FDA Issues Complete Response Letter to BLA for N-803 in BCG-unresponsive NMIBC in Situ

FDA

The FDA has issued a complete response letter (CRL) regarding the biologics license application (BLA) for N-803 (Anktiva) in combination with Bacillus Calmette-Guérin (BCG) for the treatment of patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without Ta or T1 disease.¹

The CRL indicated that the regulatory agency could not approve the BLA in its current form due to deficiencies related to the pre-license inspection of ImmunityBio’s third-party contract manufacturing organizations. A resolution to the observations from the pre-license inspection is required for potential approval of the BLA. Additionally, the FDA provided recommendations to specific Chemistry, Manufacturing, and Controls issues and assays.

The regulatory agency did not request any new preclinical or phase 3 clinical trials to evaluate the efficacy and safety of N-803 plus BCG. However, the regulatory agency did request updated data on duration of response and safety from the phase 2/3 QUILT 3.032 trial (NCT03022825) that supported the application, which was initially accepted by the FDA in July 2022.²

ImmunityBio plans to request a meeting with the FDA as soon as possible with the ultimate expectation of addressing and resolving the issues outlined in the CRL.¹

N-803 is a novel interleukin-15 (IL-15) superagonist complex comprised of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. The agent is designed to direct specific stimulation of CD8+ T cells and natural killer cells through beta gamma T-cell receptor binding without regulatory T-cell stimulation.²

Findings from cohort A of QUILT 3.032 showed that at a median follow-up of 23.9 months (range, 0.3-37.5), patients with BCG-unresponsive NMIBC who progressed on prior treatment (n = 83) and were treated with N-803 plus BCG achieved a complete response (CR) rate of 71% (95% CI, 60.1%-80.5%). The 12- and 24-month CR rates were 62% (95% CI, 48%-73.5%) and 52% (95% CI, 37%-64.9%), respectively.³

Cohort A included patients with histologically confirmed persistent or recurrent NMIBC with CIS with or without recurrent Ta/T1 disease within 12 months of receiving adequate BCG.

Patients received 50 mg of BCG plus 400 µg of N-803 intravesically once per week for 6 weeks. After first disease assessment, patients received either a 3-week maintenance course or a 6-week re-induction course at month 3. Eligible patients received maintenance treatment in the third treatment period at months 6, 9, 12, and 18, and optional maintenance was available in the fourth treatment period at months 24, 30, and 36.⁴

The primary end point for cohort A was biopsy-confirmed CR at 3 or 6 months, with a lower bound of the 95% confidence interval of at least 20%.³ Secondary end points included duration of CR, cystectomy avoidance, and time to cystectomy. Safety end points consisted of serious adverse effects (AEs) and immune AEs.

Additional data showed that the 24-month bladder cancer–specific progression-free survival (PFS) was 91% (95% CI, 81.2%-95.4%). In responders, the 24-month bladder cancer–specific PFS was 96% (95% CI, 86.5%-99.1%).

Among responders, 93% avoided cystectomy, and the median time to cystectomy was 5.1 months. The bladder cancer–specific overall survival was 100%.

Combined safety findings for patients enrolled in cohort A and cohort B (n = 160) showed that no patients experienced grade 4 or 5 serious AEs, treatment-related serious AEs, or immune-related AEs.

The most common grade 1/2 AEs included dysuria (22%), pollakiuria (19%), hematuria (18%)m fatigue (16%), micturition urgency (12%), chills (7%), bladder spasm (6%), pyrexia (5%), urinary tract infection (5%), cystitis noninfective (4%), nocturia (3%), diarrhea (3%), nausea (2%), positive bacterial test (2%), cystitis (25%), influenza-like illness (2%), and urinary tract pain (2%). No specific grade 3 AEs occurred in 1% or more of patients.

References

1. Report of unscheduled material events or corporate event. ImmunityBio. May 9, 2023. Accessed May 11, 2023. https://ir.immunitybio.com/static-files/307bb4e5-4082-4b4d-9f39-edbb7943ee51
2. ImmunityBio announces FDA acceptance of biologics license application for N-803 in BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ. News release. Immunity Bio. July 28, 2022. Accessed May 11, 2023. https://immunitybio.com/immunitybio-announces-fda-acceptance-of-biologics-license-application-for-n-803-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-carcinoma-in-situ/
3. Chang SS, Chamie K, Gonzalgo ML, 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. J Clin Oncol. 2022;40(suppl 6):431. doi:10.1200/JCO.2022.40.6_suppl.431
4. 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 April 19, 2023. Accessed May 11, 2023. https://www.clinicaltrials.gov/ct2/show/NCT03022825