To date, five second-line immunotherapies for the treatment of bladder cancer are available. While these immune checkpoint inhibitors are effective in a subset of patients, the majority of patients have disease progression while receiving this therapy. Anti-tumor efficacy by inhibiting the PD/L-1 pathway depends on an immune response against tumor cells. Consequently, tumors with a non-inflamed phenotype are less likely to respond to immune checkpoint inhibitor therapy. Recent research has found that mutations in FGFR3 and FGFR3 expression are strongly associated with the non-inflamed bladder cancer phenotype (Sweis 2015; Kilgour 2016). Furthermore, luminal type I bladder cancers, which have the highest expression of FGFR3 when compared across bladder cancer subtypes, have the poorest response rate to the checkpoint inhibitor atezolizumab (Rosenberg 2016).
B-701 is a monoclonal antibody specific for FGFR3 that blocks activation of the wildtype and genetically activated receptor. Preclinical studies have shown that B‑701 suppresses FGFR3-mediated cell proliferation and exerts strong anti-tumor activity in mouse xenograft models of bladder cancer. B-701 is currently being tested in two clinical trials (B701-U21 and B701-U22). Preliminary results from B-701-U21 (a trial in which B-701 is being tested in combination with docetaxel or as a single agent to treat advanced UCC) has previously been reported, with early promising data in the combination setting especially in patients with FGFR3 aberration (Bellmunt, ASCO 2017).
The design and objectives of study B701-U22 are described here. This is a Phase 1b multi-center, single-arm, open-label study in subjects with locally advanced or metastatic UCC, who have progressed following platinum-based chemotherapy, have no prior immune checkpoint inhibitor therapy, and have satisfactory performance status, including adequate hematologic and end organ function (Clinicaltrials.gov Identifier NCT03123055). It will evaluate the safety, tolerability and the efficacy of B-701 in combination with pembrolizumab. Efficacy will be measured by ORR, PFS, DCR, DOR and OS. Eligible subjects will have tumor biopsies taken prior and approximately 2 weeks after treatment with a single dose of B-701 (25 mg/kg) to evaluate the effects of FGFR3 blockade on immune cell infiltrate. Subjects will then receive treatment of B-701 (25 mg/kg) plus pembrolizumab (200 mg) Q3W until disease progression. This global trial is currently enrolling.
