N-803 in Combination With BCG Yields Encouraging Responses in BCG-Unresponsive Bladder Cancer

Karim Chamie, MD

Patients with BCG-unresponsive, non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) had promising responses to Bacille Calmette-Guérin (BCG) plus N-803 (ALT-803), updated data from cohort A of the phase 2/3 QUILT-3.032 trial (NCT03022825) presented during the 2021 American Urological Association Annual Meeting show.¹

Results showed that the study met its primary end point, with a complete response (CR) rate of 72% (95% CI, 61%-81%), and a 58.6% (95% CI, 43.1%-71.2%) probability of maintaining a CR for at least 12 months. Additionally, at a median follow-up of 20.4 months, the median duration of CR was 19.9 months (95% CI, 7.8–not reached).

“Eighty-five percent of our patients avoided a cystectomy,” according to lead study author Karim Chamie, MD, associate professor of urology at the University of California, Los Angeles. “This intravesical administration is quite favorable, and quite familiar amongst those who normally treat patients with BCG-unresponsive bladder cancer.”

N-803 is an interleukin-15 superagonist that activates and proliferates endogenous natural killer and CD8-positive T cells without inducing T-regulatory simulation.

QUILT-3.032 enrolled 81 patients with histologically confirmed BCG-unresponsive NMIBC, with persistent or recurrent CIS within 12 months of receiving adequate BGC treatment. Patients were treated with 50 mg of BCG plus 400 mg of intravesical N-803 weekly for 6 weeks, followed by re-induction for re-induction and maintenance for up to 3 years.

The primary end point was biopsy confirmed CR at 3 and 6 months, with a lower bound 95% confidence interval of at least 20%. Secondary end points included duration of CR, cystectomy avoidance, and time to cystectomy. Furthermore, safety end points included incidence of serious adverse effects (AEs) and immune AEs.

Notably, the analysis included patients who achieved a CR at 3 months, as well as those who achieved a CR after rescue and reinduction at 6 months.

Those were enrolled were heavily pretreated patients with a median of 5.0 transurethral resections of a bladder tumor, and a median of 12.0 prior BCG instillations. Additionally, 42% of patients had received prior treatment with chemotherapy, and 17% were previously treated with checkpoint inhibitors, vicinium, interferon, etc.

Additional data showed that among patients who achieved an initial complete response at 3 months, there was a 64% (95% CI, 47.3%-77.3%) probability of maintaining that response at 12 months, and a 61% (95% CI, 43.2%-74.5%) probability of maintaining it at 18 months.

Notably, as of May 2021, the combination showed a 30% durable response at 18 months. Eighty-five percent of patients have not progressed to radical cystectomy through a data analysis as of this time point, as well.

In terms of safety, the combination was well tolerated, with no incidence of treatment-related serious AEs, immune-related AEs, or treatment-related AEs (TRAEs) that were grade 4/5 in severity. Grade 3 TRAEs occurred in just 2 patients and included urinary tract infection and arthralgia. The most frequent grade 1/2 AEs were dysuria (22%), hematuria (16%), and pollakiuria (19%).

In comparison to other FDA-approved treatments for this patient population, N-803 plus BCG significantly improved outcomes. Previous data with pembrolizumab (Keytruda) showed that the agent induced at CR rate of 41% at any time, and a median duration of CR of 16.2 months at 24.1 months follow-up. Similarly, valrubicin elicited an 18% CR rate, and a median duration of CR of less than 6 months. Moreover, the cystectomy-free rate for the two drugs was 63% and 76%, respectively.

_Reference

_{Chamie K, Chang S, Gonzalgo M, et al. Phase 2/3 clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients (cohort A). Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD09-05.}