FDA Accepts BLA for N-803 in BCG-Unresponsive NMIBC Carcinoma In Situ

The FDA has accepted the biologics license application for N-803 as a treatment for patients with Bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer carcinoma in situ with or without Ta or T1 disease.

The FDA has accepted the biologics license application (BLA) for N-803 as a treatment for patients with Bacillus Calmette–Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease, according to ImmunityBio, Inc.1

Acceptance of the BLA is based on positive results from a series of studies of the investigational treatment, including the ongoing QUILT 3.032 trial (NCT03022825) examining N-803 plus BCG in patients with BCG-unresponsive NMIBC.

Findings from this study showed improved efficacy and safety, including over a 50% increase in response and median duration in 71% of patients who had failed on previous therapies when compared with other FDA-approved alternatives, such as valrubicin and pembrolizumab (Keytruda), for this indication. Further, ​​these patients showed a complete response with a median duration of 26.6 months and had a cystectomy avoidance rate of 91% and 100% bladder cancer overall survival at 24 months with 0 serious adverse events (AEs)reported.

“This BLA acceptance brings us a very important step closer to being able to offer this promising combination therapeutic to more people living with NMIBC and, ultimately, reduce the incidence of cystectomies,” said Patrick Soon-Shiong, MD, executive chairman and global chief scientific and medical officer at ImmunityBio, in the press release. “This is a compelling example of the power of inducing trained innate immune memory to potentially provide long-term, durable effects against serious, life-threatening diseases.”

In the open-label, single-arm, multicenter, phase 2/3 QUILT-3.032 study, intravesical BCG plus N-803 or N-803 alone is being examined as treatment for patients with BCG unresponsive high-grade NMIBC. Patients enrolled in the study will receive BCG plus N-803 or N-803 through use of a urinary catheter in the bladder, weekly for 6 consecutive weeks, which makes up the initial induction treatment period.2

After the first disease assessment, eligible patients will be administered either a 3-week maintenance course or a 6-week re-induction course as the second treatment period at month 3. Patients will then continue to receive maintenance treatment in the third treatment period at months 6, 9, 12, and 18, and be given the option to receive maintenance treatment in the fourth treatment period at months 24, 30, and 36. Complete duration of the study is 60 months.

A total of 81 patients with histologically confirmed BCG-unresponsive NMIBC were enrolled in the trial, each of whom had persistent or recurrent CIS within 12 months of receiving adequate BGC treatment. Primary end points of the study are complete response (CR) and disease-free rate, with secondary end points including response at 6, 9, 12, 18, and 24 months, and complete response.

Updated results of the trial were presented at the 2022 American Society of Clinical Oncology Meeting and revealed QUILT 3.032 to meet its primary end point of CR with a rate of 71% with a median duration of CR of 24.1 months in responders. There was a 99% bladder cancer specific overall survival at 2 years and a 53% disease-free survival (DFS) rate at 18 months for patients with papillary disease. Additionally, 91% of patients avoided cystectomy and 96% showed 24 month bladder cancer specific progression-free survival (PFS).

Papillary patients had a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. The median time to cystectomy in the 4 responders was 12.9 months compared with 7.8 in the 8 non-responders, resulting in a 5.1 month delay in cystectomy. Further, pharmacokinetic data did not show any systemic levels of N-803 and activity was confined to the bladder.

No incidence of treatment-related serious AEs, immune-related AEs, or treatment-related AEs (TRAEs) that were either grade 4/5 were reported. Grade 3 TRAEs were observed in only 2 patients and included urinary tract infection and arthralgia. The most frequent grade 1/2 AEs consisted of dysuria (22%), pollakiuria (19%), hematuria (18%), fatigue (16%), and urgency (12%). All other AEs were seen at 7% or less.

With a well-tolerated profile, the trial showed patients were given a greater chance to avoid radical cystectomy, which consists of the bladder removal. This surgery remains one of the last remaining options for patients who do not respond to other therapies due to its cost to the healthcare system and the added high risk of mortality and complications that can affect patient quality of life.

ImmunityBio announces FDA acceptance of biologics license application for N-803 in BCG-Unresponsive non-muscle-invasive bladder cancer carcinoma in situ. News release. ImmunityBio, Inc. July 28, 2022. Accessed July 29, 2022.
QUILT-3.032: A multicenter clinical trial of intravesical bacillus calmette-guerin (BCG) in combination with ALT-803 (N-803) in patients with BCG unresponsive high grade non-muscle invasive bladder cancer. ClinicalTrials.gov. Updated June 16, 2022. Accessed July 29, 2022. https://clinicaltrials.gov/ct2/show/NCT03022825
Chamie K, Chang S, Gonzalgo M, et al. FFinal clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC). Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 2-6, 2022; virtual. Abstract 4508.
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