Positive efficacy and safety of N-803 plus BCG infusion in BCG-unresponsive NMIBC

Intravesical Bacillus Calmette-Guerin (BCG) is active against non-muscle-invasive bladder cancer (NMIBC), but bladder cancer recurs and even progresses in a significant number of patients. The addition of N-803, a first-in-class IL-15 immunostimulatory fusion protein, to BCG was safe and had a significant clinical benefit in heavily pre-treated patients with NMIBC in the QUILT-3.032 trial.

Innate immune memory is hypothesised to be an important mechanism mediating BCG therapy in NMIBC [1]. N-803 is a high-affinity IL-15 immunostimulatory fusion protein that promotes proliferation and activation of natural killer (NK) cells and CD8-positive T cells but not regulatory T cells. A phase 1b trial demonstrated that intravesical N-803 plus BCG induced complete responses in BCG-naïve NMIBC patients, without recurrences for 24 months [2].

QUILT-3.032 (NCT03022825) is an open-label, multicentre, phase 2/3 study that evaluates the efficacy and safety of N-803 plus BCG. The study enrolled 160 patients with heavily BCG-pre-treated NMIBC of whom 83 patients had carcinoma in situ (CIS; Cohort A) and 77 had papillary disease (Cohort B). All patients received intravesical N-803 plus BCG. The primary endpoint for Cohort A was biopsy-confirmed complete response, and the primary endpoint for Cohort B was disease-free rate at 12 months. Secondary endpoints included duration of response, cystectomy free rate, and safety. Dr Sam Chang (Vanderbilt University Medical Center, TN, USA) presented the phase 3 results [3].

In Cohort A, the complete response rate was 71%, irrespective of subgroup characteristics. At 12, 18, and 24 months, 62%, 55%, and 52% of patients were still responding, respectively (see Figure). Cystectomy avoidance rate in responders was 93% and bladder cancer-specific overall survival was 100% after 24 months of follow-up. In Cohort B, median disease-free survival was 23.6 months. Disease-free rates at 12, 18, and 24 months were 57%, 53%, and 48%, respectively. Disease-free survival rate was irrespective of subgroup characteristics. Cystectomy avoidance rate was 95% and bladder cancer-specific survival was 99% (median follow-up 20.7 months).

Figure: Duration of complete response in Cohort A [3]



The treatment was safe and tolerable. There were 0% treatment-related serious adverse events and 0% immune-related serious adverse events, with <1% grade 3 adverse events. The most common grade 1/2 treatment-related adverse events were dysuria (22%), pollakiuria (19%), and haematuria (18%).

Dr Chang concluded that “treatment of both CIS and papillary disease with N-803 plus BCG was safe, well tolerated, and had a clinically meaningful benefit. Moreover, N-803 plus BCG induced a durable response and a significant avoidance of cystectomy. Given these results, N-803 represents a significant advance in the treatment options for BCG-unresponsive CIS and papillary NMIBC.”

1. Van Puffelen JH, et al. Nat Rev Urol 2020;17:513–525.


2. Rosser CJ, et al. Oncoimmunology. 2021;10:1912885.


3. Chang SS, et al. Positive efficacy and safety phase 3 results in both CIS and papillary cohorts BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) after IL-15RαFc superagonist N-803 (Anktiva) and BCG infusion. Abstract 431, ASCO GU 2022, 17–19 February.

 

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Posted on 8 April, 20228 April, 2022