In bladder cancer, inappropriate FGFR3 signaling is implicated in the pathogenesis of advanced and metastatic bladder cancer tumors, with approximately 20% having activating FGFR3 mutations, fusions, and a significant percentage (≥50%) demonstrating over-expression of the receptor. FGFR3 is a driver for metastatic bladder cancer in humans. Activation of the receptor is believed to promote both the growth and survival of cancer cells. Thus, blocking its activity may not only directly inhibit tumor growth, but may also enhance the effectiveness of standard-of-care chemotherapy by depriving the tumor cells of potent survival signals. Vofatamab blocks the major mechanisms of FGFR3 activation that have been described in bladder cancer as shown below:
Vofatamab is Highly Unique in that it Blocks Multiple Mechanisms of FGFR3 activation associated with Bladder Cancer
Vofatamab as Monotherapy and in Combination
The ability of vofatamab to suppress tumor growth in in-vivo bladder cancer models has been assessed either alone or in combination with chemotherapy. Vofatamab as a single agent potently inhibits the growth of bladder cancer tumors in xenografts expressing wild-type, and the commonly reported mutant or fusion forms of FGFR3.
Further, in combination with standard of care chemotherapy for bladder cancer, vofatamab greatly enhances the inhibition of the growth observed with single agent chemotherapy. Gemcitabine is part of a regimen used as first line treatment for metastatic bladder cancer while paclitaxel is commonly used as the standard of care for patients with refractory metastatic bladder cancer, thus we tested whether the combination of gemcitabine with vofatamab or paclitaxel with vofatamab would enhance the suppression of tumor growth as compared to either single agent. When mice bearing human tumor xenografts were treated with a combination of either vofatamab and paclitaxel or vofatamab and gemcitabine, tumor growth was highly suppressed and animal survival was dramatically extended. This data, suggests that addition of vofatamab to standard of care chemotherapy in either setting will be of clinical benefit.
Recently reported data that show FGFR3 expression and mutation are associated with poor immune cell infiltration into bladder cancers (Sweis et al 2015). It is hypothesized that FGFR3 blockade with voftamab may also enhance the efficacy of immune checkpoint inhibitors.
Bladder cancer is the sixth most commonly diagnosed cancer in the U.S.A. Over 90% of bladder cancer is urothelial cell carcinoma (UCC). It is estimated that 74,000 new cases and 16,000 deaths from bladder cancer will occur in 2015 in the U.S. alone. There are an estimated 151,100 new cases and 52,400 deaths annually in Europe.
Worldwide the incidence of bladder cancer is approximately 550,000 patients with a prevalence of over 1.6 million cases per year1. Patients who have advanced or metastatic disease (T3 and T4 staging) account for approximately 20% of the prevalence while those in earlier stages of disease (in situ, T0, T1, Ta and T2) represent the remainder.
As previously noted, approximately 20% of patients with advanced or metastatic disease will have FGFR3 mutations or fusions. In non-invasive disease, 40-70% of the patients will have these mutations or fusions, depending on the stage of the disease.
1source: Globacan, 2018