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Clinical Development of FGFR3 Inhibitors for the Treatment of Urothelial Cancer

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Clinical Development of FGFR3 Inhibitors for the Treatment of Urothelial Cancer Bladder Cancer 5 (2019) 87–102 87 DOI 10.3233/BLC-180205 IOS Press Review Clinical Development of FGFR3 Inhibitors for the Treatment of Urothelial Cancer Tony Ibrahima, Marco Gizzib, Ratislav Bahledac and Yohann Loriota,d,∗ aD´epartement de M´edecine Oncologique, Gustave Roussy, Universit´e Paris-Sud, Universit´e Paris-Saclay, Villejuif, France bDepartment of Medical Oncology. Grand Hˆopital de Charleroi, Charleroi, Belgium cDrug Development Department (DITEP), Gustave Roussy, Villejuif France dInserm 981, Universit´e Paris-Sud, Universit´e Paris Saclay, Villejuif, France Received: 29 November 2018 Accepted: 4 March 2019 Abstract. The fibroblast growth factor receptor 3 (FGFR3) plays critical roles in driving oncogenesis of a subset of patients with urothelial carcinomas (UC). Growing evidence from preclinical studies suggests that FGFR3 inhibition can reduce proliferation and survival in vitro and in vivo models of FGFR3-altered UC. Early clinical trials investigating selective FGFR3 inhibitor have reported preliminary signs of antitumor activity in advanced UC patients with selected FGFR3 mutations or fusions. Currently, phase 3 trials with erdafitinib and rogaratinib are enrolling patients with known FGFR3 alterations. Future combinations with targeted therapies or immune checkpoint inhibitors may increase the efficacy of selective FGFR3 inhibitors. Herein, we discuss current clinical development of FGFR3 inhibitors as well as unsolved questions with regards to patient selection, management of toxicities and mechanisms of resistance to selective FGFR3 inhibitors. Keywords: Urothelial cancer, bladder cancer, fibroblast growth factor 3, tyrosine kinase INTRODUCTION the treated patients [1–11]. Innovative strategies aim- ing to improve metastatic UC treatment efficacy have Metastatic urothelial carcinoma (UC) is frequent learned from targeted therapies in solid tumors such and has a poor prognosis. The clinical manage- as lung and breast cancers. Given the need for alter- ment of advanced UC has improved over the last native treatments in advanced UC, there is a growing decade mainly owing to novel immunotherapies interest in targeting oncogenic pathways in UC. Over targeting immune checkpoint receptors. However, the last few years, genome sequencing techniques anti-programmed cell death 1 (PD1) and anti- have led to a better understanding of the molecular programmed death-ligand 1 (PDL1) monoclonal biology of UC. Recently, the Cancer Genome Atlas antibodies yield a tumor response in only one-fifth of (TCGA) project has elucidated the high degree of het- erogeneity underlying cancer cell development [12, ∗ Correspondence to: Yohann Loriot, Departement´ de Medicine´ 13] and has led to the classification of muscle-invasive Oncologique, 114 rue Edouard Vaillant, 94805 Villejuif, France. bladder cancer (MIBC) into molecular subtypes. Tel.: +33 1 42 11 52 76; Fax: +33 1 42 11 52 11; E-mail: yohann. [email protected]. These subtypes exhibit distinct sensitivity to therapies ISSN 2352-3727/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 88 T. Ibrahim et al. / FGFR3 Inhibitors in Urothelial Cancers owing to their distinct genomic and transcriptomic cer” and “Fibroblast Growth Factor”, “carcinoma” features. DNA and epigenetic alterations have been and “Fibroblast Growth Factor Receptor”. A total of identified in up to 60% of bladder cancers. Impor- 117 trials were identified. Eighty-one studies were tantly, potential targetable alterations involving the excluded due to other types of cancer or the absence of fibroblast growth factor receptor 3 (FGFR3)have FGFR3 inhibitors. A total of 36 trials were selected. been found in up to 20% of MIBC making these molecular aberrations highly attractive for pharma- cological inhibition. Genomic alterations of FGFR3 THE FGFR3 PATHWAY AND FGFR3 are among the best described oncogenic pathway in ALTERATIONS UC [14] and have led to extensive and ongoing inves- tigations of FGFR3-targeted therapies in this disease. The FGFR family contains four highly conserved In this review, we highlight the diverse oncogenic transmembrane tyrosine kinase receptors (FGFR1-4) FGFR3 signaling mechanisms in UC, current clin- with 22 identified ligands to date [15, 16]. Each ligand ical development of FGFR3 inhibitors and finally needs to interact with extracellular matrix proteins to perspective and challenges of anti-FGFR3 therapy bind to its receptor, mainly with the heparan sulphate in UC. proteoglycans (HSPG) [15–17]. The dimerization of FGFR leads to the phosphorylation of the intracel- lular tyrosine kinase domains which results in the MATERIAL AND METHODS activation of a cascade of downstream events includ- ing the mitogen-activated protein kinase (MAPK), A review of the literature has been conducted in the signal transducer and activator of transcription February 2018 using the pubmed Medline database, (STAT), the phosphoinositide-3-kinase (PI3K)/Akt, Cochrane database, ascopubs.org, esmo.org, clini- the nuclear factor-kappa B, and the PLC-gamma caltrials.org databases and scholar.google.com fol- DAG/PKC/IP3-Ca2+ pathways resulting in DNA lowing PRISMA (Preferred Reporting Items for transcription (Fig. 1). These pathways have critical Systemic Reviews and Meta-analysis) guidelines. roles in cell proliferation, metabolism and survival We searched for clinical trials articles with the fol- [18, 19]. lowing keywords: “Receptors, Fibroblast Growth FGFRs are present in many types of normal and Factor”, “Urinary Bladder Neoplasms”, “Carcinoma, tumor cells and have been shown to play an important Transitional Cell” in pubmed database; “Fibrob- role in tumor cell growth, survival, and migra- last Growth Factor” and “urothelial carcinoma” or tion as well as in maintaining tumor angiogenesis. “Fibroblast Growth Factor” and “bladder cancer” in FGFR activating mutation, gene amplification, and Cochrane database; “fibroblast growth factor receptor translocation have been associated with neoplastic inhibitor” in ascopubs.org; “fibroblast growth factor progression and tumor vascularization in multi- receptor inhibitor” in esmo.org database; and “fibrob- ple cancer types, including breast, lung, prostate, last growth factor receptor 3” AND “bladder cancer”, endometrial, gastric, and UC [20]. “fibroblast growth factor receptor 3” AND “urothe- FGFR3 gene is located on the short arm of the lial carcinoma”, “fibroblast growth factor receptor chromosome 4 (location p16.3) and contains 19 exons 3” AND “urothelial cancer” in scholar.google.com and 18 introns spanning 16.5 kb (Fig. 2). In an anal- (Supplementary Figure 1). Search results were ysis of 4,853 tumors by next-generation sequencing restricted to English language only. Studies were (NGS), aberrant FGFR3 have been identified in 22% selected based on title and abstract reading by two of UC, 4% of glioma, 3% of carcinoma of unknown authors (TI, YL). Then, for relevant abstracts, the primary and endometrial carcinoma, 2% of pancre- full text was reviewed; discrepancies were resolved atic, ovarian, and gastric carcinoma [21]. In addition, via consensus after discussion between the authors. nearly 5% of glioblastomas harbour the FGFR3- Duplicates, clinical studies which did not include TACC3 rearrangement which is mutually exclusive clinical outcome measures were excluded. The search with MET and EGFR alterations. FGFR3 overex- was complemented by additional sources, mainly pression may be detected by immunohistochemistry the reference lists of evaluated studies and meet- (IHC) while fusions and mutations could be detected ing abstracts. From clinical.gov database, the search by in situ hybridization methods (fluorescence FISH was performed using the following terms: “Can- or chromogenic-CISH) as well as quantitative real- T. Ibrahim et al. / FGFR3 Inhibitors in Urothelial Cancers 89 Fig. 1. FGFR signaling pathways. Fig. 2. FGFR3 gene alterations. 90 T. Ibrahim et al. / FGFR3 Inhibitors in Urothelial Cancers time PCR, targeted sequencing, and NGS [22, 23]. of metabolic responses that drive mitochondrial However, these techniques may be limited by intra- metabolism [29]. tumor heterogeneity and results may vary according to the segment and the type of tissue obtained at biopsy [23]. Detecting genomic alterations in circu- CLINICAL FEATURES ASSOCIATED lating tumor DNA (ctDNA) may be an alternative WITH FGFR3 GENE ALTERATION solution to overcome this barrier [23]. The prognostic value of FGFR3 alterations in UC is still unclear, as some studies have shown no asso- DYSREGULATION OF FGFR SIGNALING ciation between FGFR3 gene alterations and tumor IN UC recurrence or patient survival [30, 31], while others retrospective studies showed that FGFR3 mutations Aberrant FGFR3 alterations have been described are associated with lower risk of progression [32]. In in 15-20% and up to 60% of MIBC and non-muscle very early disease, the frequency of FGFR3 muta- invasive bladder cancer (NMIBC), respectively [13, tions is highest [24]. In stage Ta tumors, several 24]. Mutations represent nearly 70% of the alter- studies indicate that those with mutations appear at ations, rearrangements 20%, and overexpression 10% lower risk of recurrence and progression [30, 31]. (Fig. 2 & 3). The most common mutations involve Similarly, in stage T1 tumors, favorable outcome is exon 7 and 10 and are: S249C (60%), Y375C associated with the presence of mutations
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