FDA Postpones Approval Decision for N-803 in BCG-Unresponsive NMIBC Carcinoma In Situ


FDA approval has not been granted to N-803 for the treatment of Bacillus Calmette–Guérin-unresponsive non-muscle-invasive bladder cancer carcinoma in situ.

The FDA has issued a complete response letter (CRL) to ImmunityBio regarding the biologics license application (BLA) for N-803, a proposed 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.

In the CRL, the FDA cited insufficient inspection of a third-party manufacturer. The regulatory body stated that ImmunityBio must resolve the observations process in their SEC filing before the BLA can be reviewed. No efficacy or safety issues related to N-803 were mentioned in the CRL.

ImmunityBio is seeking approval for the proposed indication based on results from multiple of studies of N-803, including the open-label, single-arm, multicenter, phase 2/3 QUILT 3.032 trial (NCT03022825), support this approval of N-803 in patients with BCG-unresponsive NMIBC.1

In QUILT 3.032, efficacy and safety were improved with N-803. Among patients for whom previous therapies have failed, 71% had a complete response (CR) and the median duration of response of 26.6 months.2 With N-803, the cystectomy avoidance rate was 91%, and the 24-month bladder cancer overall survival rate was 100%. Further, no serious adverse events (AEs) were reported.

“What we found was in patients with both carcinoma in situ, as well as papillary disease, that's non-invasive bladder cancer, patients that were heavily pretreated with this combination therapy had excellent results with very few [adverse events]. That's the bottom line,” Sam S. Chang, MD, MBA, Professor Department of Urology, Patricia and Rodes Hart Professor of Urologic Surgery, and chief surgical officer and chief of the Division of Urologic Oncology at Vanderbilt Ingram Cancer Center, and investigator of QUILT 3.032 told Targeted OncologyTM in an interview.

N-803, an IL-15 superagonist, has a mechanism of action that results in proliferation of natural killer and T cells, leading to a secondary boost in immunological response from treatment with BCG or other checkpoint inhibitors for other indications.

Those enrolled in the QUILT 3.032 trial were patients with persistent or recurrent carcinoma in situ within 12 months of undergoing adequate treatment with BCG (cohort A) or papillary recurrent high-grade Ta-T1 disease within 6 months of finishing adequate treatment with BCG. Patients were treated with BCG 50 mg plus 400 μg of intravesical N-803 every week for 6 weeks or reinduction for 6 weeks plus maintenance up to a maximum of 3 years.2

The primary end point evaluated in cohort A was biopsy-confirmed CR at 3 or 6 months, and in cohort B, the primary end point was disease-free rate at 12 months. Secondary end points of the study consisted of duration of CR, cystectomy avoidance, time to cystectomy, and safety.

At the 2022 American Society of Clinical Oncology Meeting, updated results from QUILT 3.032 showed that the study met its primary end point. A 99% bladder cancer specific overall survival rate was seen at 2 years and there was a 53% disease-free survival (DFS) rate at 18 months for patients with papillary disease. Additionally, 96% showed 24-month bladder cancer specific PFS.1

The 12-month DFS rate for papillary patients was 57%, the 24-month DFS rate was 48%, and 95% of patients avoided cystectomy. The median time to cystectomy in the 4 responders was 12.9 months vs 7.8 in the 8 non-responders, which led to a 5.1-month delay in cystectomy. Additionally, pharmacokinetic data did not show any systemic levels of N-803 and activity was confined to the bladder.

For safety, there was no incidence of grade 4/5 treatment-related serious AEs, immune-related AEs, or treatment-related AEs (TRAEs) reported. Only 2 patients had grade 3 TRAEs and included urinary tract infection and arthralgia. Further, 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.

1. 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.

2. 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

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