Preliminary data from ongoing trials indicate promising results for novel therapies in treating non-muscle-invasive bladder cancer (NMIBC). Detalimogene voraplasmid (EG-70), a non-viral intravesical gene therapy, and gemcitabine-based combinations are showing significant efficacy and tolerable safety profiles in different NMIBC patient populations.
Detalimogene Voraplasmid (EG-70) in BCG-Unresponsive NMIBC
The phase 2 LEGEND trial (NCT04752722) evaluated detalimogene voraplasmid in patients with Bacillus Calmette-Guérin (BCG)-unresponsive NMIBC with carcinoma in situ (CIS). The study reported an any-time complete response (CR) rate of 71% among evaluable patients (n = 21). Specifically, the 3-month CR rate was 67%, and the 6-month CR rate was 47%. Kaplan-Meier analysis estimated a 6-month CR rate of 51%.
According to Dr. John Arthur Taylor, the treatment-related adverse events (TRAEs) were largely consistent with instrumentation and intravesical administration, with no grade 3 or higher TRAEs reported. Common TRAEs included bladder spasm (19.0%), dysuria (21.4%), and fatigue (11.9%), all of which were reversible.
Shreyas S. Joshi, MD, MPH, highlighted that EG-70 delivers genetic material into bladder cells via a nanoparticle, potentially benefiting patients who cannot receive adenoviral-based therapies. The ongoing trial aims to provide a bladder-sparing option for patients who have failed BCG treatment.
Gemcitabine and Docetaxel in BCG-Naive NMIBC
In BCG-naive, high-risk NMIBC patients, a phase II trial of sequential gemcitabine and docetaxel demonstrated a 100% complete response rate at three months and 92% at twelve months. The treatment involved weekly induction therapy for six weeks, followed by monthly maintenance for two years in responders.
Dr. Sunil Patel and Dr. Max Kates from Johns Hopkins University presented this data, noting that no patients were upstaged to T2, underwent cystectomy, or developed clinical, nodal, or metastatic lesions. Grade 3 adverse events occurred in approximately 20% of patients, with no grade 4 or 5 events. The safety profile was comparable to that of BCG.
Max Kates emphasized the logistical aspects, noting that while gemcitabine/docetaxel requires slightly longer chair time, the chemotherapy drugs are more straightforward for the pharmacy to mix compared to BCG. The combination's effectiveness may stem from different mechanisms of action, as combination therapies have historically shown better outcomes than monotherapies in oncology.
Gemcitabine-BCG Combination in BCG-Exposed NMIBC
For BCG-exposed NMIBC, a combination of gemcitabine and BCG showed promising early oncological efficacy and safety. A phase 2 trial presented by Dr. Gal Wald at the Society of Urologic Oncology (SUO) 25th Annual Meeting reported a complete response rate of 98% at 3 months, 94% at 6 months, and 81% at 12 months.
The study included patients with high-grade Ta, T1, and/or CIS disease within 24 months of prior BCG exposure. The treatment regimen consisted of gemcitabine 2000 mg twice weekly and BCG TICE strain 50 mg weekly, followed by SWOG maintenance BCG for patients without high-grade recurrence.
Treatment-related adverse events were primarily grade 1 or 2, with only 5% of patients experiencing a grade 3 event (urinary tract infection or BCG-related pneumonitis). Based on these findings, a phase 3 randomized trial (GAIN) is scheduled to open in May 2025.
The Evolving Treatment Landscape
These studies collectively highlight the evolving treatment landscape for NMIBC, with a focus on bladder-sparing approaches and improved patient outcomes. As BCG shortages and tolerability issues persist, novel therapies and combination strategies offer hope for patients seeking alternatives to radical cystectomy. Further research and larger phase 3 trials are crucial to validate these findings and establish new standards of care.
