays are increasingly used in clinic. Despite their rapid adoption, best practices for use and interpretation need better definition. We assessed key clinically-relevant questions using a prospectively collected cohort of EGFR-mutant pts. Methods: Starting in 2015, serial cfDNA testing via Guardant360 NGS was obtained fromMGHpts with advanced EGFR-mutant NSCLC across multiple lines of therapy in an IRB-approved project. Medical records were analyzed retrospectively, tissue was genotyped by institutional NGS (SNaPshot), scans were assessed by RECIST. Correlations were tested by Wilcoxon Rank-Sum. Results: 372 plasma samples were collected from 89 pts, covering 150 therapy regimens including 26 drugs (targeted, immune, cytotoxic). To assess genotype correlation, we examined matched cfDNA and tissue biopsies at clinical progression for 60 regimens (51 pts). cfDNA-tissue concordance was 73% for founder EGFR mutations (n=60), 72% for T790M (n=60) and 89% for MET amp (n=53). Excluding 15 samples without detectable founder mutation (presumed ?non-shedders?), concordance for T790M=89% and MET=90%. To assess if relative change in cfDNA allelic fraction (AF) correlates with radiographic response, we examined 21 regimens (19 pts) with cfDNA samples at baseline and ≤ 30 days, and 3 aspects of the Guardant360 report. 12/ 21 regimens yielded PR by scans. Decrease in cfDNA AF in the 1st month of therapy correlated with ultimate PR whether assessing the change in AF of founder EGFR (p=0.03), largest AF regardless of gene (p=0.02) or sum of all detected AFs (p=0.02). Conclusions: CommercialcfDNA assays are readily available, facilitate serial AF monitoring and provide clinically-relevant data at acquired resistance. Among EGFR pts, we found real world cfDNA-tissue correlation of founder mutations and T790M was high and resistance mutation (T790M, MET) results in cfDNA may be most reliable when founder EGFR mutations are detected. Importantly, MET amp had high cfDNA-tissue concordance, which was unexpected. Early AF decrease (within 1st month of therapy) significantly correlates with radiographic response regardless of which aspect of the Guardant360 report is considered. Further investigation is needed to inform optimal use and interpretation of cfDNA assays.