乌鸦传媒

WASHINGTON -- An investigational interferon-based gene therapy led to complete responses in more than half of patients with non–muscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG) therapy, a single-arm multicenter phase III trial reported.

Among 103 patients with carcinoma in situ (CIS) with or without Ta/T1 disease, 53% achieved a complete response by 3 months with nadofaragene firadenovec (formerly rAd-IFNα/Syn3), meeting the study's primary endpoint, and about half of these patients maintained their disease-free status out to a year, reported Colin Dinney, MD, of MD Anderson Cancer Center in Houston.

"Late recurrences after 12 months were rare -- so if you got to 12 months you were unlikely to recur with high-grade disease," Dinney told the audience here at the Society of Urologic Oncology (SUO) annual meeting.

Dinney said the complete response rate of 24.3% at 1 year compares favorably to the 10% rate reported with valrubicin (Valstar), the only approved agent in this disease state.

In 48 patients with papillary tumors on the trial, 72.9% achieved a complete response at 3 months and 42.8% maintained this level of response out to 12 months.

The FDA has defined "BCG unresponsive" disease as patients with high-grade T1 disease following initial induction BCG, those with high-grade Ta/T1 disease who relapse within 6 months from their prior BCG treatment, and those with persistent CIS with or without recurrent Ta/T1 disease within a year of completing BCG.

There hasn't been a new agent approved for NMIBC since the 1998 approval of valrubicin, and FDA guidelines for developing new drugs in this setting note that "a high complete response rate is not meaningful if the response duration is short." Randomized trials using placebo as a comparator are considered unethical -- as such, the agency has allowed single-arm registration trials in this setting.

"There really is no alternative treatment for BCG-unresponsive patients, and that's why in this phase III trial there's no control arm, because there is no alternative treatment," Stephen Williams, MD, MS, of the University of Texas Medical Branch in Galveston, told 乌鸦传媒. "That's why other potential therapies -- immunotherapies -- are being explored."

Pembrolizumab (Keytruda) for NMIBC has been tested in the KEYNOTE-057 trial; on Dec. 17, an will review whether the data support an indication in this setting.

Nadofaragene firadenovec is an adenovirus vector-based gene therapy that contains the interferon alfa-2b gene. The therapy is administered intravesically once every 3 months via a catheter. An earlier phase II trial testing the therapy reported a 30% complete response rate in patients with BCG-relapsed or refractory CIS and a 50% high-grade recurrence-free survival at 12 months.

Long-term data out to 2 and 3 years will be critical with nadofaragene firadenovec, Williams said, but added that it's "very important for the FDA to move fast on this as a potential approval," given the lack of alternatives in this setting -- current guidelines recommend that radical cystectomy be offered to patients with BCG-unresponsive disease, which brings poor quality-of-life along with it.

But Williams, who noted that he is the medical director for high-value care at his health system, also cautioned that while achieving a complete response can justify upfront costs of a therapy by preventing downstream costs and disease progression, a cost-benefit analysis of any new agent still needs to be considered in this setting.

"Cost-effectiveness is absolutely warranted before we do widespread dissemination, particularly when an agent may be the only agent available," he said.

In his conclusion, Dinney highlighted the convenient dosing schedule of nadofaragene firadenovec and said the agent "provides a favorable benefit-risk profile for patients facing cystectomy."

Among the safety cohort of 157 patients in the trial, 70.1% had any treatment-related adverse event (AE), 1.9% had serious AEs, and 3.8% had grade 3 AEs. No grade 4 treatment-related AEs or drug-related deaths were reported. The most common (>10%) drug-related AEs of any grade were bladder discharge around the catheter (24.8%), fatigue (19.7%), bladder spasm (15.9%), micturition urgency (15.3%), chills (11.5%), dysuria (10.8%), and pyrexia (10.2%).

Aside from fatigue, most AEs were transient, said Dinney, with the median toxicity duration being less than 2 days overall.

Other Options

While FDA says it would be unethical to compare any new agent against placebo in BCG unresponsive NMIBC, retrospective data at SUO showed one option (intravesical gemcitabine plus docetaxel) that physicians are currently turning to in the clinic for such patients.

Among 276 patients treated over a nearly 10-year period, the recurrence-free rate at 12 months reached 60%, and 46% remained recurrence-free at 24 months, reported Nathan Brooks, MD, of the University of Iowa Health Care, during a poster presentation at the meeting.

High-grade recurrence-free survival was 60% at 12 months and 46% at 24 months.

Among the 218 patients who responded at 4 months, 170 went on to maintenance therapy while 48 did not. Not undergoing maintenance treatment was linked with worse recurrence-free survival (HR 2.37, 95% CI 1.36-4.11, P<0.01).

Williams called the results on intravesical gemcitabine plus docetaxel promising, but emphasized the retrospective nature of the study. "I use that in my clinical practice as my salvage regimen for patients that do not want to undergo cystectomy," he said, calling it both cost-effective and a strong option in an area with few alternative options.

"With these agents that are going to be coming about, they're obviously going to be more costly than conventional generic chemotherapeutic agents that we have at hand, and I think we have to be mindful of what the responses are in the context of those costs," said Williams.

The study from Brooks and colleagues looked at patients treated from 2009 to 2018 at six institutions in the U.S. Patients were treated with 1 g of gemcitabine and 37.5 mg of docetaxel every 6 weeks. Cystoscopy and cytology were performed every 3 months. Median age of the cohort was 73, and 81% were men. About half (46.4%) had failed BCG at least twice, and 38% were classified as unresponsive.

About 40% of patients reported side effects, which were led by frequent urination (22.1%), dysuria (15.6%), and hematuria (10.5%). Only about one in 10 patients needed to delay treatment due to an adverse event. The 1- and 2-year rates of overall survival in the cohort were 97% and 87%, respectively.

Limitations, according to the researchers, included that the group of patients was highly selected and that different institutions used different treatment protocols.