N-803 Plus BCG Generates Strong, Durable Response in Non–Muscle Invasive Bladder Cancer

N-803, a novel IL-15 superagonist, in combination with intravesical Bacillus Calmette–Guérin (BCG) induced an overall response in more than two-thirds of patients with non–muscle invasive bladder cancer (NMIBC), according to findings from the registrational QUILT 3.032 trial (NCT03022825). Findings recently published in NEJM Evidence also demonstrated a median duration of response (DOR) longer than 2 years with the combination.¹

“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,” Patrick Soon-Shiong, MD, executive chairman and global chief scientific and medical officer with ImmunityBio, said in a news release.² The biotechnology firm has developed N-803.

“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,” he added. “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.”

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 received 400 μg/instillation N-803 with (n = 84; cohort A) or without (n = 10; cohort C) 50 mg/instillation BCG. Patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC also received N-803 plus BCG (n = 77; cohort B).

All patients received study treatment through a urinary catheter in the bladder weekly for 6 consecutive weeks during the induction treatment period. Response assessments occurred every 3 months through month 24, and every 6 months from month 24 to month 60 for all cohorts.

At a median follow-up of 23.9 months (range, 3.2-37.5), 71% (95% CI, 59.6%-80.3%) of patients evaluable for response in cohort A had complete response (CR) with a median duration of 26.6 months (95% CI, 9.9-not reached [NR]). The 12-month CR rate was 45% (95% CI, 34.1%-56.5%).

At 24 months, the Kaplan-Meier–estimated probability of avoiding cystectomy was 89.2% and the disease-specific survival rate was 100% in patients with CR. The estimated probability of remaining cystectomy free for at least 24 months was 89.2% in responders vs 63.2% in nonresponders.

In cohort B, the Kaplan–Meier estimated DFS rate was 55.4% (95% CI, 42.0%-66.8%) at 12 months and 48.3% (95% CI, 34.5%-60.7%) at 24 months among 72 patients evaluable for response. The median DFS was 19.3 months (95% CI, 7.4-NR) and the cystectomy rate was 7%.

At a median follow-up of 7.9 months (range, 4.1-11.8) in cohort C, 20% (n = 2/10) of patients achieved CR at 3 months and only 1 (10%) maintained CR at 6 months. Investigators discontinued this cohort due to futility after 6 months.

NMIBC represents about 80% of new bladder cancer diagnoses. Patients with intermediate- or high-risk disease typically receive transurethral resection of the bladder tumor (TURBT) followed by BCG intravesical instillation. However, the recurrence rate is 30% to 40% even in patients who receive adequate treatment with BCG, and up to 50% of patients who achieve CR will relapse. Study authors noted that “patients with BCG-unresponsive NMIBC are extremely unlikely to benefit from additional BCG therapy and represent a patient population in need of novel treatment options.”

Recent study results suggest that BCG establishes “trained immunity” as the molecular basis for its immunotherapeutic effect in bladder cancer and that this trained immunity may be enhanced with a second unrelated stimulus. Investigators in the QUILT 3.032 trial hypothesized that N-803 could act as this secondary unrelated stimulus which would induce proliferation of NK and T cells and synergistically enhance BCG efficacy.

To be eligible for enrollment, patients had to be free from resectable disease following TURBT. Those with high-grade Ta and/or T1 disease had to have undergone a complete resection before study treatment.

Key exclusion criteria included life expectancy of less than 2 years, inadequate organ function, clinical signs of severe cardiac dysfunction, and history or evidence of muscle-invasive, locally advanced, metastatic and/or extravesical bladder cancer, or any other cancer, other than nonmelanoma skin cancer, within the past 5 years.

The primary end point for cohorts A and C was CR rate at any time as assessed by urine cytology, cystoscopy, and local pathology results. The primary end point for cohort B was 12-month disease-free survival (DFS) rate.

Investigators concluded that the safety profile of the combination is comparable to BCG monotherapy. In cohorts A and C (n = 161), the most frequent grade 3 treatment-emergent adverse effects (TEAEs) included hematuria (2%) and urinary tract infection (2%); the incidence of all other TEAEs was 1%. There was a single incidence (1%) of a grade 5 TEAE, a cardiac arrest, and 3 grade 3 immune-related TEAEs.

Twenty-four (15%) patients experienced TEAEs requiring hospitalization, 8 (5%) of which were bladder related. The most common such event was hematuria (2%).

Seven (70%) patients in cohort C experienced at least 1 TEAE, all of which were grade 1/2 except for a grade 3 stroke in one patient that led to hospitalization.

The FDA is currently reviewing the biologics license application (BLA) for N-803 plus BCG for the treatment of NMIBC CIS. The agency is scheduled to make a ruling by May 23, 2023.

References

1. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 superagonist NAI in BCG-unresponsive non–muscle-invasive bladder cancer. NEJM Evid. Published online November 10, 2022. doi:10.1056/EVIDoa2200167
2. NEJM Evidence publishes results for ImmunityBio’s QUILT 3.032 registrational trial of IL-15 superagonist N-803 plus BCG in patients with bladder cancer. News release. ImmunityBio. November 10, 2022. Accessed January 3, 2022. https://bwnews.pr/3Igrle9