Abstract 2147: Development of preclinical models to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies

Abstract

The last 20 years have witnessed the identification of an increasing number of druggable oncogenic drivers and the development and clinical use of specific inhibitors against these targets. Unfortunately, patients treated with targeted therapies consistently develop resistance and progression under treatment. Hence, important scientific, pharmaceutical and medical research efforts are directed towards understanding the mechanisms of acquired resistance to explore new therapeutic pathways. The MATCH-R clinical trial enrolls patients with oncogene-driven cancer who have had previous clinical response to targeted therapy and subsequently experienced disease progression. In the framework of this project, Gustave Roussy and XenTech are joining forces to develop a panel of patient-derived xenografts (PDXs) derived from biopsies collected from these patients at the stage of acquired resistance. These PDX models will be used to improve knowledge on the mechanisms underlying resistance to treatment and to evaluate response to new treatments. In this perspective, the development of 75 PDX-AR (Active Resistance) models is planned over 3 years. All the models are maintained under the same therapeutic pressure the parental tumor was submitted to at the time of biopsy, and will be subjected to extensive phenotypic and genotypic characterization. The following models have been established so far: • ENDx-MR-004-AR (endometrial): resistant to the combination of MEK and MDM2 inhibitors; • LCx-MR-007-AR: (NSCLC): resistant to third generation EGFR inhibitor (osimertinib); • UREx-MR-015A-AR (ureter) and VEx-MR-086A-AR (bladder): resistant to a FGFR inhibitor (erdafitinib); • PARx-MR-010-AR (parotid): resistant to a NOTCH Inhibitor; • TCx-MR-122-AR (colon): resistant to an ATR inhibitor. To favor successful xenograft establishment, the first two passages were performed without drug treatment, which was applied from the third passage on. When doing so, some models showed resistance from the first passage under treatment, whereas others showed stabilization under treatment at the first passages and rapidly acquired resistance over passages. These different behaviors might underlie different mechanisms of resistance, irreversible (monoclonal) for the former, reversible (polyclonal) for the latter. Parallel to the development of UREx-MR-015A-AR, we developed the UREx-MR-015B-SD (stable disease) model from a biopsy collected from a different metastasis in the same patient, but stabilized by the therapy. Comparative analysis of these two models will provide important insights into the mechanisms of resistance to FGFR inhibitors. The MATCH-R PDX project will provide a unique preclinical platform for identifying resistance mechanisms to current targeted therapies and developing next generation therapeutic strategies. Citation Format: Olivier Déas, Ludovic Bigot, Guillaume Lang, Yohann Loriot, Fabrice Andre, Jean Charles Soria, Benjamin Besse, Stefano Cairo, Marie Tavernier, Katell Mevel, Enora Le Ven, Jean-Gabriel Judde, Luc Friboulet. Development of preclinical models to accelerate the identification of next generation treatments for patients with acquired resistance to targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2147.

Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

“…Enapotamab vedotin induces potent antitumor activity in an osimertinib-resistant NSCLC PDX model in vivo. Finally, we assessed the in vivo antitumor activity of enapotamab vedotin in the AXL-expressing PDX model LCx-MR007, derived from a patient with NSCLC who acquired resistance to osimertinib in the clinic (27,28). Although osimertinib had no effect on tumor growth, tumor regression was observed in mice treated with enapotamab vedotin at a dose of 4 mg/kg ( Figure 6A).…”