Abstract 6443: Enhanced detection of ctDNA molecular response for immunotherapy treated non-small cell lung cancer through analyses of cell-free and matched white blood cell DNA

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Abstract Introduction: Immune checkpoint inhibitors (ICIs) have greatly improved clinical outcomes for patients with non-small cell lung cancer (NSCLC), however, programmed death-ligand 1 (PD-L1) and tumor mutation burden (TMB) have failed to consistently predict therapeutic response and outcomes in this population. There remains a critical unmet need to identify patients who are likely to experience clinical benefit from treatment, particularly as additional treatment regimens become available. Longitudinal cell-free tumor DNA (ctDNA) assessments have recently been applied as a strategy to identify molecular response (mR) and better predict long term clinical response. Through this real-world analysis of NSCLC, we explore the technical and biological considerations associated with determination of ctDNA mR through matched cell-free and white blood cell (WBC) DNA analyses and apply this optimized approach to assess therapeutic response to ICIs. Methods: Plasma from 50 patients with advanced or metastatic NSCLC who received ICIs from 2017-2019 at Hospital del Mar had detectable pre-treatment ctDNA and underwent analysis using the 521 gene PGDx elio plasma complete liquid biopsy assay. Patient blood was collected prior to the start of ICI therapy, early on-treatment (median 4 weeks; range 2.4-9 weeks) and longitudinally throughout clinical follow-up and disease progression. Matched WBCs were also analyzed for each patient to identify alterations arising from germline polymorphisms and clonal hematopoiesis (CH). 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 compared to radiographic response, progression-free, and overall survival (OS). Results: Best overall response for patients within the cohort was 4% complete response, 26% partial response, 34% stable disease, and 36% progressive disease. The removal of germline or CH variants allowed for improved characterization of tumor-specific somatic alterations and associations with radiographic and survival-based endpoints. With the integrated ctDNA and matched WBC approach, we observed a mR rate of 34% (17/50) with a median OS of 36.8 months compared to 9.2 months for patients experiencing molecular progression at the early on-treatment timepoint (HR 5.6, 95% CI 2.4-12.7, p<0.001, log-rank test). Specifically, of all patients that survived ≤12 months after initiation of treatment, 84% (21/25) were categorized as experiencing molecular progression through early on-treatment ctDNA analyses. Conclusions: This real-world study of ICI treated, advanced NSCLC highlights the opportunity afforded through integrated analyses of ctDNA and matched WBCs to accurately determine mR and the associations with radiographic response and OS. Citation Format: Jennifer B. Jackson, Pedro Rocha, James R. White, Andrew P. Georgiadis, Ellen L. Verner, Amy Greer, Rafael Bach Mora, Laura Masfarré Pintó, Nil Navarro, Álvaro Taus, Beatriz Bellosillo Paricio, Sergi Clavé, Mark T. Sausen, Edurne Arriola. Enhanced detection of ctDNA molecular response for immunotherapy treated non-small cell lung cancer through analyses of cell-free and matched white blood cell DNA [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 6443.

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