FGFR2b represents a novel target for treatment of urothelial cancer

Background: FPA144 was developed as an FGFR2b-specific humanized monoclonal antibody to treat patients with cancer that over-expresses FGF receptor 2b. FPA144 blocks ligand binding and has been glyco-engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical models have demonstrated that FPA144 treatment triggers a cascade of immune responses: NK cells are recruited to the tumor microenvironment, PD-L1 is up-regulated, followed by infiltration of T cells. In a mouse syngeneic model with modest FGFR2b overexpression this immune cascade resulted in tumor growth inhibition that was dependent on Fc effector function. The anti-tumor activity of FPA144 was augmented in combination with PD-1 blockade (Powers, AACR 2016). During Phase 1 dose escalation in the first-in-human clinical trial (NCT02318329), a patient with urothelial cancer (UC) was treated with FPA144 at the 3mg/kg dose level. This patient had a durable, complete response to FPA144. Here, we explore the potential utility of FPA144 in UC by assessing the frequency of FGFR2b overexpression in samples from UC patients. Methods: Immunohistochemistry (IHC) was performed on normal bladder and archival UC samples using the FPR2-D mouse monoclonal antibody, which is specific for FGFR2b. Formalin-fixed paraffin-embedded UC sections, both primary and metastatic, whole section or in tissue microarray format, were stained and detected using a chromogenic substrate. Membranous tumor cell staining intensity was scored on a scale of 0-3. Tumors with 1+ membranous reactivity in ^10% of tumor cells were considered positive. Results: Normal bladder has weak staining of the transitional epithelium (