FDA Accepts BLA Resubmission for N-803 in BCG-Unresponsive, High-Risk NMIBC In Situ

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

The FDA has accepted the resubmission of a biologics license application (BLA) seeking the approval of N-803 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

In May 2023, the FDA issued a complete response letter (CRL) to the initial BLA for N-803, where the regulatory agency cited deficiencies related to the pre-license inspection of ImmunityBio’s third-party contract manufacturing organizations as the reason the application could not be approved in its prior form.² The FDA also provided ImmunityBio—the developer of N-803—with recommendations to specific Chemistry, Manufacturing, and Controls issues and assays.

“We are pleased that the FDA has accepted ImmunityBio’s resubmission of the BLA as a complete response, following our productive interactions leading up to the resubmission. We look forward to working closely with the Agency to finalize the review and to bringing this important immune-enhancing therapeutic to patients suffering from bladder cancer,” Patrick Soon-Shiong, MD, executive chairman and global chief scientific and medical officer at ImmunityBio, stated in a news release.¹

The target action data for the resubmitted BLA under the Prescription Drug User Fee Act is April 23, 2024.

The BLA is supported by data from the phase 2/3 QUILT-3.032 trial (NCT03022825). Although the FDA’s CRL did not request any new preclinical or phase 3 clinical trials evaluating N-803 plus BCG, the regulatory agency requested updated data on duration of response and safety from QUILT-3.032.²

Findings from cohort A of QUILT-3.032 presented at the 2022 ASCO Annual Meeting showed that at a median follow-up of 23.9 months, patients with BCG-unresponsive NMIBC who experienced disease progression on prior treatment (n = 82) and were treated with N-803 plus BCG experienced a complete response (CR) rate of 71% (95% CI, 59.6%-80.3%). The median DOR was 26.6 months 95% CI, 9.9-not reached). The 12-, 18-, and 24-month DOR rates were 61.6% (95% CI, 47.3%-73.1%), 56.3% (95% CI, 41.5%-68.8%), and 53.2% (95% CI, 38.0%-66.2%), respectively.³

Cohort A enrolled patients with histologically confirmed persistent or recurrent NMIBC with CIS with or without recurrent Ta/T1 disease who received adequate BCG within the past 12 months. Cohort B included patients with papillary disease.

All patients received 50 mg of BCG plus 400 µg of intravesical N-803 once per week for 6 weeks.

After first disease assessment, patients either received a 3-week maintenance course or a 6-week re-induction course. In the third treatment period, eligible patients then received maintenance therapy at months 6, 9, 12, and 18, and optional maintenance was given in the fourth treatment period at months 24, 30, and 36.⁴

CR rate at any time with a lower bound of the 95% confidence interval of at least 20% served as the trial’s primary end point.3 Secondary end points included duration of CR, cystectomy avoidance, and time to cystectomy.

Additional data from cohort A showed that 9% of responders underwent cystectomy, and 16% of all patients received cystectomy.

The 12-, 18-, and 24-month estimated progression-free survival rates were all 96.4% (95% CI, 86.2%-99.1%). The bladder cancer–specific overall survival rate was 100%.

Pooled safety findings for patients enrolled in cohort A and cohort B (n = 161) showed that no grade 4 or 5 treatment-related adverse effects (TRAEs) were reported. One percent of patients had serious TRAEs, and no patients experienced serious immune-related AEs or treatment-related deaths.

The most common grade 1/2 AEs included dysuria (22%), pollakiuria (20%), hematuria (17%), fatigue (16%), micturition urgency (12%), chills (7%), bladder spasm (6%), pyrexia (5%), urinary tract infection (6%), cystitis noninfective (4%), nocturia (3%), diarrhea (3%), nausea (2%), positive bacterial test (2%), cystitis (2%), influenza-like illness (2%), and urinary tract pain (2%).

References

FDA accepts ImmunityBio’s BLA resubmission as complete and sets new PDUFA date. News release. ImmunityBio. October 26, 2023. Accessed October 26, 2023. https://immunitybio.com/fda-accepts-immunitybios-bla-resubmission-as-complete-and-sets-new-pdufa-date/
US Securities and Exchange Commission. Form 8-K. May 9, 2023. Accessed October 26, 2023. https://ir.immunitybio.com/static-files/307bb4e5-4082-4b4d-9f39-edbb7943ee51
Chamie K, Chang SS, Gonzalgo M, et al. Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC). J Clin Oncol. 2022:40(suppl 16):4508. doi:10.1200/JCO.2022.40.16_suppl.4508
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 August 2, 2023. Accessed October 26, 2023. https://clinicaltrials.gov/study/NCT03022825