Characterization of a PDX panel covering molecular diversity of non-small cell lung cancer to accelerate the development of precision therapy

Abstract Lung cancer remains the first cause of cancer-related deaths worldwide, of which Non-Small Cell Lung Cancer (NSCLC) represents more than 80% of patients with advanced disease at the time of diagnosis. NSCLC is a highly heterogenous disease, and the identification of its main actionable oncogenic drivers (i.e. EGFR, ALK, PI3K/AKT/mTOR, RET, MET, BRAF and NTRK/ROS1) and the development of specific inhibitors against these targets has transformed therapeutic care. In addition, immune-checkpoint therapy has emerged as an indispensable treatment modality, especially for patients lacking actionable oncogenic drivers, although biomarkers for predicting response to immune-checkpoint inhibition have remained elusive. Despite these new therapeutic options, NSCLC remains a lethal disease in the majority of patients due to tumor plasticity and selection leading to frequent resistance development and disease progression. Efforts are therefore needed to identify drugs and drug combinations that can prevent or overcome these resistance pathways. Patient-Derived Xenografts (PDX) models developed in immune-compromised mice recapitulate the disease more faithfully than any other in vivo model in terms of histopathologic and genomic features. They have proven their relevance in the study of pathways leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel effective therapies, facilitating the translation of preclinical results in the clinical setting. We describe a platform of over 35 NSCLC PDX models covering most of the molecular diversity of the disease, that have been fully characterized at the molecular level and for their response to a panel of cytotoxic chemotherapies and targeted therapies. These NSCLC PDX models have been established in immune-deficient mice from tumor biopsies collected in treatment-naïve patients or in patients having acquired resistance following an initial objective response to a variety of targeted inhibitors (EGFRi, ALKi, ROSi, BRAFi,⋯) in the MATCH-R clinical trial. In addition, 4 PDX models were established from circulating tumor cells (CTC) isolated from the blood of advanced NSCLC patients. Finally, some of these NSCLC PDX models were established in highly immunodeficient mice humanized with human PBMCs or CD34+ cells allowing testing of efficacy of bispecific T-Cell engager antibody or immune-checkpoint inhibitors. This panel of NSCLC PDX models provides a powerful preclinical platform to improve our knowledge on the mechanisms underlying resistance to treatment and to rapidly evaluate response to new treatments and translate this knowledge to the clinic. Citation Format: Delphine Nicolle, Laura Brulle-Soumare, Katell Mevel, Ludovic Bigot, Tala Tayoun, Benjamin Besse, Françoise Farace, Luc Friboulet, Didier Decaudin, Erwan Corcuff, Anaïs Joachim, Bernard Malissen, Ana Zarubica, Hervé Luche, Jean-Gabriel Judde, Olivier Deas. Characterization of a PDX panel covering molecular diversity of non-small cell lung cancer to accelerate the development of precision therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4678.