Abstract 564: Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various FGFR-deregulated cancer cell lines and xenograft models

Abstract

Abstract Introduction: Futibatinib, a selective, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, has antitumor activity in FGFR-deregulated cancer models. The potential synergistic antitumor effects of targeted therapy plus chemotherapy (chemo) was evaluated by combining futibatinib with cytotoxic agents in in vitro and in vivo models. Methods: Gastric, breast, lung, endometrial, and bladder cancer cell lines with various FGFR aberrations were treated with futibatinib and cytotoxic agents (5-FU, paclitaxel, cisplatin, or gemcitabine) individually or in combination. In vitro cytotoxicity of futibatinib was assessed by PARP cleavage activity. Any combination effect on cell growth was determined by the Bliss independence method, combination index (CI; CalcuSyn software), or isobologram analysis. The antitumor effects of futibatinib plus S-1 or paclitaxel and futibatinib plus gemcitabine or cisplatin were evaluated in gastric FGFR2-amplified SNU-16 and endometrial FGFR2-N549K-mutated AN3CA mouse xenograft models, respectively, by measuring relative tumor volume (RTV). Results: A synergistic effect on cell growth inhibition was observed with futibatinib plus chemo in SNU-16 cells (CIs at ED90 were 0.50 [5-FU], 0.71 [paclitaxel], 0.76 [cisplatin], and 0.29 [gemcitabine]). Increased PARP cleavage and decreased cell growth were observed in SNU-16 cells treated with futibatinib plus 5-FU vs monotherapy. Synergized cell growth inhibition occurred in various FGFR-deregulated cancer cell lines. In xenograft models, vs monotherapy, a significant reduction (P<0.01) in RTV occurred with futibatinib plus S-1, paclitaxel (Table), or cisplatin and a numerically greater reduction with futibatinib plus gemcitabine. Table.Relative tumor volume in SNU-16 mouse xenografts treated with futibatinib or paclitaxel or combination therapyTreatment (mg/kg/d)Relative tumor volumeDay 0Day 4Day 8Day 11Day 15Control11.562.373.344.58Futibatinib (5)a11.321.952.773.83Futibatinib (15)a11.211.822.453.16Paclitaxel (60)b10.480.410.410.59Futibatinib + paclitaxel (5 + 60)c10.470.270.170.14Futibatinib + paclitaxel (15 + 60)c10.440.220.120.07aDays 1-14 (oral).bDay 1 (intravenous).cDays 1-14 + Day 1. Conclusions: Futibatinib showed a synergistic antitumor effect in vitro and in vivo when combined with various cytotoxic agents. These data are promising and warrant further investigation. Citation Format: Hiroshi Sootome, Akihiro Miura, Toshiharu Komori, Hiroshi Hirai. Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various FGFR-deregulated cancer cell lines and xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 564.