During the Friday morning plenary session of the 2022 American Urological Association (AUA) annual meeting, Karim Chamie, MD, associate professor of medicine at UCLA, began by reviewing that intravesical Bacillus Calmette-Guérin (BCG) is the current standard of care treatment for patients with high grade non–muscle-invasive bladder cancer (NMIBC). BCG induction is believed to work by impacting and training macrophages that then cause a release of cytokines and tumor necrosis factor. Subsequently, natural killer (NK) cells and T cells are activated, and target bladder cancer cells, ultimately leading to death of bladder cancer cells.
The combination of NK cells1 and T cells2 is essential to be effective against bladder cancer cells. Based on animal models, investigators hypothesized that the combination of BCG and interleukin-15 (IL-15) would further augment the efficacy of T-cell and NK-cell response, resulting in activation of memory T cells, which would in turn create an immune memory response with the potential to increase disease-free survival (DFS).
Dr. Chamie explained that this hypothesis led to the design of the phase 2/phase 3 QUILT 3032 trial. The trial aimed to assess the safety and efficacy of adding N-803 (an IL-15 superagonist complex) to BCG. Enrolled patients had NMIBC with carcinoma in situ with or without (CIS ±) papillary disease and had previously received BCG but were unresponsive to treatment. Patients were stratified into 2 cohorts, one with CIS ± papillary tumor, and one with papillary disease alone (papillary cohort). Inclusion criteria included histologic confirmation of NMIBC with persistent or recurrent CIS ± papillary disease, with recurrence limited to within 12 months before enrollment.
All patients enrolled in the trial received intravesical BCG 50 mg plus N-803 400 µg instilled once weekly for 6 weeks, followed by maintenance therapy for patients who had an initial complete response (CR). Patients who had only a partial response were offered the option for reinduction. Safety endpoints were aimed at identifying potential serious adverse events (SAEs) and immune-related adverse events (irAEs). Efficacy endpoints were based on US Food and Drug Administration guidance to evaluate for a CR at any time, with the lowest 95% confidence limit at >20%. Secondary endpoints included duration of CR, whether patients underwent subsequent cystectomy, and the time to cystectomy.
There was a total of 83 patients in the CIS ± papillary cohort and 77 patients in the papillary cohort. The median age in both cohorts was 72 years, and 87% of patients in the CIS ± papillary and 74% in the papillary cohort identified as male. Eastern Cooperative Oncology Group (ECOG) performance status was 0 for most patients, indicating full activity. Importantly, there was a mean of 4 transurethral resections of bladder tumor for both cohorts. Mean prior administrations of intravesical BCG were 16.6 in the CIS ± papillary cohort and 12.3 in the papillary cohort.
Dr. Chamie then reviewed the safety profile of N-803, explaining that the risk for treatment-related SAEs was 1% and the rate of irAEs was 0%; the treatment-related discontinuation rate was 3%. No treatment-related grade 4 or grade 5 AEs were reported. The most common grade 1 and grade 2 morbidities included dysuria, urinary frequency, hematuria, and urgency. The incidence of grade 3 AEs was <1% overall. Dr. Chamie concluded that these safety profile findings were consistent with the hypothesis that N-803 activity acts locally without having a significant IL-15 systemic effect.
Next, Dr. Chamie focused on the efficacy data. Based on CR rates of the CIS ± papillary cohorts, 71% of patients had a CR at any time, and the median duration of that response was approximately 2 years. The CR rate was 62% at 12 months, 55% at 18 months, and 52% at 24 months. The cystectomy rate was 7% for those who responded initially, and 15% for all patients (including those who did or did not respond). Bladder cancer-specific progression-free survival was 91% at 2 years, while the overall survival rate in this cohort was 100%. The median follow-up time was 2 years.
This efficacy was maintained when accounting for the multiple variables and demographics evaluated, including age, race, gender, presence of CIS ± papillary disease, previous prior therapy, and whether patients had undergone reinduction. All patients benefited from the combination of N-803 plus BCG, and patients were followed for nearly 2 years (23.6 months). In the papillary cohort, median DFS was similar to that in the CIS group at 12 months (57%), 18 months (53%), and 2 years (48%). The primary endpoint was met for 73 patients, and 95% avoided a radical cystectomy. The median follow-up time was 21 months. Similar to the CIS ± cohort, efficacy was retained even when accounting for multiple variables and demographics including age, gender, race, and tumor histology.
Dr. Chamie concluded that this study evaluating the addition of intravesical N-803 to BCG for the treatment of patients with high-grade NMIBC with CIS showed a clinically meaningful benefit without compromising safety or tolerability. Indeed, the tolerability of the drug combination was consistent and similar to that in patients who received BCG alone in other studies (SAEs of 1% in QUILT 3032 vs 2% in other studies, and 3% treatment-related discontinuations of 3% vs 2% in other studies). In patients with papillary tumors, the rate of DFS was 56% at 12 months and 48% at 2 years. Overall bladder cancer-specific survival was reported in 99% of patients, and 96% avoided cystectomy at 2 years while maintaining good tolerability and a low rate of AEs.