Circulating tumor DNA dynamics following molecularly targeted therapy for non–small cell lung cancer.

Abstract

8652 Background: Biomarkers to guide treatment escalation following suboptimal response to molecular targeted therapy are urgently needed for patients (pts) with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) has shown promise for monitoring residual disease following definitive treatment, but ctDNA dynamics following targeted therapy response remain understudied. Methods: We examined a real-world, multi-institution cohort of pts with NSCLC undergoing personalized, tumor-informed ctDNA testing (Signatera, Natera, Inc.) and clinical annotations from a deidentified commercial claims dataset (Forian’s Hybrid data ecosystem, CHRONOS). Longitudinal ctDNA results were evaluated before and after targeted therapy initiation and summarized by treatment line, clinical context, and demographic and clinicopathologic features as available. Results: We identified 839 pts (14.0%, 11.1%, 19.4%, and 55.5% with stages I, II, III, and IV) across 395 US institutions, who had ctDNA profiling and were treated with molecularly targeted agents. Median age was 71 years (range 25-93), 67.0% were female, and 85.3% had tumors with adenocarcinoma histology. Pts underwent a median of 4 ctDNA tests/pt (range: 1–58) over a median follow-up of 9 months (range: 0-75). Amongst ctDNA positive tests (n=1705 tests for 408 pts), median ctDNA levels were 1.20 mean tumor molecules/mL (range 0.01–36,599). Pts received osimertinib (58.5%), alectinib (10.7%), sotorasib (5.6%), adagrasib (3.7%), afatinib (3.7%), and capmatinib (3.0%). ctDNA tests prior to targeted therapy (baseline) were available for 336 patients, of which 49.7% (167/336) had detectable ctDNA (“ctDNA(+)”). Among these ctDNA(+) cases, 123 pts had longitudinal ctDNA assessment. ctDNA clearance observed in 38.2% (47/123); 52.1% (25/48) in stage I-III and 29.3% (22/75) in stage IV. Among the 169 pts with baseline ctDNA(-), 115 pts had ctDNA assessed longitudinally. Of these, 89.6% (103/115) remained serially negative, while 10.4% (12/115) had any time ctDNA(+). Among commonly used targeted therapies, ctDNA clearance was observed across multiple agents, and is summarized in table 1. We further analyzed associations between ctDNA dynamics, during different treatment lines, and clinical outcomes. Conclusions: In a multi-institution cohort, ctDNA clearance was observed in pts with NSCLC treated with molecularly targeted therapies. Clearance rates varied by treatment type. The use of ctDNA monitoring to guide treatment escalation in this population warrants further study. Targeted Therapy Pts with ctDNA available pre and post-therapyN Pts with baseline ctDNA(+) N Pts with ctDNA clearanceN (%) osimertinib 128 54 26 (48.1) alectinib 22 7 3 (42.9) sotorasib 15 14 4 (28.6) adagrasib 12 10 2 (20.0) Includes only therapies with more than 10 pts who had pre- and post-treatment ctDNA availability.