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

Abstract

3052 Background: Genomic profiling through liquid biopsies (LB) has enabled precision oncology decision making, however a key challenge lies in critically interpreting LB data to optimize patient care. Methods: We report results from the first planned interim analysis of an observational biomarker trial, designed to evaluate the clinical utility of serial LB in patients with advanced/metastatic solid tumors (NCT05585684). Primary endpoints were to determine feasibility, prevalence of actionable alterations in LB and the fraction of patients with enacted genotype-matched therapies. Secondary endpoints included progression-free (PFS) and overall survival (OS), time to subsequent therapy and concordance between LB and tumor next generation sequencing (NGS). Exploratory endpoints included correlation of ctDNA dynamics with survival. Serial LBs were obtained at baseline, 1-3 weeks on therapy and at progression using a CAP/CLIA validated NGS panel (Labcorp, MD). Patient-matched white blood cell (WBC) NGS was utilized to identify clonal hematopoiesis (CH)-derived variants. Actionability of genomic alterations was assessed by an ensemble multi-resource programmatic approach; results were reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB). Results: Between March 2023 and July 2024, 51 patients with NSCLC, SCLC and esophageal cancer were enrolled, with 45 evaluable baseline and 12 progression LBs reviewed at JH MTB. Median turnaround time from baseline and progression LB to MTB recommendation was 14 and 13 days respectively. Patient-matched analyses of baseline WBC samples revealed 30.1% (n = 22) CH-derived alterations. The frequency of actionable variants was 28.8% (n = 21) at baseline, 23.3% (n = 7) on therapy and 21.7% (n = 5) at progression. Of the 45 patients reviewed at baseline, 33 received a recommendation for genotype-matched therapies; 48.5% (n = 16) based on tumor molecular profiling, 15.2% (n = 5) based on LB alone and 36.3% (n = 12) based on LB and tissue NGS. Thirteen patients were treated according to MTB recommendations. Patients who were treated with genotype-matched MTB recommended therapies had longer OS and PFS compared to those who received alternate therapies (not reached-NR vs. 14.8 months, log-rank p = 0.028 and NR vs 6.2 months, log-rank p = 0.21 respectively). Among the 12 patients reviewed at progression, 5 received an MTB recommendation for genotype-tailored therapies based on LB alone (n = 3) or in combination with tissue NGS (n = 2). Early on-therapy ctDNA clearance was associated with longer PFS and OS (log rank p = 0.02 and p = 0.06). Conclusions: Our findings highlight the value of a multidisciplinary MTB when supported by comprehensive liquid biopsy molecular information to inform therapy selection and improve patient outcomes. Clinical trial information: NCT05585684 .