Abstract 318: Mechanisms of acquired resistance to FGFR inhibitors in molecularly-selected solid tumors: A prospective cohort from the MATCH-R study
Authors: Francesco Facchinetti, Rastislav Bahleda, Antoine Hollebecque, Yohann Loriot, Gonzalo Recondo, Ludovic Bigot, Ken A. Olaussen, Gilles Vassal, Stefan Michiels, Rosa L. Frias, Justine Galissant, Tony Sourisseau, Claudio Nicotra, Maud Ngo-Camus, Linda Mahjoubi, Ludovic Lacroix, Etienne Rouleau, Catherine Richon, Aurélie Abou-Lovergne, Olivier Deas, Nathalie Auger, Thierry De Baere, Frederic Deschamps, Eric Solary, Jean-Yves Scoazec, Eric Angevin, Alexander Eggermont, Fabrice André, Benjamin Besse, Jean-Paul Thiery, Jean-Charles Soria, Christophe Massard, Luc Friboulet
Journal: Cancer Research (2019)

Abstract Background: Molecular alterations involving FGFR family genes (FGFR 1-4) are emerging driver events in a variety of solid tumors, mainly represented by urothelial carcinoma (UC) and intrahepatic cholangiocarcinoma (CC). Several tyrosine kinase inhibitors (TKI) are in clinical development to counteract FGFR-driven diseases, being especially active against activating gene mutations and rearrangements. Progression on these targeted agents eventually appears and the understanding of molecular mechanisms of resistance is crucial to develop novel strategies. Methods: In the MATCH-R prospective study (NCT02517892), patients with unresectable or metastatic cancer are included upon acquired resistance to targeted therapies or immunotherapy, defined as progressive disease after complete/partial response or stable disease for six months. Serial blood samples are collected and tumor biopsy is performed upon progression. Targeted NGS, CGH, WES and RNAseq are performed on the tissue samples. PDX models and patient-derived cell lines are developed to fully investigate the underlying mechanisms of resistance. Only patients receiving TKI for FGFR-mutated or -rearranged tumors were included (i.e. FGFRamplifications were excluded) in the analysis. Results: From June 2015 to November 2018, 113 patients treated with a TKI were included in the MATCH-R study, of which 17 (15%) had received an FGFR inhibitor. Tumor types and corresponding molecular aberrations were as follows: 8 CC (n=6 FGFR2-rearranged, n=1 FGFR2:C383R, n=1 FGFR3:S249C), 7 UC (n=5 FGFR3:S249C, n=1 FGFR3:R248C, n=1 FGFR3:Y373C), 1 breast (FGFR3-rearranged) and 1 ovarian (FGFR2-rearranged) cancers. Evaluable tumor biopsies were taken upon progression to treatment with erdafitinib (n=12), pemigatinib (INCB54828) (n=3) or TAS-120 (n=4). Two patients underwent multiple biopsies as progressing on sequential FGFR inhibitors. Resistance mechanisms consisted of polyclonal secondary mutations (n=5), bypass pathways activation (n=3) and the remaining nine cases are still under investigation. PDX models/patient-derived cell lines were obtained in eight cases and extensively characterized in three. Adaptive treatment with novel FGFR TKI or combinatorial strategies aiming to block the bypass pathways allowed to restore sensitivity in both cell lines (readouts: IC50 and Western Blots) and PDX (readout: median tumor growth). Novel mutations potentially implicated in resistance to FGFR TKI were characterized by infecting Ba/F3 cells with respective lentiviral vectors, as well as the inhibitory potential of the differential FGFR inhibitors. Conclusions: Novel mechanisms of resistance to FGFR inhibitors in solid tumors were identified and consequent treatment strategies allowed to regain sensitivity in both patient-derived cell lines and PDX. Updated results will be presented at the Meeting. Citation Format: Francesco Facchinetti, Rastislav Bahleda, Antoine Hollebecque, Yohann Loriot, Gonzalo Recondo, Ludovic Bigot, Ken A. Olaussen, Gilles Vassal, Stefan Michiels, Rosa L. Frias, Justine Galissant, Tony Sourisseau, Claudio Nicotra, Maud Ngo-Camus, Linda Mahjoubi, Ludovic Lacroix, Etienne Rouleau, Catherine Richon, Aurélie Abou-Lovergne, Olivier Deas, Nathalie Auger, Thierry De Baere, Frederic Deschamps, Eric Solary, Jean-Yves Scoazec, Eric Angevin, Alexander Eggermont, Fabrice André, Benjamin Besse, Jean-Paul Thiery, Jean-Charles Soria, Christophe Massard, Luc Friboulet. Mechanisms of acquired resistance to FGFR inhibitors in molecularly-selected solid tumors: A prospective cohort from the MATCH-R study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 318.