Abstract 3500: Combinations of ARQ087 with chemotherapeutic agents are safe and show a striking antitumor activity in different xenograft models

Abstract ARQ087 is a non ATP-competitive tyrosine kinase inhibitor with activity against the FGFR receptor family, and currently in Phase I clinical studies for the treatment of advanced solid tumors. It potently inhibits FGFR1, 2, and 3, as well as mutant FGFR2 (N549H) and FGFR3 (K650E/M) with IC50 values in the low nanomolar range in biochemical assays. ARQ 087 has shown potent anti-proliferative activity in a panel of cancer cells with deregulated FGFR1 and FGFR2 pathways and exerted a dose-dependent antitumor activity in in vivo systems with FGFR1/FGFR2-driven xenografts model (H1581 and SNU-16 respectively) and models harboring FGFR2-activating mutation (AN3CA and MFE296). Given orally in a 15 daily administration, ARQ 087 has shown a very safe profile while inducing tumor regressions in FGFR driven models. The feasibility of combining ARQ087 with chemotherapy was investigated in H1581 FGFR1-amplified lung xenograft and in SNU16-FGFR2 driven gastric xenografts. Tumor bearing mice, were randomized to receive vehicle, ARQ087, paclitaxel, carboplatin as single agents, ARQ087 and paclitaxel, ARQ087 and carboplatin, paclitaxel and carboplatin as doublets; and the triple combination of ARQ087 with carboplatin and paclitaxel. Similar experimental setting was applied in nude mice bearing SUN16 xenografts, but instead of paclitaxel, capecitabine was given. The choice of the anticancer agents to be combined with ARQ087 was supported by the fact that these drugs are currently used for the treatment of various cancers clinically. In both experimental settings the drugs given as single agents showed moderate anti-tumor activity. Combination of two agents was more active than the single ones alone and combination of three agents has shown the most antitumor activity. In particular, combination of ARQ 087 with paclitaxel and carboplatin in H1581 bearing mice resulted in tumor regression and only 1/8 tumor re-grew after 30 days from the last drug administration versus 6/8, 4/8 e 5/8 in treatment groups with paclitaxel alone, combination of ARQ087 with paclitaxel, and combination of paclitaxel with carboplatin respectively. Of importance, no toxic deaths nor premature stopping or delaying of drug administration occurred. These data clearly suggest that ARQ087 can be safely combined with chemotherapy and that the combinations are much more active than the monotherapies. Citation Format: Rosaria Chilà, Federica Guffanti, Terence Hall, Francesca Ricci, Massimo Broggini, Giovanna Damia. Combinations of ARQ087 with chemotherapeutic agents are safe and show a striking antitumor activity in different xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3500. doi:10.1158/1538-7445.AM2015-3500