Elsevier

The Lancet Oncology

Volume 23, Issue 2, February 2022, Pages 248-258
The Lancet Oncology

Articles
Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study

https://doi.org/10.1016/S1470-2045(21)00660-4Get rights and content

Summary

Background

Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study.

Methods

The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597.

Findings

Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths.

Interpretation

With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.

Funding

Janssen Research & Development.

Introduction

Until the past decade, after failure of platinum-based chemotherapy, second-line treatment options for patients with advanced urothelial carcinoma have been scarce, with poor activity and response rates that range from 10% to 20%.1, 2 Erdafitinib is a potent and selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor3 that has been approved in Brazil, Canada, Chile, Hong Kong, Israel, Jordan, Peru, Taiwan, Thailand, Saudi Arabia, Singapore, and the USA4 to treat adults with locally advanced or metastatic urothelial carcinoma with FGFR3/2 alterations who progressed during or after one or more lines of previous platinum-based chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy. The National Comprehensive Cancer Network guidelines5 for bladder cancer recommend erdafitinib as a second-line treatment option for patients with locally advanced or metastatic urothelial carcinoma following platinum-based therapy. The European Association of Urology guidelines6 include FGFR inhibitors, such as erdafitinib, as promising therapies for second-line or later treatment of metastatic urothelial carcinoma and, although erdafitinib is not yet approved by the European Medicines Agency, it is included in the European Society for Medical Oncology guidelines.7

Research in context

Evidence before this study

We searched PubMed for clinical trials of fibroblast growth factor receptor (FGFR) inhibitors used to treat patients with urothelial cancer or bladder cancer, using the terms “bladder cancer” OR “urothelial cancer” AND “fibroblast growth factor receptor,” published from Jan 1, 2010, to Jan 1, 2021, with limits for clinical trials and no language restrictions. At the time of the initial protocol approval for the phase 2 BLC2001 study of erdafitinib (Jan 19, 2015), our searches identified one published report of a clinical trial of an FGFR inhibitor (dovitinib in combination with gemcitabine plus cisplatin or carboplatin) in patients with advanced solid tumours, in which the combination was poorly tolerated. At that time, systemic treatment for metastatic urothelial carcinoma was generally unsatisfactory and had remained unchanged for several decades. More recently, approved anti-PD-(L)1 agents provided a small improvement in response rates over traditional chemotherapy and were accompanied by immune-related adverse events that were potentially serious and sometimes fatal. Differential responses to anti-PD-(L)1 agents have been observed in different bladder cancer subtypes based on gene expression and histopathology and their underlying immune microenvironment. The primary analysis of BLC2001 was published in 2019 and, on the basis of these data, erdafitinib was the first targeted therapy approved by the US Food and Drug Administration for treatment of patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. Erdafitinib is now included in the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines as an option for second-line treatment of patients with locally advanced or metastatic urothelial cancer.

Added value of this study

Our findings show that, with longer follow-up, erdafitinib treatment continues to show consistent clinical benefits for patients with locally advanced or metastatic urothelial cancer who have tumours with specific FGFR alterations, and that erdafitinib has a manageable safety profile.

Implications of all the available evidence

The long-term follow-up of this study confirms the benefit of erdafitinib, an FGFR inhibitor, for the treatment of patients with locally advanced or metastatic urothelial cancer and specific FGFR alterations. Further research, in a randomised, controlled, phase 3 study in patients with advanced urothelial cancer, is ongoing to evaluate erdafitinib as second-line monotherapy compared with a PD-1 inhibitor or chemotherapy. Another study is ongoing to evaluate erdafitinib in combination with a PD-1 inhibitor (cetrelimab) in first-line treatment of patients with metastatic urothelial carcinoma who are ineligible for cisplatin.

Erdafitinib was approved by various regulatory authorities on the basis of the results of an open-label phase 2 study (BLC2001) in patients with locally advanced and unresectable or metastatic urothelial carcinoma and prespecified FGFR3/2 alterations.8 Participants had disease progression during or after one or more lines of previous chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy.8 On the basis of results from a planned interim analysis, the selected schedule of erdafitinib was once daily 8 mg/day continuously, with the possibility of pharmacodynamically guided uptitration to 9 mg (henceforth 8 mg/day UpT).8 In the primary analysis, erdafitinib was associated with an investigator-assessed objective tumour response in 40 (40%; 95% CI 31–50) of 99 patients in the selected regimen group;8 all responses were confirmed. Additionally, at a median follow-up of 11·2 months (IQR 8·2–15·6), median progression-free survival was 5·5 months (95% CI 4·2–6·0) and, at a median follow-up of 11·0 months (IQR 8·5–14·1), median overall survival was 13·8 months (95% CI 9·8–not reached [NR]).8 Treatment-related adverse events of grade 3 or worse were reported in 45 (46%) of 99 patients at the time of the primary analysis.8

We aimed to assess the longer-term efficacy and safety of the selected regimen of erdafitinib among patients treated in the BLC2001 study.

Section snippets

Study design and participants

The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America (appendix pp 2–3). As described previously,8 eligible patients were aged 18 years or older, with locally advanced and unresectable or metastatic urothelial carcinoma; measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; at least one FGFR3 mutation or FGFR2/3 fusion, as listed in a prespecified panel,

Results

Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen (60 patients received 8 mg/day and 41 patients were uptitrated to 9 mg/day; appendix p 6, table 1). Of the 101 patients who were treated with the 8 mg/day UpT regimen, two died due to progressive disease before the first disease evaluation after the baseline assessment.

At the clinical cutoff date for this analysis (Aug 9, 2019),

Discussion

In this analysis of the BLC2001 study, with a median efficacy follow-up of 24·0 months, treatment with erdafitinib showed consistent efficacy in patients with locally advanced or metastatic urothelial carcinoma and FGFR alterations, in keeping with the primary analysis (median follow-up of about 11 months).8 There were no new safety signals with a median treatment exposure of 5·4 months. The confirmed investigator-assessed objective response rate was 40% (95% CI 30–49), with promising

Data sharing

Janssen Pharmaceutical Companies of Johnson & Johnson's data sharing policy is available at https://www.janssen.com/clinical-trials/transparency. As noted on this website, requests for study data access can be submitted through the Yale Open Data Access Project website at http://yoda.yale.edu.

Declaration of interests

EFB has received grants or contracts from Pfizer and Astellas Pharma; honoraria from Exelixis and Bayer; and stocks or stock options from Exelixis, Becton Dickinson, Calithera Biosciences, Gilead Sciences, Medtronic, Clovis Oncology, and Macrogenics, outside of the submitted work. ID has received grants or contracts from Roche/Genentech, AstraZeneca, and Astellas Pharma; consulting fees from Roche/Genentech, MSD Oncology, Bayer, Bristol Myers Squibb, Seattle Genetics, Pharmacyclics Janssen

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  • Cited by (0)

    Members are listed in the appendix (pp 2–3)

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