Addition of N-803 Results in Efficacy, Safety in NMIBC CIS Unresponsive to BCG

Patients with Bacillus Calmette-Guerin (BCG)–unresponsive, non-muscle invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) who were treated with N-803 (also known as ALT-803) added to BCG Vaccine experienced promising response rates and a tolerable safety profile, according to data presented at the 2021 Genitourinary Cancers Symposium.¹

The findings, taken from cohort A of the phase 2/3 QUILT-3.032 trial (NCT03022825), showed that at a median follow-up of 10.7 months, 71% of evaluable patients (n = 51/72) achieved a complete response (CR) at any time (95% CI, 59%-81%), meeting the primary end point of the study.

Moreover, investigators reported a 56% probability of maintaining a CR with this approach at 12 months (95% CI, 38.8%-70.3%). Among responders, the estimated median duration of CR was 19.2 months (95% CI, 7.3–not reached [NR]). Notably, the majority of patients, or 87.5%, (n = 70/80) have not progressed to radical cystectomy.

“N-803 is an IL-15 superagonist antibody cytokine fusion protein with significant binding capacity to the IL-2R beta and gamma and increased half-life of the Fc receptor,” Karim Chamie, MD, MSHS, an associate professor in residence of urology and Society of Urologic Oncology Fellowship Director at the University of California, Los Angeles, explained during a presentation on the findings. “This results in significant accrual of T cells and natural killer cells without upregulation of regulatory T cells.”

Results from the phase 1 trial examining N-803 plus BCG indicated that all patients (n = 9) with high-risk NMIBC experienced a durable CR or no recurrence. All patients were disease free at 24 months. Based on these data, the FDA granted N-803 a fast track therapy designation in December 2019; this led to the launch of the phase 2/3 trial to further examine this approach.²

To be eligible for enrollment on the trial, patients had to have histologically-confirmed BCG-unresponsive CIS with or without Ta or T1. Investigators defined BCG-unresponsive disease as persistent or recurrent CIS within 12 months of being treated with BCG; at least 5 of 6 doses of initial induction course with at least 2 of 3 doses of maintenance treatment or at least 2 of 6 doses of a second induction course were required.

Eighty patients were enrolled to cohort A and they received 50 mg of BCG in combination with 400 μg of N-803 intravesically weekly x6 induction or single re-induction x3 plus maintenance.

The primary end point of the study is CR at any time with a lower bound 95% confidence interval of 20% or greater. At least 24 of the 80 patients enrolled needed to have experienced a CR to meet this end point. Key secondary end points included duration of CR and CR rate at 6 and 12 months. Other end points included progression-free survival, time to cystectomy, cystectomy rate, overall survival, and CR rate at any time per Central Pathology Review.

The mean age of patients enrolled on the study was 72.5 years, with 84% of patients aged 65 years or older. The majority of patients were male (86%), and most patients were white (90%). Eighty-two percent of patients had an ECOG performance status of 0, while 18% had a status of 1.

The median time from last previous BCG dose to study entry was 6.2 months and the mean time was 8.0 months. Additionally, the mean time from last prior BCG dose to first detected recurrence was 3.6 months with a median time of 2.7 months. Moreover, the median time from first detected recurrence to study entry was 2.3 months with a mean time of 4.6 months. The majority of patients had CIS at first recurrence (69%), with 21% had CIS/Ta and 9% had CIS/T1.

“This is a heavily pretreated cohort with the median number of transurethral resection of the bladder tumor being 5.0 [and] a median number of prior BCG instillations being 16.2,” said Chamie. “One hundred percent of patients received prior BCG. In addition to that, 78% of patients received additional therapy with BCG, including checkpoint inhibitors [3%], chemotherapy [59%], interferon [13%], and vicinium [3%].”

N-803 demonstrated promising results compared with other FDA-approved agents or investigational therapeutics in the space, such as pembrolizumab (Keytruda), which yielded a 41% CR rate at any time and a median duration of response of 16.2 months in responders.³ Similarly, nadofaragene firadenovec (rAd-IFNa/Syn3) elicited a 53% CR rate at any time with a median duration of response of 9.7 months.⁴

“N-803 had a smaller cohort, however, the CR rate at any time was much higher, at 71% compared with 41% and 53% for pembrolizumab and nadofaragene, [respectively],” Chamie reported. Our median duration was also favorable, although this must be taken within the context of a shorter median follow-up of 10.7 months. The cystectomy-free rate of 88% also compares favorably, with only 1 of 10 patients demonstrating extravesical disease.”

The most common any-grade treatment-related adverse effects (TRAEs) included dysuria (18%), hematuria (15%), and pollakiuria (14%). Although grade 3 or higher TRAEs were observed during the study, with grade 3 arthralgia, myalgia, and extremity pain each reported in 1% of patients. Serious AEs were also rare but included cardiac disease (1%), hematuria (1%), and adenocarcinoma of the colon (1%).

Notably, no treatment-related serious AEs, no immune-related systemic AEs, and no grade 5 TRAEs were reported. Moreover, no TRAEs led to treatment discontinuation.

“This is an administration profile that is quite familiar to urologists and favorable as an intravesical agent,” concluded Chamie.

References:

1. Chamie K, Chang S, Gonzalgo M, et al. Phase II/III clinical results of IL-15RαFb superagonist N-803 with BCG in BCG-unresponsive non-invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients (cohort A). J Clin Oncol. 2021;39(suppl 6):510. doi:10.1200/JCO.2021.39.6_suppl.510

2. ImmunityBio granted FDA breakthrough therapy designation for N-803 IL-15 superagonist in non-muscle invasive bladder cancer. News release. BioSpace. December 4, 2019. Accessed February 13, 2021. http://bit.ly/2ZgGAvM

3. Balar AV, Kamat AM, Kilkarni GS, et al. Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): over two years follow-up of KEYNOTE-057. J Clin Oncol. 2020;38(suppl 15):5041-5041. doi:10.1200/JCO.2020.38.15_suppl.5041

4. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet. 2021;22(1):P107-117. doi:10.1016/S1470-2045(20)30540-4