Bladder cancer is among the most prevalent cancers worldwide, with urothelial carcinoma accounting for approximately 90% of cases. Until recently, poor overall survival after chemotherapy combined with immune checkpoint blockade therapies for patients with advanced urothelial carcinoma highlighted the need for new therapies. Although data supports the use of targeted therapies, such as FGFR inhibitors, recent advances in the treatment of bladder cancer are changing the landscape. Enfortumab vedotin (EV) is an antibody drug conjugate (ADC) consisting of an anti-Nectin-4 antibody conjugated to monomethyl auristatin E, which specifically delivers the auristatin payload to Nectin-4 high-expressing urothelial carcinomas. While activity and durability of response from both monotherapy trials as well as combination with pembrolizumab are favorable, additional treatment options might be required for either patients not responding to treatment or those who might develop resistance. Importantly, FGFR activation through rearrangement or mutation is frequently found in the luminal papillary subtype which also expresses high levels of Nectin-4. Thus, we sought to test the potential of combining pemigatinib and EV in models of human bladder cancer which express both activated FGFR3 and Nectin-4. Our initial analysis show that FGFR3 mutant tumors express high levels of Nectin-4. We further demonstrated that two bladder cancer cell lines RT112/84 (FGFR3-TACC3 fusion) and UM-UC-14 (FGFR3S249C) are sensitive to both pemigatinib and EV in vitro and in vivo. Notably, synergistic anti-tumor effects were observed when pemigatinib was combined with EV in vivo. In addition, combination of pemigatinib with EV significantly improved overall survival when compared to single treatments in these models. Altogether, our data strongly suggest a potential for combination of these therapies in the clinic.

Citation Format: Rodrigo A. Hess, Lisa Truong, Antony Chadderton, Michelle Frascella, Leslie Hall, Holly Koblish. Synergistic effect of combination of pemigatinib with enfortumab vedotin (EV) in human bladder cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P245.