(UroToday.com) The 2023 ESMO annual meeting included a session on urothelial carcinoma, featuring a presentation by Dr. James Catto discussing results of THOR-2 cohort 1, assessing erdafitinib versus intravesical chemotherapy in patients with high-risk NMIBC with select FGFR alterations who received prior BCG treatment. Indeed, treatment options are limited for patients with high risk NMIBC who have recurrence after BCG treatment and are ineligible for/refuse radical cystectomy. Standard of care for patients with high risk NMIBC is complete TURBT followed by intravesical BCG, but after adequate BCG treatment, recurrence is frequent (12%-78%) and progression rates are high (up to 46%). Radical cystectomy is the standard of care for patients with high risk NMIBC who have recurrence after BCG, however, it is associated with high morbidity, mortality, and significant impact on quality of life.
FGFR alterations are commonly detected in NMIBC and may function as oncogenic drivers. This includes 60%-70% of patients with low risk NMIBC having an FGFR alteration and >= 30% of patients with high risk papillary NMIBC having an FGFR alteration. Previously, erdafitinib, an oral selective pan-FGFR tyrosine kinase inhibitor, demonstrated an overall survival benefit over chemo in the phase 3 THOR study in patients with locally advanced/metastatic urothelial carcinoma with FGFR alterations.1 At the 2023 ESMO annual meeting, Dr. Catto and colleagues reported the first randomized data in patients with recurrent, BCG-treated high risk NMIBC with FGFR alterations from Cohort 1 of THOR-2.
Adult patients with recurrent, BCG-treated, papillary-only high risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing/ineligible for radical cystectomy were randomized 2:1 to 6 mg oral erdafitinib or investigator’s choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint for this trial was recurrence-free survival (RFS), and secondary endpoints included RFS rate at 6 and 12 months and safety. The trial design for THOR-2 cohort 1 is as follows:
Importantly, THOR-2 used a novel definition for BCG-experienced high risk NMIBC to address the BCG shortages:
At study initiation, the erdafitinib dose was 8 mg daily with pharmacodynamically guided uptitration to 9 mg daily, aligned with the approved dose in locally advanced and metastatic urothelial carcinoma. Of the first 4 patients treated with this regimen, there were 3 that interrupted erdafitinib for grade 2 toxicities, and 2 that discontinued secondary to adverse events. Ultimately, this highlights the low acceptability for systemic toxicity in patients with NMIBC. The IMDC reviewed the safety data from the first 4 patients treated with erdafitinib and recommended changing the dose to 6 mg daily (without uptitration) to maintain activity while preventing treatment discontinuation. The 6 mg daily dose had previously shown antitumor activity in patients with metastatic disease in the 6 mg dose cohort of the BLC2001 study.1
There were 73 patients (median age: 69 years) randomized to erdafitinib (n = 49) and chemo (n = 24), however, study enrollment was discontinued because of slow accrual. The baseline demographics are as follows:
The median follow-up was 13.4 months for both groups, and median RFS was not reached for erdafitinib and was 11.6 months for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.10-0.60):
The 6- and 12-month RFS rates were 96% and 77% for erdafitinib, compared to 73% and 41% for chemotherapy, respectively. Additionally, erdafitinib demonstrated a consistent RFS benefit across subgroups, specifically tumor stage and prior BCG (experienced versus unresponsive):
Grade 3-4 treatment-related adverse events occurred in 19 (38.8%) and 4 (17.4%) patients with erdafitinib and chemotherapy, respectively, and 14 (28.6%) and 0 patients had treatment-related adverse events leading to discontinuation of erdafitinib and chemotherapy, respectively. Central serous retinopathy occurred in 19 patients (38.8%) with erdafitinib (Grade 1-2, 17 patients) and resolved in 11 patients (58%).
Dr. Catto concluded his presentation discussing results of THOR-2 cohort 1, assessing erdafitinib vs intravesical chemotherapy in patients with high-risk NMIBC with select fibroblast growth factor receptor alterations who received prior BCG treatment with the following take-home points:
- 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
- Despite a lower dose, oral erdafitinib tolerability was challenging in this population
- Targeted therapy is a valid approach in the NMIBC population
- This study makes the case for wider biomarker testing in NMIBC and also shows it is possible to randomize to two arms in this setting
- To limit toxicity, there is a need for new locally delivered targeted therapies in NMIBC – TAR-210 is an intravesical drug delivery system designed to provide local, sustained release of erdafitinib within the bladder and is being evaluated in patients with FGFR-altered high risk and intermediate risk NMIBC
Dr. Catto noted that this trial was concomitantly published in Annals of Oncology.2
Presented by: James W. Catto, MB, ChB, FRCS(Urol), PhD, FRSB, University of Sheffield, Sheffield, United Kingdom
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
References:
- Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2019 Jul 25;381(4):338-348.
- Catto JWF, Tran B, Roupret M, et al. Erdafitinib in BCG-treated high-risk non-muscle invasive bladder cancer. Ann Oncol. 2023 Oct 21 [Epub ahead of print].