(UroToday.com) At the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) session on optimizing personalized management of non-muscle invasive bladder cancer included a debate regarding the optimal therapy for BCG-unresponsive disease among patients that are not cystectomy candidates. Dr. Peter Black from Vancouver, British Columbia made the argument for intravesical therapy as the optimal treatment.
To start, Dr. Black reminds us that the standard treatment for BCG-unresponsive non-muscle invasive bladder cancer is still radical cystectomy. However, many patients are ineligible for radical cystectomy, many prefer bladder-preserving therapy, and many urologists offer bladder-preserving therapy.
There are plenty of intravesical treatment options, but the evidence for efficacy is sparse. Specifically, the efficacy for single agent intravesical chemotherapy is poor. In the SWOG S0353 phase II trial, intravesical maintenance gemcitabine was used for BCG refractory non-muscle invasive bladder cancer with a 1-year recurrence free survival rate of only 28%, which decreased to 20% at 2-years.1 The data for gemcitabine/docetaxel combination therapy are promising, but there are currently no trials. Retrospective data published in 2020 from Steinberg et al. [2] assessed outcomes of 276 patients treated with gemcitabine/docetaxel intravesical therapy, finding that the 1- and 2-year recurrence-free survival rates were 60% and 46%, and high-grade recurrence-free survival rates were 65% and 52%, respectively. Furthermore, BCG unresponsive cases with any CIS demonstrated a 50% high-grade recurrence-free survival at 2-years while papillary disease alone cases demonstrated 58% high-grade recurrence-free survival at 2-years:
Among these 276 patients, 10 (3.6%) had disease progression on transurethral resection, and 43 (15.6%) went on to radical cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasive disease. Forty-one percent of patients suffered any adverse event and 9% had to have a modified treatment schedule secondary to adverse events.
Device-assisted intravesical therapy has also been of recent interest. The HYMN phase III randomized controlled trial compared disease-free survival time between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy in NMIBC patients with recurrence following induction/maintenance BCG [3]. Patients were randomly assigned (1:1) to RITE (60min, 40mg mitomycin-C, 42 ± 2°C) or standard second-line therapy. There were 104 patients randomized (48 RITE arm versus 56 control arm) with a median follow-up for 31 patients without a disease-free survival event of 36 months. There was no significant difference in disease-free survival between treatment arms (HR 1.33, 95% CI 0.84-2.10) or in 3-month complete response rate in CIS patients (n=71; RITE 30% versus control: 47%, p=0.15). With regards to electromotive mitomycin-C there is good clinical trial evidence in the BCG-naïve setting, but limited evidence for treatment of recurrence after BCG.
However, Dr. Black notes that there are several novel intravesical therapies:
In the context of these novel agents it is important to remember that clinical trials focus on BCG-unresponsive CIS (with or without high-grade Ta/T1) and current/pending approvals are for CIS. The VISTA trial assessed efficacy of oportuzumab monatox, which had an induction phase of twice weekly treatment during weeks 1-6, followed by once weekly treatment during weeks 7-12. For responders, the maintenance delivery was every other week up to week 104. Among 93 patients with CIS, 40% had a complete response at 3 months, with a 12 month complete response rate of 17%. Dr. Black notes that FDA priority review for this treatment regimen is currently ongoing.
Nadofaragene firadenovec is a non-replicating recombinant type-5 adenovirus vector-based gene therapy that delivers a copy of the human IFNα2b gene. The Phase III trial of nadofaragene firadenovec for BCG unresponsive NMIBC was a multi-center study to investigate the safety and efficacy of intravesical nadofaragene firadenovec 75 mL once every 3 months in 157 patients with high-grade, BCG-unresponsive NMIBC. Cytology and cystoscopy (with biopsy if clinically indicated) were performed at 3, 6, and 9 months to evaluate for recurrence of high-grade disease. At 12 months, all patients underwent urine cytology, cystoscopy, and mandatory biopsy. Patients free from high-grade recurrence were eligible for retreatment at 3-month intervals while they remained high-grade recurrence free. The study met its primary endpoint with 53.4% of patients with CIS ±Ta/T1 achieving a complete response, all by 3 months, including 43.6% of these patients remaining free of high-grade recurrence at 15 months. This study was recently published in Lancet Oncology [4]. Dr. Black notes that FDA priority review for nadofaragene firadenovec is also currently ongoing.
Dr. Black then provided the following cross-trial comparison table for intravesical versus systemic therapies in the BCG-unresponsive disease space, noting that atezolizumab does not have 12-month complete response rate data, and also highlighting that systemic therapy grade 3-5 treatment related adverse events are much higher than compared to intravesical therapy:
Given that efficacy between these agents is quite comparable, treatment selection comes down to other factors such as easy of delivery, absence of contraindications, safety and perhaps cost, all of which favor nadofaragene firadenovec and oportuzumab monatox, according to Dr. Black. Additionally, 95% of patients in KEYNOTE-057 were cystectomy-eligible and these patients should proceed to salvage cystectomy after treatment failure with novel agents or intravesical chemotherapy. Dr. Black notes that truly ineligible patients will likely benefit from multiple treatment options. Currently, earlier NMIBC trials are being dominated by immunotherapy as noted in the ongoing KEYNOTE-676, CheckMate-7G8, ADAPT-Bladder, Potomac, ALBAN, and CREST trials:
Dr. Black concluded noting that all relevant parameters favor intravesical over systemic therapy for BCG-unresponsive CIS, with rare exceptions being patients that are unable to be catheterized or unable to hold an intravesical agent in their bladder. But, it is important to have other options available.
Presented by: Peter Black, MD, Senior Research Scientist, Vancouver Prostate Centre, Associate Director, Clinical Research, Vancouver Prostate Centre, Professor, Department of Urologic Sciences, University of British Columbia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
References:
- Skinner EC, Goldman B, Sakr WA, et al. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guerin. J Urol2013 Oct;190(4):1200-1204.
- Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020 May;203(5):902-909.
- Tan WS, Panchal A, Buckley L, et al. Radiofrequency-induced thermo-chemotherapy effect versus a second course of Bacillus Calmette-Guerin or Institutional Standard in Patients with Recurrence of Non-muscle-invasive Bladder Cancer Following Induction or Maintenance Bacillus Calmette-Guerin Therapy (HYMN): A Phase III, Open-label, Randomized Controlled Trial. Eur Urol. 2019 Jan;75(1):63-71.
- Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2020 Nov 27:S1470-2045(20)30540-4.