FDA Approval Sought for N-803 Plus BCG in BCG-Unresponsive NMIBC Carcinoma in Situ

US FDA

A biologics license application (BLA) seeking the approval of N-803 in combination with Bacillus Calmette-Guérin (BCG) in patients with BCG-unresponsive, non–muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease has been submitted to the FDA.¹

The application is supported by data from the phase 2/3 QUILT 3.032 trial (NCT03022825), where at a median follow-up of 23.9 months, the N-803/BCG combination produced a complete response (CR) rate of 71% (95% CI, 60.1%-80.5%) in those with CIS (n = 83; cohort A).2 The 12-month CR rate with the regimen was 60% (95% CI, 45%-72%); at 24 months, this rate was 52% (95% CI, 40%-65%).

The median duration of response (DOR) with the combination in this population was 24.1 months (95% CI, 9.9–not reached). 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.

The 12-, 18-, and 24-month rates of bladder cancer–specific progression-free survival (PFS) were 92% (95% CI, 83.4%-96.4%), 91% (95% CI, 81.2%-95.4%), and 91% (95% CI, 81.2%-95.4%), respectively. Moreover, the bladder cancer–specific overall survival (OS) rate was 100%.

“This immunotherapy represents a potential new option for bladder cancer patients who fail to respond to BCG, the current standard of care. The results of the study of N-803 plus BCG indicate that this combination provides a durable response with a reduced need for cystectomy,” Patrick Soon-Shiong, MD, executive chairman and global chief scientific and medical officer at ImmunityBio, Inc., stated in a press release. “We believe that the durable responses seen in this study provide further support for our hypothesis that by orchestrating natural killer cells, T cells, and memory T cells, long-term durable remissions can be achieved in patients suffering from cancer.”

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

Participants were given 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 permitted 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 comprised CR duration, cystectomy avoidance, and time to cystectomy. Investigators also examined serious toxicities and immune adverse effects (AEs).

The median ages in cohorts A and B were 72.8 years and 71.7 years, respectively. Most patients were older than 65 years (74% vs 74%, respectively), male (87% vs 84%), and had an ECOG performance status of 0 (82% vs 77%). In both cohorts, the mean number of transurethral resections of the bladder tumor was 4. Then mean number of prior BCG doses received in cohorts A and B were 16.6 and 12.3, respectively.

Additional data presented during the 2022 AUA Annual Meeting showed that at a median follow-up of 20.7 months, the median disease-free survival in those with papillary disease was 23.6 months. At 12 months, the DFS rate in this cohort was 57% (95% CI, 44%-68%); these rates at 18 and 24 months were 53% and 48% (95% CI, 34%-60%), respectively. Notably, 95% of these patients avoided radical cystectomy, meeting the secondary end point for the cohort.

Efficacy was maintained across all subsets examined in both cohorts.

The regimen was well tolerated. Grade 1 and 2 toxicities that were related to treatment included dysuria (22%), pollakiuria (19%), hematuria (18%), fatigue (16%), micturition urgency (12%), chills (7%), bladder spasm (6%), pyrexia (5%), urinary tract infection (5%), noninfective cystitis (4%), nocturia (3%), diarrhea (3%), nausea (2%), positive bacterial test (2%), cystitis (2%), influenza-like illness (2%), and urinary tract pain (2%).

Grade 3 treatment-related AEs comprised arthralgia, dysuria, encephalopathy, Escherichia bacteremia, hematuria, myalgia, pain in extremity, pollakiuria, sepsis, urinary tract infection, and reduced urine flow. Notably, no grade 4 or 5 effects were observed.

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.

References

1. ImmunityBio submits biologics license application for N-803 plus BCG for patients with BCG-unresponsive non-muscle invasive bladder cancer carcinoma in situ. News release. ImmunityBio, Inc. May 23, 2022. Accessed May 23, 2022. https://bit.ly/3MIALOP
2. Chamie K. IL-15RaFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) CIS and papillary cohorts. Presented at: 2022 AUA Annual Meeting; May 13-16, 2022. New Orleans, LA. PLLBA-01.