Biology

Fibroblast Growth Factor Receptor 3 (FGFR3) is a cell surface receptor for ligands called fibroblast growth factors (FGFs). FGFs regulate the growth and differentiation of cells through complex combinatorial signaling pathways, including binding with a family of 4 tyrosine kinase FGF receptors (FGFRs). In humans, there are 22 FGFs and 4 FGF receptors (FGFR1, FGFR2, FGFR3, and FGFR4). Each of the FGFRs has an extracellular domain for ligand binding, a transmembrane domain, and an intracellular split tyrosine kinase domain. The extracellular ligand-binding regions have two or three immunoglobulin-line domains (IgD1 - 3).

The receptor FGFR3 in its native state is a monomer. The binding of FGF ligands to FGFR3 monomers leads to receptor dimerization, which then triggers a cascade of cellular events, starting with phosphorylation of the intracellular domain of the FGFR3 receptor followed by intracellular messengers, which ultimately regulate the growth and differentiation of cells.

Vofatamab (B-701) is a human IgG1 monoclonal antibody that is specific for the FGFR3 and does not interact with the other FGFRs, i.e., FGFR1, FGFR2, or FGFR4. It is being used as an investigational treatment for medical conditions that are caused by activation of wild-type or mutated forms of FGFR3.

Metastatic Bladder Cancer

Bladder Cancer

In bladder cancer, inappropriate FGFR3 signaling is implicated in the pathogenesis of the majority of muscle invasive bladder cancer tumors, with approximately 20% having activating FGFR3 mutations, fusions, and a significant percentage (≥50%) demonstrating over-expression of the receptor. Recently, others have validated FGFR3 as a driver for metastatic bladder cancer in human clinical studies. 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

Genetic Mutation
Causing receptor dimerization
Wild-type
Ligand-induced dimerization
Approximately 20% of invasive UCC* Majority of FGFR3 expressing UCC*

*UCC = urothelial cell carcinoma

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, 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. Effects observed by combining either paclitaxel or gemcitabine with vofatamab were similar, suggesting 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), suggesting that treatment with vofatamab may enhance the efficacy of immune checkpoint inhibitors.

Patient Population

Bladder cancer is the sixth most commonly diagnosed cancer in the U.S.A. Over 90% of bladder cancer is urothelial cell carcinoma (UCC); other less frequent variants include squamous cell and adenocarcinoma. 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.

Seventy to 80% of bladder cancer is superficial, while 20-30% is invasive. In approximately 15% of the cases, the tumor extends beyond the wall of the bladder (stage T4). Prognosis of the metastatic T4 tumor type is poor despite surgery and systemic chemotherapy.

Therapeutic option for metastatic bladder cancer includes chemotherapy, generally gemcitabine in combination with cisplatin for 1st line treatment. Recently, atezolizumab has been approved for post-platinum metastatic bladder cancer. Despite the approval of atezolizumab, there remains a significant unmet medical need in this population, where average survival is still well below a year.

Other Cancers

FGFR3 in Other Solid Tumors

In addition to bladder cancer, a number of other solid tumors have been reported to exhibit overexpression, mutation or fusion of FGFR3, including invasive breast carcinoma, squamous cell carcinoma of the lung, and oral squamous cell carcinoma.

In addition to playing a primary role in tumorigenesis, some preclinical studies have also demonstrated that FGFR3 can cause resistance to targeted therapies in melanoma, non-small cell lung cancer and breast cancer. For instance, FGFR3 signaling has been reported to be elevated and to induce resistance to vemurafenib, a B-RAF inhibitor, in an in vitro study of a vemurafenib-resistant melanoma cell line.

Publications

Advanced/Metastatic Bladder Cancer:

Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, Culine S, von der Maase H, Vaughn DJ, Rosenberg JE. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol 2010;28:1850-5.

Bernard-Pierrot I, Brams A, Dunois-Larde C, et al. Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis 2006;27:740-74.

Cancer Genome Atlas Research Network., Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507:315-22.

Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 1999;23:18-20.

Chaffer CL, Dopheide B, Savagner P, Thompson EW, Williams ED. Aberrant fibroblast growth factor receptor signaling in bladder and other cancers. Differentiation 2007;75:831-42.

Gómez-Román JJ, Saenz P, Cuevas González J, et al. Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res 2005;11:459-65.

Gust KM, McConkey DJ, Awrey S, et al. Fibroblast Growth Factor Receptor 3 is a Rational Therapeutic Target in Bladder Cancer. Mol Cancer Ther 2013;12:1245–54.

Qing J, Du X, Chen Y, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t (4; 14)-positive multiple myeloma in mice. J Clin Invest 2009;119:1077-9.

Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, Buchanan S, Henry JR, Starling JJ, Peng SB. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 2012;287:28087-98.

Sweis RF, Spranger S, Gajewski T. Molecular drivers of the non-T cell-inflamed tumor microenvironment in urothelial bladder cancer. J Clin Oncol 2015;33:suppl;abstr 4511.


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