The use of the IL-15RAFC superagonist N-803 with intravesical bacillus Calmette-Guérin (BCG) resulted in high and more durable response rates in patients with non-muscle invasive bladder cancer (NMIBC) carcinoma in situ who were unresponsive to BCG, a phase II/III study found.

Of the 81 patients included in the analysis, 58 achieved a complete response at any time, for a complete response rate of 72% (95% CI 61-81), reported Karim Chamie, MD, of the David Geffen School of Medicine at the University of California Los Angeles, during a session of the virtual American Urological Association (AUA) annual meeting.

Over a follow-up of 20.4 months, the median duration of complete response was 19.9 months (95% CI 7.8 months to not reached).

BCG is a common intravesical immunotherapy for early-stage bladder cancer, which can be effective; however, many patients will develop BCG-unresponsive disease, leaving few therapeutic options.

“N-803 is an IL superagonist that activates and proliferates endogenous natural killer and CD8+ T cells without inducing T regulatory stimulation or proliferation,” Chamie explained. A previous small phase I trial of N-803 plus BCG in nine BCG-naive patients with high-risk NMIBC had positive results, with all nine achieving complete responses with no recurrences over the study duration of 24 months.

“This is an interesting study where patients previously unresponsive to BCG were treated with a combination of BCG and N-803, an immunostimulatory fusion protein complex that promotes activation of the patients’ immune response,” Peter Wiklund, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City, told MedPage Today.

“It is a relatively small study and 59% are still tumor free at 12 months,” said Wiklund, who was not involved in the study. “We will have to await longer follow-up before understanding if this combination will be clinically useful. Several studies with various immunotherapy combinations have shown good response rate at 12 months, but have later shown less efficacy with only around 20% after 2 to 3 years. It will be interesting to follow the results from this study going forward.”

Patients with persistent or recurrent carcinoma in situ, with or without papillary tumors, received 400 µg of N-803 with 50 mg of BCG consistent with the standard induction/maintenance treatment schedule. The primary endpoint was biopsy-confirmed complete response at 3 or 6 months, with duration of complete response, cystectomy avoidance, and time to cystectomy as secondary endpoints.

The probability of maintaining a complete response for 12 months was 58.6% (95% CI 43.1-71.2), said Chamie and co-authors.

“When stratifying the cohort into those who had a complete response at 3 months versus those who had to be rescued, the outcomes are quite different,” Chamie pointed out. Patients with a complete response at 3 months had a 64% probability of maintaining that response for 12 months (95% CI 47.3-77.3) and a 61% probability of maintaining it for 18 months (95% CI 43.2-74.5), with a median duration not reached in this cohort.

“Among those who had to be rescued because they had persistence of disease, their median duration was only 9 months,” Chamie reported.

“More importantly, 85% of our cohort did not progress to radical cystectomy,” he added.

The treatment regimen was well tolerated, with no treatment-related or immune-related serious adverse events (AEs) observed. Low-grade treatment-related AEs included dysuria, hematuria, and pollakiuria (all 16%), urgency (14%), and bladder spasm (8%).

Chamie also pointed out that when comparing N-803 and BCG with other agents for this disease that have been FDA approved, “you’ll see that our complete response rate of 72% at any time significantly outperformed that of pembrolizumab [Keytruda] (41%) and valrubicin [Valstar] (18%).”

In his presentation, Chamie referred to recommendations from the International Bladder Cancer Group published in the Journal of Clinical Oncology. In an FDA-AUA workshop, panel members had suggested that an initial complete response rate of 40% to 50% at 6 months, and a durable response rate of at least 30% for 18 to 24 months, could be clinically meaningful in the BCG-refractory population. Chamie noted that the authors of the recommendations said that they were “in partial agreement … but feel that the 30% durable response at 18 to 24 months criterion is likely too high and may not be realistically achievable.”

“I’d like to tell you today that this was achieved,” Chamie said. “As of May 19, 2021, we have a 30% durable response at 18 months.