Phase II/III single arm, multi-center study of patients with BCG-unresponsive CIS with or without papillary (Ta/T1) NMIBC treated with intravesical NAI/N-803 (400 lg/instillation) plus BCG intravesical BCG (50 mg/ instillation) (cohort A) or without BCG (cohort C). Patients with BCG-unresponsive high-grade papillary (Ta/T1) NMIBC without CIS were also treated with intravesical NAI/N-803 plus BCG (cohort B). Patients had to be absent of resectable disease after TURBT procedures, and those with high-grade Ta and/or T1 disease had a complete resection before study treatment. Biopsy was required at week 12 (approximately 3 months).
Some 80% of new bladder cancer diagnoses are non–muscle-invasive bladder cancer (NMIBC). BCG-unresponsive NMIBC is an increasingly interesting disease state for drug development in bladder cancer. Impaired T-cells and natural killer (NK) cells may contribute to BCG-unresponsiveness. The immune cell–activating interleukin-15 (IL-15) superagonist Nogapendekin alfa inbakicept (NAI), also known as N-803, can activate and proliferate NK cells and T-cells. Therefore, the hypothesis that the addition of N-803 to BCG could potentially enhance BCG efficacy was preliminarily tested in a small Phase I trial with limited toxicity and an impressive response rate. The current trial was a Phase II/III multicenter study to look at efficacy.
The primary endpoint was the incidence of a complete response (CR) at the 3- or 6-month assessment for cohorts A and C and the disease-free survival of cohort B at 12 months. Secondary endpoints include disease-specific survival, progression-free survival, overall survival, and avoidance of cystectomy.
There is considerable activity with the combination of N-803 and BCG in BCG-unresponsive NMIBC that leads to good response rates at 12 months and beyond and avoidance of cystectomy. The data are in line with expectations for novel therapies in this disease space. From this study, it emerges that the treatment is tolerable with a side effect profile that can be expected with intravesical therapy. However, the activity of N-803 as a single agent appears to be minimal. A subgroup that requires further careful observation is high-grade T1 tumors associated with CIS (HGT1/CIS), as these patients have the highest risk of progression. Only 9 patients were included in this trial. However, comparisons with other single-arm trials are always difficult in that there is substantial heterogeneity among BCG-unresponsive patient cohorts, and variation in the patient population and the quality of the TURBT among surgeons. For instance, development of UC of the prostatic urethra was not counted as treatment failure in this trial. In addition, a lower CR rate in female patients is an interesting observation, that has been seen in other trials. It will be interesting to see whether the combination is equally effective in the BCG-naïve high-risk NMIBC disease state.
A total of 171 patients were enrolled with 84 patients in cohort A, 77 patients in cohort B, and 10 patients in cohort C. In cohort A, 82 patients were evaluable with at least 3-month follow-up. Overall, a CR at any time was seen in 71% of patients (45 patients with response to initial treatment and 13 patients with response to re-induction). The CR rate was 45% at 12 months and 33% at 18 months for patients in cohort A. Furthermore, progression-free survival at 24 months was 84.7%. In the 71% of patients with a CR, only 7% underwent a subsequent cystectomy. In cohort B, the 12-month DFS for 72 evaluable patients was 55.4% and the cystectomy rate among responders was also 7%. In Cohort C, a CR at 3 months was only achieved in 2 (20%) patients. Despite reinduction at 6 months, only one patient (10%) maintained a CR at 6 months. Treatment-related adverse events in cohorts A and B were grade I to 2 in 86%.