Novel interventions show promise for bladder cancer
Two novel intravesical agents, cretostimogene grenadenorepvec and sustained-release intravesical gemcitabine, show significant clinical activity and excellent safety in non-muscle invasive bladder cancer (NMIBC). Both agents have been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration.
Cretostimogene grenadenorepvec, a highly immunogenic adenovirus, showed 75.5% complete response (CR) in cohort 3 of the phase 3 BOND-003 study of patients with BCG-unresponsive NMIBC with carcinoma in situ.
TAR-200, an intravesical device for sustained gemcitabine delivery, showed 82.4% complete response in BCG-unresponsive NMIBC in SunRISe-1. Initial results for papillary-only MNIBC from the same trial showed 81.1% nine-month disease-free survival (DFS).
The three Practice-Changing, Paradigm-Shifting (P2) Clinical Trials in Urology were presented during the Saturday morning Plenary session.
Mark Tyson, MD, MPH
“These data mark an important advancement for patients with this disease who are unwilling or unable to undergo radical cystectomy,” said Mark Tyson, MD, MPH, associate professor of urology at Mayo Clinic Alix School of Medicine. “Importantly to patients (in BOND-003), 97% remain progression-free and 84.5% avoided cystectomy.”
Cretostimogene is an oncolytic immunotherapy that selectively targets Rb-E2F pathway-altered cancers. Viral replication results in tumor lysis while sparing healthy tissue and primes a tumor-specific immune response in the tumor microenvironment.
Dr. Tyson noted that the dual mechanism of action is both highly effective and well-tolerated. Nearly all patients, 97.3%, completed all protocol-defined treatments, and there were no treatment-related discontinuations or Grade ≥3 treatment-related adverse events (TRAEs) or deaths. The most common adverse events (AEs) were bladder spasm, pollakiuria and urgency, all Grade 1 or 2.
Dr. Tyson said the first results from Cohort P in high-grade disease showed 90.5% recurrence-free survival with a consistent safety profile. More detailed results will be reported in the Learning Lab on Monday.
Patients with high-risk BCG-unresponsive NMIBC currently have few options, at least in the U.S.: pembrolizumab, 41% CR; nadofaragene firadenovec, 51% CR; or nogapendekin alfa inbakicept + BCG, 62% CR.
Joseph Jacob, MD, MCR
“The overall CR for TAR-200 monotherapy was 82.5%. This is the highest CR rate reported to date,” said Joseph Jacob, MD, MCR, associate professor of urology, SUNY Medical University. “These CRs were rapid, with a median onset of 2.8 months. The responses remain consistently high across all patient subgroups, including those with and without papillary disease.”
Quality of life was consistent throughout treatment, Dr. Jacob said. Office-based insertion via catheter was 99% successful, and most adverse events were Grade 1-2. Five patients had TRAEs, and three patients discontinued due to TRAEs.
TAR-200 is currently under review by the FDA, he reported, and the manufacturer has launched a preapproval access program in the U.S.
The sustained-release gemcitabine device showed even more robust results in the first 24 patients in a cohort with high-risk papillary-only BCG-unresponsive NMIBC. Of the 650,000 bladder cancers diagnosed annually, 75% have NMIBC and half are high-risk.
After a median follow-up of 12.8 months, the six-month DFS was 85.3%, and the nine-month DFS was 81.5 %. DFS was consistently high across Ta and T1 disease.
“The median disease-free survival was not reached,” said Felix Guerrero-Ramos, MD, PhD, FEBU, coordinator of urologic oncology and bladder cancer at 12 de Octubre University Hospital in Madrid, Spain. “Only three patients had to undergo a radical cystectomy.”
Overall survival at nine months was 95.6% with no new safety signals, Dr. Guerrero-Ramos said. Most AEs were Grade 1-2 lower urinary tract symptoms and resolved rapidly.
A phase 3 SunRISe-5 study of TAR-200 vs. intravesical chemotherapy in a larger cohort is ongoing, he added. Additional information on TAR-200 will be available on Monday in the Learning Lab.
