The future of bladder cancer therapy: Optimizing the inhibition of the fibroblast growth factor receptor

Highlights

• Targeted therapies in advanced/metastastic bladder cancer have significant challenges due to molecular heterogeneity.

• FGFRs have been considered as promising drug targets for the therapy of various cancers, including advanced/metastatic bladder cancer.

• Several inhibitors targeting FGFRs are in development.

• Erdafitinib has been approved by FDA as a therapy for metastatic BC in patients who have progressed to platinum-based chemotherapy.

Abstract

Therapeutic options for metastatic bladder cancer (BC) have seen minimal evolution over the past 30 years, with platinum-based chemotherapy remaining the mainstay of standard of care for metastatic BC. Recently, five immune checkpoint inhibitors (ICIs) have been approved by the FDA as second-line therapy, and two ICIs are approved as first-line treatment in selected patients. Molecular alterations of muscle-invasive bladder cancer (MIBC) have been reported by The Cancer Genome Atlas. About 15% of patients with MIBC have molecular alterations in the fibroblast growth factor (FGF) axis. Several ongoing trials are testing novel FGF receptor (FGFR) inhibitors in patients with FGFR genomic aberrations. Recently, erdafitinib, a pan-FGFR inhibitor, was approved by the FDA in patients with metastatic BC who have progressed on platinum-based chemotherapy. We reviewed the literature over the last decade and provide a summary of current knowledge of FGF signaling, and the prognosis associated with FGFR mutations in BC. We cover the role of FGFR inhibition with non-selective and selective tyrosine kinase inhibitors as well as novel agents in metastatic BC. Efficacy and safety data including insights from mechanism-based toxicity are reported for selected populations of metastatic BC with FGFR aberrations. Current strategies to managing resistance to anti-FGFR agents is addressed, and the importance of developing reliable biomarkers as the therapeutic landscape moves towards an individualized therapeutic approach.

Introduction

Bladder cancer (BC) is a major global health challenge with 549,393 new cases and nearly 200,000 deaths during 2018 [1]. In 2018, estimated BC incidence and mortality in Europe were 197,100 and 65,000 cases, respectively [2]. Urothelial carcinoma (UC) is the most common histologic subtype of BC and represents nearly 90% of all cases. Other less common subtypes are squamous cell carcinoma, adenocarcinoma, and small cell carcinoma [3]. Around 30% of cases are diagnosed as muscle-invasive bladder cancer (MIBC) and most are locally advanced or metastatic at diagnosis, requiring systemic treatment [4].

The initial The Cancer Genome Atlas (TCGA) analysis in 131 BCs identified several targetable genomic alterations in 69% of the tumors [5]. More recently, a cohort of 412 chemotherapy-naïve MIBC tumors from the TCGA project was reported [6]. About 70% of all mutations were due to apoliprotein B mRNA editing catalytic polypeptide-like (APOBEC) mediated mutagenesis [7]. The analysis identified 58 significantly-mutated genes, the most frequent being TP53, PI3K, KRAS, FGFR, ERBB2, RB1, ELF3 and chromatin-modifying genes such as MLL2, ARID1A and KDM6A [5]. According to the TCGA study, FGFR3 is altered in approximately 12% of cases. Using mRNA sequencing data from 408 tumors, the TCGA defined BC into five mRNA expression-based subtypes [5]: luminal-papillary (defined by FGFR3 mutations, TACC3 fusions, and low progression risk), luminal-infiltrated (fibroblastic and immune marker expression), luminal (KRT20 and SNX31 expression), basal-squamous (female preponderance and immune marker expression) and neuronal (neuroendocrine gene expression and high proliferation signatures). High mutation load was more commonly found in APOBEC-high tumors and chromatin regulatory in DNA damage response gene, while APOBEC-low tumors were associated with mutations in FGFR3 and KRAS. APOBEC-high tumors were associated with better overall survival (OS) compared to APOBEC-low tumors [5], [6].

A wealth of preclinical studies in BC cell lines and xenograft models have confirmed that FGFR alterations confer sensitivity to FGFR inhibitors, forming the basis for the clinical development of FGFR3 inhibitors in selected patients with BC harboring FGFR dysregulations.

We performed a literature review to identify preclinical and clinical advances with inhibitors of the FGF signaling pathway in BC over the last decade. An overview of the FGF/FGFR axis is presented along with the current clinical status of FGFR inhibitors that represent potential novel therapeutic drugs targeting the FGFR pathway. We also describe potential mechanisms for primary or secondary resistance and discuss mechanism-based toxicity in targeting the FGFR pathway.