FDA Accepts BLA for N-803 in BCG-Unresponsive Non–Muscle Invasive Bladder Cancer in Situ

The FDA has accepted for review a biologics license application (BLA) for the IL-15 superagonist N-803 for the treatment of patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease.¹

The BLA is based in part on findings from the ongoing phase 2/3 QUILT 3.032 trial (NCT03022825), in which 71% (95% CI, 60.1%-80.5%) of patients with BCG-unresponsive NMIBC who progressed on prior treatment achieved a complete response (CR). The 12-month CR rate with the regimen was 62% (95% CI, 48%-74%); at 24 months, this rate was 52% (95% CI, 37%-65%).

The regulatory agency is scheduled to decide on the BLA by May 23, 2023, under the Prescription Drug User Fee Act. If approved, N-803 plus BCG would represent the first immunotherapy combination for this indication in 23 years that can be delivered directly to the bladder to generate natural killer (NK) cells and T cells.

“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,” Patrick Soon-Shiong, MD, executive chairman and global chief scientific and medical officer at ImmunityBio, stated in a 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.”

N-803 is an antibody cytokine fusion protein that generates NK and T cells that, when combined with BCG, results in a synergistic immune response.

Previously, N-803 was granted a breakthrough therapy designation and fast track designation for use in combination with BCG in patients with BCG-unresponsive NMIBC CIS.

QUILT 3.032 is an open-label, multicohort, multicenter study that enrolled patients with histologically confirmed BCG-unresponsive disease with persistent or recurrent CIS, with or without recurrent Ta or T1 disease. Patients were enrolled within 1 year of receiving BCG. Those with CIS comprised cohort A, and those with papillary histology (n = 77) made up cohort B.

Patients received 50 mg of intravesical BCG in combination with 400 µg of N-803 weekly for 6 cycles followed by 6 cycles of maintenance treatment in those who experienced a CR for up to 2 years. Those who did not experience a CR but responded to treatment were allowed to receive another 6 cycles of re-induction with the combination regimen.

The primary end point was CR at any time, and secondary end points included CR duration, cystectomy avoidance, and time to cystectomy. Serious toxicities and immune adverse effects (AEs) were also evaluated.

Additional findings presented during the 2022 Genitourinary Cancers Symposium demonstrated that with a median duration of follow-up of 23.9 months (range, 0.3-37.5), the median duration of response (DOR) was 24.1 months (95% CI, 9.9-not reached) in cohort A.² Sixty-two percent (95% CI, 48.0%-73.5%) of patients experienced a DOR of at least 12 months, 55% (95% CI, 40.1%-67.3%) experienced a DOR of at least 18 months, and 52% (95% CI, 37.0%-64.9%) had a DOR of at least 24 months.

Moreover, the cystectomy avoidance rate was 93%, and the median time to cystectomy was 5.1 months.

The 24-month rate of bladder cancer–specific progression-free survival was 91% (95% CI, 81.2%-95.4%), and the 24-month bladder cancer–specific overall survival rate was 100%.

In terms of safety, no patients in cohort A experienced treatment-related grade 4 and 5 AEs, treatment-related serious AEs, or immune-related AEs. The most common grade 1/2 AEs included dysuria (22%), pollakiuria (19%), and hematuria (18%). All grade 3 AEs occurred in less than 1% of patients, which included arthralgia, bacteremia, dysuria, encephalopathy, Escherichia bacteremia, hematuria, myalgia, pain in extremity, pollakiuria, sepsis, urinary tract infection, and urine flow decrease. 

“We are pleased the FDA has begun its review, and ImmunityBio is prepared to move rapidly to manufacturing and marketing should the Agency approve our therapeutic for this indication,” Richard Adcock, president and chief executive officer of ImmunityBio, said.

References

1. 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 August 1, 2022. https://bit.ly/3zmRnX8
2. 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