On November 10, 2022 ImmunityBio, Inc. (NASDAQ: IBRX),– NEJM Evidence reported that has published results from the QUILT 3.032 trial studying N-803 plus BCG in adults with NMIBC CIS with or without Ta/T1 papillary disease (Press release, ImmunityBio, NOV 10, 2022, View Source [SID1234623729]). These positive data form the basis of ImmunityBio’s BLA for BCG-unresponsive NMIBC CIS, which the FDA accepted for review in July 2022.

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The published results demonstrate that in patients with BCG-unresponsive NMIBC CIS and papillary disease, BCG plus N-803 (referred to as NAI) CRs were achieved with a persistence of effect with 90% probability of avoiding cystectomies in responders, a life-changing procedure of removing the bladder, and 100% bladder cancer-specific survival at 24 months. This investigational therapy represents an important clinical benefit addressing an unmet need of avoiding a cystectomy in this high-risk bladder cancer population.

"The peer review and publication of data in NEJM Evidence highlights the significance of the positive results of the QUILT 3.032 trial in patients with BCG-unresponsive NMIBC," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio. "We’re targeting the 10th most commonly diagnosed cancer and the one with the highest lifetime treatment costs per patient as a result of the prolonged course of the disease and the need for repeated surgical and treatment intervention. These data further our understanding of N-803’s unique role in potentially boosting the proliferation of natural killer and T cells while synergistically enhancing BCG efficacy."

Patients with intermediate or high-risk NMIBC typically receive a treatment of transurethral resection of the bladder tumor (TURBT) followed by BCG intravesical instillation. However, cancer will recur in 30% to 40% of patients with NMIBC despite adequate treatment with BCG. Moreover, even among those in whom a complete response is achieved with BCG, up to 50% see their cancer return.

Treatment options for BCG-unresponsive NMIBC patients are limited. Pembrolizumab was approved by the FDA for this indication in 2020, based on findings from the KEYNOTE-057 study in which the CR rate in NMIBC CIS patients was 41% with a median response duration of 16.2 months. The combination of N-803 plus BCG produced both a higher CR rate and more durable responses.

In patients who received intravesical N-803 plus BCG (cohort A), a CR was achieved in 58 (71%) of 82 patients (95% confidence interval [CI]=59.6 to 80.3; median follow-up, 23.9 months), with a median duration of 26.6 months 95% CI 59.9 months to [upper bound not reached]). At 24 months in patients with CR, the Kaplan–Meier–estimated probability of avoiding cystectomy and of disease-specific survival was 89.2% and 100%, respectively.

In patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC who received N-803 plus BCG (cohort B), the Kaplan–Meier–estimated disease-free survival (DFS) rate was 55.4% (95% CI=42.0% to 66.8%) at 12 months, with median DFS of 19.3 months (95% CI=7.4 months to [upper bound not reached]).

Most adverse events for patients receiving BCG plus NAI were grade 1 to 2 (86%) and comparable to adverse events associated with BCG alone.

About the QUILT 3.032 Trial

In this phase 2/3, open-label, multicenter study, patients with BCG-unresponsive bladder carcinoma in situ (CIS) with or without Ta/T1 papillary disease were treated with intravesical N-803 plus BCG (cohort A) or N-803 alone (cohort C). Patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC also received N-803 plus BCG (cohort B). The primary end point was the incidence of CR at the 3- or 6-month assessment visit for cohorts A and C, and the disease-free survival (DFS) rate at 12 months for cohort B. Durability, cystectomy avoidance, progression-free survival, disease-specific survival, and overall survival were secondary end points for cohort A.

The results of this phase 2/3 study are currently being reviewed by the FDA, and a decision from the FDA regarding approval for use of the biologics N-803 plus BCG in adults with BCG-unresponsive NMIBC CIS is expected on May 23, 2023.

ImmunityBio’s IL-15 superagonist N-803

The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 (generic name nogapendekin alfa inbakicept or NAI) is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation. N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 has been studied in more than 700 patients in multiple phase 1 and 2 trials in both liquid and solid tumors. In addition to the study in NMIBC, it is currently being studied in trials for pancreatic cancer, non-small-cell lung cancer, non-Hodgkin’s lymphoma, and HIV.

N-803 has received both Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC CIS, as well as Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC CIS. However, it is important to note such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval. Seminal patents covering intravesical administration of BCG and N-803 were issued (US 11,173,191 B2 and US 9,925,247 B2) providing term coverage until 2035.