Abstract 726: Comprehensive genomic profiling of cell-free DNA and matched white blood cells improves accuracy of ctDNA molecular response in immunotherapy treated NSCLC

Abstract Introduction: Assessment of molecular response (mR) to targeted and immunotherapies (IO) in solid cancer is an emerging clinical liquid biopsy application. Current approaches have demonstrated promising results but have predominately relied on tumor-informed strategies and small to intermediate-sized next generation sequencing (NGS) gene panels. Lack of tissue availability and emergence of comprehensive genomic profiling (CGP), however, limit the practicality of implementing these approaches in a clinical setting. Furthermore, biological signals from non-tumor derived alterations arising from clonal hematopoiesis (CH) may confound detection of tumor-specific alterations for therapy selection and longitudinal monitoring. To address these limitations, we evaluated the 521-gene PGDx elio™ plasma complete assay with an integrated matched white blood cell (WBC) analysis algorithm to longitudinally assess cell-free tumor DNA (ctDNA) through a baseline plasma-informed approach and correlate mR to radiographic response and outcomes. Methods: Plasma from 57 patients with mNSCLC who received IO from 2017-2019 at Hospital del Mar had detectable pre-treatment ctDNA. Blood was collected prior to the start of therapy, early on-treatment (median 4 weeks) and longitudinally throughout clinical follow-up and disease progression. Germline and CH variants were identified and removed through matched WBC NGS analyses. mR was calculated as the percent change in mean variant allele frequency of the tumor-specific alterations assessed at the early on-treatment timepoint compared to the pre-treatment timepoint and then compared to radiographic response (RR) and overall survival (OS). Results: Thirty percent (17/57) of patients had a complete or partial radiographic response, with median follow up of >12 months. A tumor-specific genomic landscape analysis at baseline demonstrated associations between mR, recurrently mutated genes, and clinical outcomes. Removal of non-tumor derived cell-free DNA (cfDNA) variants improved characterization of mR and associations with radiographic and survival-based endpoints. A mR rate of 33% (19/57) was observed with a median OS of 53 months compared to 8.4 months for patients experiencing molecular progression at the early on-treatment timepoint (HR 4.8, 95% CI 2.2-10.2, p<0.001). Of all patients that survived ≤12 months after initiation of treatment, 85.7% (24/28) were categorized as experiencing molecular progression through early on-treatment cfDNA analyses. Conclusions: CGP of cfDNA with integrated matched WBC analyses improves accuracy of mR and associations with RR and outcomes. This tumor-agnostic approach for assessment of genomic alterations at baseline and mR early on-treatment improves our ability to associate liquid biopsy-based biomarkers with patient and treatment-level outcomes. Citation Format: Jennifer B. Jackson, Pedro Rocha, James White, Andrew Georgiadis, Ellen Verner, Amy Greer, Rafael Bach Mora, Laura Masfarré, Nil Navarro, Beatriz Bellosillo, Sergi Clavé, Mark Sausen, Edurne Arriola. Comprehensive genomic profiling of cell-free DNA and matched white blood cells improves accuracy of ctDNA molecular response in immunotherapy treated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 726.