Bladder cancer is the 9th most common malignancy world-wide.1 On April 12, 2019, the U.S. Food and Drug Administration (FDA) approved erdafitinib, a novel personalized treatment targeting genetic alterations of fibroblast growth factor receptor (FGFR) subtypes (FGFR2 or FGFR3).2 This approval has the potential to affect many patients in Hong Kong, where 443 new cases were registered according to the most recent Hong Kong Cancer Registry (HKCaR) data from 2016.3
FGFR genetic alterations are associated with increased tumor growth, metastasis, and angiogenesis.4 For example, FGFR3 mutations were documented in up to 80% of non-muscle-invasive cases of urothelial carcinoma (UC).4 Hence, targeted therapies against key genetic mutations have become a paradigm for certain cancer subtypes. Erdafitinib is an orally administered FGFR tyrosine kinase inhibitor which specifically inhibits FGFR1-4 with minimal non-specific inhibitory activity toward vascular endothelial growth factor receptors (VEGFR) and other related kinases. As a consequence of the FGFR tyrosine kinase inhibition, erdafitinib exhibits anti-proliferative activity which results in potent and dose-dependent tumor reduction.4
A clinical trial published in 2019 first evaluated the safety, pharmacokinetics, and pharmacodynamics of erdafitinib which showed good tolerability and encouraging clinical activity (NCT01703481).5 Eligible adult patients with advanced solid tumors for which standard antineoplastic therapy was no longer effective were included in the study.5 187 patients (72%) had an identifiable FGFR alteration, the most common being FGFR mutations and fusions.5 Evidence of antitumor activity was seen in FGFR mutation- and fusion-positive UC, with an objective response rate (ORR) of 46.2%.5 For the safety assessment based on physical examination, eye exam, vital signs, ECOG performance status, hematology/biochemistry, and electrocardiography (ECG), the profile was found to be tolerable, manageable, and consistent with expected treatment-related adverse events for a potent and selective FGFR inhibitor.5 The most common treatment-related adverse events (TRAEs) were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%).5 The study includes several limitations including the study design aiming to assess dosing, safety and tolerability, in addition to small overall study participant numbers across multiple tumor types.5
More recently, another randomized study has demonstrated the safety and efficacy of erdafitinib in a phase 2 setting (NCT02365597). In this multicenter and open-label study, patients were randomized 1:1 for either 28 day cycles of 6mg/day of continuous dosing or 10mg/day intermittent dosing (7 days on/7 days off), with the dose uptitrated if no significant TRAEs were observed.6 Patients with measurable UC and specific FGFR2/3 mutations or translocations were evaluated for a primary endpoint of ORR.6 In this study confirmed ORRs were 35% and 24%, and disease control rates were 74% and 73% for continuous and intermittent dosing groups, respectively.
The favourable safety profile issued from these studies have helped lead the FDA’s decision to grant accelerated approval to the drug. The FDA has also approved a companion diagnostic using FGFR alterations (Therascreen FGFR Kit) to be used for the accompanying therapeutic indication.2 This new approval will help expand the benefits of personalized immunotherapies to Hong Kong and other populations.
1. Wong MCS, Fung FDH, Leung C, et al. The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection. Sci Rep. 2018;8.
2. Commissioner O of the. FDA approves first targeted therapy for metastatic bladder cancer. FDA. (Accessed May 27, 2019, at http://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-metastatic-bladder-cancer)
3. Hong Kong Cancer Registry, Hospital Authority. (Accessed May 27, 2019, at http://www3.ha.org.hk/cancereg/allagesresult.asp.)
4. Perera TPS, Jovcheva E, Mevellec L, et al. Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor. Mol Cancer Ther. 2017;16(6):1010-1020.
5. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors | Clinical Cancer Research. (Accessed May 27, 2019, at http://clincancerres.aacrjournals.org/content/early/2019/05/14/1078-0432.CCR-18-3334.)
6. Loriot Y, Necchi A, Park SH, et al. Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing. JCO. 2018;36(6_suppl):411-411.