Gene Therapy Promising in BCG-Unresponsive Bladder Cancer

Sara Freeman

August 06, 2020

More than half the patients with high-grade bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC) treated with nadofaragene firadenovec, an investigational intravesical viral gene therapy, achieved a clinical response at 3 months in a phase 3 trial.

The results "provide a significant efficacy benefit that, pending regulatory approval, might offer patients with a difficult-to-treat bladder cancer a bladder-sparing alternative," said Neal Shore, MD, medical director for the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

There is clearly an unmet need for new bladder-sparing treatments in these patients, said Fred Witjes, MD, from the Radboud Institute for Molecular Life Science in Nijmegen, the Netherlands, who discussed trial findings during the virtual European Association of Urology 2020 Congress.

"The drugs that we have are old and there is a limited availability for both MMC [mitomycin-C] and BCG. We need some alternatives for initial adjuvant therapy," he explained. "The unmet need is, of course, especially there in BCG-unresponsive patients or BCG-unresponsive CIS [carcinoma in situ]."

"Clinically appropriate patients with BCG-unresponsive NMIBC are currently faced with radical cystectomy," Shore explained during his presentation at the congress.

Nadofaragene firadenovec is a viral-based gene therapy that consists of a replication-deficient adenovirus that delivers the gene for interferon alpha-2b (IFNα 2b). When administered with the polyamide compound Syn3, the viral vector can deliver the IFNα 2b gene to the epithelial lining of the bladder. The gene is subsequently incorporated into cellular DNA, meaning that large amounts of the IFNα 2b protein can be produced locally.

For their open-label, randomized trial, Shore and his colleagues looked at 157 patients with a mean age around 70 years. All participants had carcinoma in situ or high-grade Ta (noninvasive) or T1 (invasive) papillary disease with or without carcinoma in situ, and all had been unresponsive to standard intravesical treatment with BCG in the previous 12 months.

Nadofaragene firadenovec was administered once every 3 months, for up to four doses in the first year. If patients showed no signs of high-grade disease recurrence at 12 months, they were offered continued treatment.

For patients with high-grade carcinoma in situ, the complete response rate was 53.4% at 3 months and 24.3% at 12 months. For patients with papillary tumors, the response rate was 73.0% at 3 months and 44% at 12 months.

The majority of study participants (72%) received two or three courses of BCG overall; that rate was 68.3% for those with carcinoma in situ and 80.0% for those with papillary disease. Just over half the patients with carcinoma in situ were refractory to BCG, as were 70% of those with papillary disease.

Almost one third of patients will not respond to BCG, and more than 50% will experience recurrence and progression during long-term follow-up, according to results from the phase 2 study of nadofaragene firadenovec, which Shore was involved in.

In that trial of 40 patients, the response rate was 30% at 12 months for those with carcinoma in situ, and durable responses were seen out to 36 months. Investigators reported no dose-limiting toxicities or immune toxicity.

In the phase 3 study, treatment-emergent adverse events were experienced by 93% of participants, but the vast majority were transient and grade 1 or 2 events; approximately 17% were grade 3. There was one grade 4 event, but this was not related to the study treatment.

The most common treatment-emergent adverse events were instillation-site discharge, reported by 33.1% of the patients; fatigue, reported by 23.6%; bladder spasm, reported by 19.7%; micturition urgency, reported by 17.8%; and hematuria, reported by 16.6%.

"Follow-up and treatment of these patients is ongoing in an extension study," Shore said.

"We do really need something new in nonmuscle invasive bladder cancer," Witjes observed. "There has to be an alternative to cystectomy and, fortunately, news is coming."

"There is a highly unmet need, but we have to realize that there is a lot in the pipeline," he explained. "We have trials with immune checkpoint blockade, vaccines, genetic therapy, and drug-delivery systems."

Nadofaragene firadenovec creates "adaptive immunity that may be lifelong," Witjes reported. "Nadofaragene firadenovec has a good basis, has consistent, good results, and it has a good safety profile. In light of current developments, I think this certainly is an interesting option."

The study was sponsored by FKD Therapies Oy and conducted in collaboration with the Society of Urologic Oncology Clinical Trials Consortium. Shore reports receiving research and consulting fees from Amgen, Astellas, Bayer, BMS, Dendreon, Fergene, Ferring, Janssen, Merck, Myovant, Nymox, Pacific Edge, Nucleix, Pfizer, Sanofi-Genzyme, Sun Pharma, and Tolmar. Witjtes reports receiving advisory or lecturer fees from multiple companies, but none relevant to his comments.

European Association of Urology (EAU) 2020 Congress. Presented July 17, 2020.

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