Abstract 970: Liquid biopsy-informed precision oncology clinical trial to evaluate the utility of ctDNA comprehensive genomic profiling
Authors: Fatteh Maria , Conroy Michael , Wanchoo Timsy , Teh Selina Shiqing , Wehr Jaime , Balan Archana , Karchin Rachel , Verner Ellen , Karaindrou Katerina , Xian Rena , Gocke Christopher , Lin Ming-Tseh , Fitzpatrick Peggy , Hann Christine L. , Murray Joseph C. , Lam Vincent K. , Feliciano Josephine L. , Brahmer Julie R. , Marrone Kristen A. , Forde Patrick M. , Fiallos Katie , Petry Dana , Botsis Taxiarchis , Sausen Mark ,   the Johns Hopkins Molecular Tumor Board Investigators, Canzoniero Jenna , Tao Jessica , Anagnostou Valsamo 
Published: March 2024

Abstract
Background: The expanding role of next-generation sequencing (NGS) in precision oncology has led to a paradigm shift towards genotype-targeted therapies, with liquid biopsies (LBs) offering a minimally invasive means of comprehensive genomic profiling.
Methods: This is an observational LB-informed precision oncology clinical trial with primary endpoints to assess feasibility and determine the prevalence of actionable mutations in LB informing genotype-targeted therapeutic recommendations by the Johns Hopkins Molecular Tumor Board (JH MTB; NCT05585684). Secondary endpoints are progression-free and overall survival, ctDNA dynamics assessment, and concordance between plasma and tumor NGS. Target enrollment is 150 patients with advanced solid tumors who have progressed on at least one line of systemic therapy. Serial LB-derived genotypes are obtained at baseline, early on therapy, and upon progression using a CLIA ultra-sensitive 33-gene panel NGS assay (Elio Plasma Resolve, Personal Genome Diagnostics/Labcorp). Variant actionability is assessed by an ensemble knowledgebase, registry, and computational characterization approach, and results are reviewed by the JH MTB, followed by treatment recommendations.
Results: The trial’s pre-specified interim analysis included 30 enrolled patients with evaluable LBs; 30 baseline, 13 on-therapy, and 6 progression LBs were analyzed. Twenty-five patients had non-small cell lung cancer among which 9 were EGFR-mutated, 1 patient had small cell lung cancer, 3 patients had gastro-esophageal cancer, and 1 patient had a neuroendocrine tumor. In total, 74 variants were identified across all time points; these were cross-referenced in somatic and germline registries, variant knowledgebases, and the biomedical literature, together with computational characterization of functional consequence to assign mutation actionability. Tumor-confirmed variants comprised 36% of baseline and 42% of both on-therapy and progression variants. At baseline, 20% of the variants were putatively clonal hematopoiesis-derived with similar findings at the on-therapy timepoint. Thirty percent of baseline variants and 33% of variants at progression were deemed actionable. Upon JH MTB review, 29% of patients received a genotype-matched therapeutic recommendation based on LB results, with MTB recommendations followed in 38% of the patients. In analyzing ctDNA dynamics, of the 13 patients with on-therapy samples, 23% showed ctDNA clearance, 31% showed persistence, while 46% had undetectable ctDNA at both time points. Among patients with LBs at the time of progression, a third showed ctDNA emergence, a third had ctDNA persistence, and the remainder had undetectable ctDNA throughout the follow-up period.
Conclusion: Our findings highlight the clinical relevance of liquid biopsies in guiding treatment selection and monitoring.
Citation Format: Maria Fatteh, Michael Conroy, Timsy Wanchoo, Selina Shiqing Teh, Jaime Wehr, Archana Balan, Rachel Karchin, Ellen Verner, Katerina Karaindrou, Rena Xian, Christopher Gocke, Ming-Tseh Lin, Peggy Fitzpatrick, Christine L. Hann, Joseph C. Murray, Vincent K. Lam, Josephine L. Feliciano, Julie R. Brahmer, Kristen A. Marrone, Patrick M. Forde, Katie Fiallos, Dana Petry, Taxiarchis Botsis, Mark Sausen, the Johns Hopkins Molecular Tumor Board Investigators, Jenna Canzoniero, Jessica Tao, Valsamo Anagnostou. Liquid biopsy-informed precision oncology clinical trial to evaluate the utility of ctDNA comprehensive genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 970.