Results from the Phase 2 randomized, open-label THOR-2 study evaluating erdafitinib (Balversa®; Janssen Biotech), a small molecule inhibitor of fibroblast growth factor receptor (FGFR), versus investigator choice of intravesical chemotherapy in patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) and select fibroblast growth factor receptor (FGFR) alterations which recurred after Bacillus Calmette-Guérin (BCG) therapy, reduced the risk of disease recurrence or death compared with intravesical standard-of-care chemotherapy.
High-risk non-muscle-invasive bladder cancer (HR-NMIBC) is a type of non-invasive bladder cancer that is more likely to recur or spread beyond the lining of the bladder, called the urothelium, and progress to invasive bladder cancer compared to low-risk NMIBC. HR-NMIBC makes up 15–44% of patients with NMIBC and is characterized by a high-grade, large tumor size, presence of multiple tumors, and CIS. Radical cystectomy is currently recommended for NMIBC patients who fail BCG therapy, with over 90% cancer-specific survival if performed before muscle-invasive progression. Given that NMIBC typically affects older patients, many may be unwilling or unfit to undergo radical cystectomy. The high rates of recurrence and progression can pose significant morbidity and distress for these patients.
Novel treatment option
Erdafitinib is a once-daily, oral FGFR kinase inhibitor that received accelerated approval in 2019 for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) which has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Patients are selected for therapy based on an FDA-approved companion diagnostic for erdafitinib. The companion diagnostic, QIAGEN therascreen® FGFR RGQ Reverse-transcription (RT)-polymerase chain reaction (PCR) Kit, is the first PCR-based companion diagnostic approved to detect FGFR alterations.
The therascreen® FGFR test detects the presence of FGFR alterations in the tumor tissue of patients with mUC. If one or more of the genetic alterations or fusions are detected, the patient may be a candidate for treatment with erdafitinib.
THOR 2 (NCT04172675) is a Phase 2 randomized, open-label study evaluating erdafitinib versus investigator choice of intravesical chemotherapy in participants with NMIBC who recurred after BCG therapy. Patients are categorized to one of three cohorts based on their disease presentation: patients with HR-NMIBC and a papillary tumor only, where early cancer cells are still confined within the innermost layer of the bladder lining (Cohort 1), patients with HR-NMIBC presenting as carcinoma in situ (CIS) with or without a concurrent papillary tumor (Cohort 2), or patients with intermediate-risk NMIBC presenting with papillary disease only (Cohort 3). Patients in Cohort 1 are randomized to receive either erdafitinib or chemotherapy (mitomycin C or gemcitabine) in a 2:1 ratio and all patients in Cohorts 2 and 3 will receive erdafitinib. The Cohort 1 primary endpoint is RFS; secondary endpoints include RFS at six- and 12-months, time to progression, overall survival, plasma concentration of erdafitinib and number of patients with adverse events. The study consists of screening period, treatment phase, follow-up phase and long-term extension phase.
Data from Cohort 1 of the study were featured today in a Proffered Paper Late-Breaking Session (Abstract #LBA102) at the European Society for Medical Oncology (ESMO) 2023 Congress taking place October 20-24, 2023 in Madrid, Spain, and simultaneously published in Annals of Oncology.
Of the 73 participating patients included in Cohort 1, 49 patients were randomized to erdafitinib while 24 patients were randomized to chemotherapy. Oral erdafitinib reduced the risk of recurrence of disease or death by 72% compared with intravesical chemotherapy in patients with high-risk resected papillary Ta/T1 NMIBC harboring FGFR mutations or fusions with recurrence after BCG treatment and who refused or were ineligible for radical cystectomy.
With a median follow-up of 13.4 months at the data cutoff, median recurrence-free survival (RFS) was not met in patients who received erdafitinib and was 11.6 months for patients who received chemotherapy (Hazard Ratio [HR]=0.28; 95% Confidence Interval [CI], 0.13-0.62; nominal p=0.0008). The six-month RFS in patients randomized to erdafitinib was 96% compared to 73% in those assigned to chemotherapy. The 12-month RFS in patients assigned to erdafitinib was 77% compared to 41 percent in patients who received chemotherapy.
Grade 3 or 4 serious treatment-related adverse events (TRAEs) were observed in fifteen patients (31%) who received erdafitinib and one patient (4%) randomized to chemotherapy. A total of fourteen patients (29%) assigned to erdafitinib and zero patients who received intravesical chemotherapy had TRAEs that lead to discontinuation of treatment. Central serous retinopathy occurred in 19 patients (39%) who received erdafitinib and resolved in 11 patients (58%).
In addition to the Phase 2 THOR-2 study, erdafitinibis being studied in the Phase 3 THOR (NCT03390504) study comparing erdafitinib in two cohorts; erdafitinib versus standard of care chemotherapy (investigators choice of docetaxel or vinflunine) after at least one line of treatment including an anti-programmed death (ligand) 1 (PD-[L]1) agent (Cohort 1); and erdafitinib compared to pembrolizumab after one prior treatment not containing an anti-PD-(L)1 agent (Cohort 2) in patients with metastatic or unresectable urothelial carcinoma, with selected FGFR genetic alterations, who showed disease progression during or after one or two prior lines of treatment.
“Patients with NMIBC who experience disease recurrence after BCG treatment have limited treatment options, and those eligible patients with FGFR alterations who received erdafitinib in the THOR-2 trial had far fewer recurrences against patients treated by the current standard of care,” said James W.F. Catto, Ph.D., Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK and presenting author of the study.
“Our findings underscore the importance of detecting certain genetic biomarkers to identify patients who may benefit from treatment with a targeted therapy like erdafitinib,” Catto added.
“Janssen’s ongoing development of erdafitinib reinforces our commitment to bringing targeted, precision medicines to patients with FGFR-driven bladder cancer,” said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC.
“These results support the importance of testing for FGFR in early-stage bladder cancer and potential benefit with erdafitinib in patients with high-risk non-muscle-invasive bladder cancer where disease progression and poor outcomes are common,” Patel further noted.
In August 2023, Janssen submitted a Supplemental New Drug Application to the U.S. Food and Drug Administration seeking the full approval of erdafitinib based upon data from Cohort 1 Phase 3 THOR study. The Company also submitted a marketing authorization application to the European Medicines Agency in September 2023.
A Study of Erdafitinib in Participants With Advanced Solid Tumors and Fibroblast Growth Factor Receptor (FGFR) Gene Alterations. ClinicalTrials.gov ID [NCT04083976]
A Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Participants With Advanced Urothelial Cancer and Selected Fibroblast Growth Factor Receptor (FGFR) Gene Aberrations (THOR) ClinicalTrials.gov ID [NCT03390504]
A Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in Participants Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) ClinicalTrials.gov ID [NCT04172675]
Highlights of Prescribing Information
Erdafitinib (Balversa®; Janssen Biotech) [Prescribing information]
 Grab-Heyne K, et al. Intermediate and high-risk non-muscle-invasive bladder cancer: an overview of epidemiology, burden, and unmet needs. Front Oncol. 2023;13:1170124.
 Lieblich A, et al. The management of non-muscle-invasive bladder cancer: A comparison of European and UK guidelines. J Clin Urol. 2018;11(2):144-148.
 Claps F, et al. BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets. Int J Mol Sci. 2023;24(16):12596.
 Brooks NA, O’Donnell MA. Treatment options in non-muscle-invasive bladder cancer after BCG failure. Indian J Urol. 2015;31(4):312-319. doi:10.4103/0970-1591.166475.
 Guancial EA, et al. Bladder cancer in the elderly patient: challenges and solutions. Clin Interv Aging. 2015; 10:939–949.
 Chamie K, et al. Recurrence of high-risk bladder cancer: A population-based analysis. Cancer. 2013. 119(17):3219–3227.
 Catto J, et al. THOR-2 Cohort 1: Results of Erdafitinib (Erda) vs Intravesical Chemotherapy (Chemo) in Patients (Pts) With High-Risk Non–Muscle-Invasive Bladder Cancer (HR NMIBC) With Select Fibroblast Growth Factor Receptor Alterations (FGFRalt) Who Received Prior Bacillus Calmette-Guérin (BCG) Treatment. 2023 European Society for Medical Oncology Congress. Presented at the 2023 European Society for Medical Oncology Congress.
 Catto J, et al. Erdafitinib in BCG-treated high-risk non-muscle invasive bladder cancer. Annals of Oncology. Published online: October 20, 2023. [Article]
 U.S. Food & Drug Administration. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. Online. Last accessed on October 20,2023..
 ASCO Publications. Phase 3 THOR study: Results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). Online. Last accesses on October 20, 2023.
Featured image: Doctor talking a with patient in hospital exam room. Photo courtesy: 2019 Fotolia/Adbobe.