Abstract 3080: Activity of pan-FGFR inhibitor rogaratinib and PI3K inhibitor copanlisib in preclinical urothelial bladder cancer models
Authors: Isabel S. Jerchel, Pascale Lejeune, Rita Lampignano, Alexander Walter, Ralf Lesche, Atanas Kamburov, Dominik Mumberg, Peter Ellinghaus, Oliver Politz, Sylvia Gruenewald
Journal: Cancer Research (2019)

Abstract Rogaratinib is a potent small molecule pan-FGFR inhibitor that leads to downregulation of MAPK and PI3K signaling (1). In a recent Phase I study rogaratinib demonstrated higher ORR in locally advanced or metastatic urothelial bladder cancer (UBC) with FGFR mRNA overexpression in patients with PIK3CA and RASwildtype than in those harboring PIK3CA or RAS mutations (2). In UBC, about 25% of tumors contain mutated PIK3CA of which 75% represent hot spot mutations E545K or E542K (3). Copanlisib is a potent pan class I PI3K inhibitor with predominant activity against the α and δ isoforms being approved for treatment of relapsed follicular lymphoma (4). We evaluated the activity of rogaratinib in cellular and in vivo efficacy studies in bladder cancer models in monotherapy and in combination with copanlisib. Cell proliferation and viability in response to rogaratinib, copanlisib or the combination of both was studied in rogaratinib-sensitive UBC cell lines like RT112 as well as in a recombinant RT112-PIK3CAE545K cell line. Rogaratinib potently inhibited cell proliferation with IC50 values in the double nM range. Copanlisib’s potency varied between 20 and 900 nM. In combination, rogaratinib and copanlisib increased cell death and were synergistic as shown by their proliferation combination indices for the absolute IC50 and IC80. Expression of the PIK3CAE545K hot spot mutant in RT112 cells decreased the anti-proliferative efficacy of rogaratinib but did not change the sensitivity to copanlisib. In vivo, rogaratinib led to tumor regression in the FGFR1-expressing JMSU1 xenograft and strongly inhibited tumor growth in the FGFR3-driven RT112 model. Copanlisib did not show significant inhibition of tumor growth in monotherapy in either model. In the JMSU1 model the combination was not superior to rogaratinib alone at maximal tolerated doses. In the RT112 as well as in the RT112-PIK3CAE545K model, the combination significantly improved anti-tumor activity. In a PDX model with FGFR3 overexpression and a PIK3CAH1047R hot spot mutation rogaratinib did not inhibit tumor growth significantly while copanlisib displayed significant anti-tumor effects. The combination of both drugs reduced tumor growth compared to either monotherapy group. In conclusion, in UBC tumor models overexpressing FGFR with differing sensitivities to rogaratinib, its anti-tumor activity could be further enhanced when combined with copanlisib and suggests that PIK3CA mutations may play a role in reduced sensitivity of UBC to FGFR inhibition. These promising results warrant further development of rogaratinib in monotherapy and in combination. Clinical trials with rogaratinib are currently recruiting (NCT03517956, NCT03410693, NCT03473756). References: Jerchel et al. Cancer Res. 2018; 78: Abs. 4781. Joerger et al. JCO 2018; 36: Abs. 4513. Platt et al. Clin. Cancer Res. 2009; 15:6008. Markham, A. Drugs. 2017; 77:2057. Citation Format: Isabel S. Jerchel, Pascale Lejeune, Rita Lampignano, Alexander Walter, Ralf Lesche, Atanas Kamburov, Dominik Mumberg, Peter Ellinghaus, Oliver Politz, Sylvia Gruenewald. Activity of pan-FGFR inhibitor rogaratinib and PI3K inhibitor copanlisib in preclinical urothelial bladder cancer models [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 3080.