Abstract 3908: Liquid biopsy-informed precision oncology clinical trial to evaluate the utility of ctDNA genomic profiling for therapy optimization in patients with advanced or metastatic solid tumors.

Abstract Background: Genomic profiling via liquid biopsies (LB) has advanced precision oncology decision-making; however, a major challenge is critically interpreting LB data to improve the selection and order of genotype-specific therapies. Methods: We present updated results from the first planned analysis of an observational biomarker trial, aimed at assessing the clinical utility of serial LB in patients with advanced or metastatic solid tumors (NCT05585684). Primary endpoints assessed feasibility, prevalence of actionable alterations, and fraction of patients receiving genotype-matched therapies. Secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and concordance between LB and tumor next-generation sequencing (NGS). Serial LBs at baseline, early (1-3 weeks) on therapy, and at progression, employed a clinically validated 33-gene panel NGS assay (Labcorp Plasma Focus). Matched white blood cell (WBC) NGS was used to identify clonal hematopoiesis (CH)-derived variants. Mutation actionability was evaluated using a multi-resource programmatic approach, and levels of evidence (1-4) were assigned, followed by review at the Johns Hopkins Molecular Tumor Board (JH MTB). Results: Among 50 patients, 45 baseline and 12 progression LBs were reviewed at MTB. JH MTB classified 72.5% (n=50) of baseline alterations as tumor-derived. In 19 patients with archival tissue NGS, 32 variants were detected in the baseline LB, of which 78.1% were also detected in tissue NGS. Furthermore, 23.2% (n=16) of LB alterations at baseline, 20.0% (n=6) early on-therapy, and 13.0% (n=3) at progression were CH derived. Upon MTB review, 29.2% variants at baseline, 21.9% at early on-therapy and 26.1% at progression were classified as actionable (58.8% level 1, 11.8% level 2, 11.8% level 3 and 17.6% level 4 evidence). Of 45 patients reviewed, 38 received therapeutic recommendations and 57.9% initiated recommended therapy. Patients treated with MTB recommended therapies had significantly longer median PFS and OS compared to those who received standard of care (p=0.027 and p=0.00062 respectively). MTB-recommended therapy selection was independently associated with PFS and OS, in multivariate analyses adjusting for clinical covariates including sex, smoking status, age, and prior lines of systemic therapy (p=0.043 and p=0.006, respectively). Subset of patients treated with genotype-matched MTB recommendations had significantly longer median PFS and OS compared to those who received standard of care (p=0.026 and p=0.0074 respectively). Conclusion: Our findings emphasize the importance of precision oncology interventions driven by programmatic workflows within a multidisciplinary MTB, supported by comprehensive LB molecular information to guide therapy selection and improve patient outcomes. Citation Format: Amna Jamali, Jaime Wehr, Jenna VanLiere Canzoniero, Maria Fatteh, Katerina Karaindrou, Michael Conroy, Ilias Ziakas, Mohamed Sherief, Timsy Wanchoo, Faith Too, Lily Scharpf, Ruth Moges, Dana Petry, Kala Visvanathan, Ellen Verner, Amy Greer, Kory Kreimeyer, Jonathan Spiker, Rachel Karchin, Christine L. Hann, Vincent K. Lam, Joseph Christopher Murray, Josephine Feliciano, Kristen Marrone, Julie R. Brahmer, Ming-Tseh Lin, Taxiarchis Botsis, Hao Wang, Mark Sausen, Christopher D. Gocke, Rena Xian, Jessica Tao, Valsamo (Elsa) K. Anagnostou. Liquid biopsy-informed precision oncology clinical trial to evaluate the utility of ctDNA genomic profiling for therapy optimization in patients with advanced or metastatic solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3908.