BLA Submitted to the FDA for N-803 Plus BCG in BCG-Unresponsive Bladder Cancer


A biologics license application has been submitted to the FDA for N-803 plus Bacillus Calmette-Guérin as treatment for patients with BCG-unresponsive non-muscle invasive bladder cancer in situ with or without Ta or T1 disease.

A biologics license application has been submitted to the FDA for the first-in-class cytokine interleukin-15 (IL-15) superagonist, N-803 (ALT-803), plus Bacillus Calmette-Guérin (BCG) as treatment for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ with or without Ta or T1 disease, according to ImmunityBio, Inc.1

The basis of the BLA comes from the results of prior studies in bladder cancer including the pivotal QUILT 3032 study (NCT03022825). Within the trial, findings revealed that 71% of patients who had failed on previous therapies demonstrated over a 50% increase in response and median duration compared to other FDA-approved alternatives, such as valrubicin and pembrolizumab (Keytruda), a systemic checkpoint inhibitor therapy for this indication.

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

Previously, N-803 was granted breakthrough therapy and fast track designations by the FDA when used in combination with BCG for the treatment of patients with BCG-unresponsive NMIBC CIS. N-803 plus BCG would be the first new immunotherapy in 23 years for this patient population. The IL-15 superagonist provides a new treatment option for patients with this form of bladder cancer as it is able to be delivered directly to the bladder to induce natural killer cells and T cells.

QUILT-3.032 is a phase 2/3, open-label, single-arm, multicenter study of intravesical BCG plus N-803 or N-803 alone as treatment for patients with BCG unresponsive high-grade NMIBC. Patients enrolled in the study will recieve BCG plus N-803 or N-803 through use of a urinary catheter in the bladder, weekly for 6 consecutive weeks. This time makes up the initial induction treatment period.

Then, after the first disease assessment, patients who are eligible will be given either a 3-week maintenance course or a 6-week re-induction course as the second treatment period at month 3. These patients will continue to receive maintenance treatment in the third treatment period at months 6, 9, 12, and 18, and have the option to receive maintenance treatment in the fourth treatment period at months 24, 30, and 36. The complete duration of the study is 60 months.

A total of 81 patients with histologically confirmed BCG-unresponsive NMIBC were enrolled in the trial who had persistent or recurrent CIS within 12 months of receiving adequate BGC treatment. Primary end points of the trial include complete response (CR) and disease-free rate, with secondary end points including response at 6, 9, 12, 18, and 24 months, and complete response.

Results of the trial were presented at the 2021 American Urological Association Annual Meeting and showed that QUILT 3.032 met its primary end point, with a CR rate of 72% (95% CI, 61%-81%), and a 58.6% (95% CI, 43.1%-71.2%) probability of maintaining a CR for at least 12 months. At a median follow-up of 20.4 months, the median duration of CR was 19.9 months (95% CI, 7.8–not reached).

Additionally, patients who achieved an initial complete response at 3 months showed a 64% (95% CI, 47.3%-77.3%) probability of maintaining that response at 12 months, and a 61% (95% CI, 43.2%-74.5%) probability of maintaining it at 18 months. As of May 2021, the durable response of the combination at 18 months was 30%. Also at this time, a total of 85% of patients had not progressed to radical cystectomy through a data analysis as of this time point.

In regard to safety, there was no incidence of treatment-related serious adverse events (AEs), immune-related AEs, or treatment-related AEs (TRAEs) that were either grade 4/5. Grade 3 TRAEs only occurred in 2 patients and consisted of urinary tract infection and arthralgia. The most frequent grade 1/2 AEs were dysuria (22%), hematuria (16%), and pollakiuria (19%).

Overall, the trial showed that the therapeutic combination had a well-tolerated profile and gave patients a greater chance to avoid radical cystectomy which consists of the removal of the bladder. This surgery remains one of the last remaining options for patients who do not respond to other therapies due to its cost to the healthcare system and the added high risk of mortality and complications that can affect patient quality of life.

Further data from the study will be presented within an oral presentation at the 2022 American Society of Clinical Oncology Annual Meeting on June 3-7.

“The results from the QUILT series of ongoing trials across multiple tumor types, including pancreatic, lung and other solid tumors, could lead to a paradigm shift in cancer therapy that ImmunityBio is developing. We are hopeful that this combination immunotherapy of BCG acting as a prime and N-803 as the boost to the immune system will not only provide a new path for these patients, but also help us continue to broaden our understanding of how we might apply this novel mechanism of action to other difficult-to-treat diseases,” added Patrick Soon-Shiong, in the press release.

  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 25, 2022.
  2. QUILT-3.032: A multicenter clinical trial of intravesical bacillus calmette-guerin (BCG) in combination with ALT-803 (N-803) in patients with BCG unresponsive high grade non-muscle invasive bladder cancer. Accessed May 25, 2022.
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