Abstract

9532 Background: ctDNA from patient plasma has demonstrated diagnostic utility in non-small cell lung cancer (NSCLC). Longitudinal changes in mutant allele frequency (MAF) have great potential to refine clinical management on targeted therapies. Methods: S1403 was a first-line phase II study of afatinib w or w/o cetuximab in pts with EGFR-mutant NSCLC. Between March, 2015 and April, 2018, 174 pts were randomized with 168 determined to be eligible. The study closed early due to futility. Plasma specimens were prospectively collected at baseline, Cycle 3 Day 1 (C3D1; 8 weeks) and at progression, and processed for batch analysis of ctDNA by next-generation sequencing (Guardant 360). A complete case analysis approach was used. The Kaplan-Meier method was used to estimate survival distributions, a Cox model to estimate hazard ratios and confidence bounds, and the log-rank test to compare distributions. A landmark analysis was used to assess predictive value of ctDNA clearance at C3D1. Results: 104 patients (62%) had analyzable baseline plasma specimens available, with EGFR mutations detected in 83 (80%). PFS was significantly shorter for pts with EGFR ctDNA positivity at baseline (p = 0.03) (Table) compared to those with no detectable ctDNA, likely a prognostic effect. Kinetic changes in ctDNA MAFs were analyzed in 79 pts with matching baseline and C3D1 specimens. Of 62 cases with detectable ctDNA at baseline, 68% (42/62) became undetectable at C3D1 (“ctDNA clearance”); ctDNA clearance relative to residual ctDNA was associated with significantly longer PFS (p = 0.00001) and OS (0.003) (Table). To date, 29 pts had matching at-progression samples. T790M mutations were observed at progression in 6/29 (24%) cases. Other putative emergent resistance factors include: a TACC3-FGFR3 and an EML4-ALK fusion, MET exon 14 skipping, multiple MET amplifications and NF1 frameshift mutations. Conclusions: Clearance of EGFR ctDNA after 60 days of therapy was associated with a substantial and statistically significant improvement in subsequent PFS and OS. Incorporation of ctDNA kinetics into routine clinical care represents a promising platform to identify patients with inferior outcomes on TKIs and detect targetable emergent resistance mechanisms. [Table: see text]

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