Abstract B078: Unraveling resistance and optimizing treatment through molecular profiling in patients with NSCLC and oncogenic fusions
Authors: Aldea Mihaela , Pop Vlad , Marinello Arianna , Ivashkin Andrei , Vasseur Damien , Gendarme Sebastien , Tagliamento Marco , Gazzah Anas , Remon Jordi , Ben-Ammar Imen , Frelaut Maxime , Abdayem Pamela , Lavaud Pernelle , Hollebecque Antoine , Rouleau Etienne , Loriot Yohann , Friboulet Luc , Nikolaev Sergey , Italiano Antoine , Barlesi Fabrice , Planchard David , Besse Benjamin 
Published: December 2023

Abstract
Introduction: In non-small cell lung cancer (NSCLC) with oncogenic fusions, resistance development complicates optimal therapeutic sequencing. This study investigates the resistance landscape in NSCLC with oncogenic fusions and evaluates the efficacy of subsequent treatment tailoring based on the molecular profile at progression.
Methods: This is a single center, retrospective study, including patients with advanced NSCLC and ALK, ROS1, RET or NTRK fusions, with a molecular profile at progression after targeted therapy (TKI), between January 2015 and February 2023. Molecular profile was performed on tissue or liquid samples, with next-generation sequencing (NGS) (targeted DNA and/or RNA panels, WES/RNA sequencing). In case of TKI sequencing, more than one NGS results were available for selected patients. Alterations at time of resistance were classified into on-target, bypass alterations, and polyclonal/complex resistance (with at least two types of resistance concurrently present in the same biopsy). The primary objective was to assess the clinical utility of NGS to guide subsequent treatment at progression after TKI.
Results: A total of 95 patients (61 ALK, 21 ROS1, 12 RET, 1 NTRK) had 179 samples collected. Patients were female in 51 (54%), had a median age of 53 years (IQR 41-60), never smokers in 52 (55%) cases and adenocarcinoma histology in 88 (94%) of cases. Molecular profile was performed by liquid biopsy in 83 (66%) cases, other liquids in 3 (2%) and tissue in 40 (32%) cases. There were 126 contributive samples (70%) for 69 patients. Resistance was explained by 60/126 (48%) samples for 41 patients: on-target in 27 (47%), bypass in 22 (39%), and polyclonal resistance in 8 (14%) samples. Three out of 7 samples evaluable for mutational signatures via WES showed Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) signatures. The time until the first occurrence of resistance was 34.2 months (95%CI 26-65.3) for on-target, 23.6 months (95%CI 18.8-97.4) for by-pass and 16.5 months (95%CI 7.2-NR) for polyclonal resistance. The early occurrence of by-pass or polyclonal resistance in the first 12 months was associated with a younger age (median 37 vs 52 years, p=0.044). Among the 60 NGS results explaining resistance for 41 patients, 56 (93%) NGS results informed treatment tailoring. Drug tailoring was conducted in 16 patients for 23 NGS reports, revealing a median overall survival of 18.6 months (95% CI 11.8 – NR) for patients receiving an effective tailored treatment, versus 7.3 months (95%CI 2.9 – NR) for those without tailoring (p=0.088).
Conclusion: Our findings underscore the value of using NGS to inform treatment tailoring in NSCLC patients with oncogenic fusions. Special focus should be placed on younger patients who might be prone to early development of bypass or polyclonal resistance.
Citation Format: Mihaela Aldea, Vlad Pop, Arianna Marinello, Andrei Ivashkin, Damien Vasseur, Sebastien Gendarme, Marco Tagliamento, Anas Gazzah, Jordi Remon, Imen Ben-Ammar, Maxime Frelaut, Pamela Abdayem, Pernelle Lavaud, Antoine Hollebecque, Etienne Rouleau, Yohann Loriot, Luc Friboulet, Sergey Nikolaev, Antoine Italiano, Fabrice Barlesi, David Planchard, Benjamin Besse. Unraveling resistance and optimizing treatment through molecular profiling in patients with NSCLC and oncogenic fusions [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B078.