N-803 Plus BCG Elicits 72% CR in BCG-Unresponsive, High-Grade Non-Muscle Invasive Bladder Cancer

Patrick Soon-Shiong, MD

Intravesical Bacillus Calmette-Guerin (BCG) in combination with N-803 (Anktiva) was found to induce a complete response (CR) rate of 72% in patients with non-muscle invasive bladder cancer (NMIBC) in high-risk carcinoma in situ (CIS) disease, meeting the primary end point of the phase 2/3 QUILT 3.032 trial (NCT03022825).¹

Fifty-one of 71 evaluable patients achieved a CR with the combination, and these patients had a 59% probability of maintaining their response for at least 12 months. Additionally, to date, the median duration of these CRs is 19.2 months.

Regarding safety, only 1% of participants experienced treatment-emergent toxicities that were considered to be serious, although none were determined to be associated with the treatment. The efficacy and safety data reported from the study suggest that N-803/BCG could represent a novel option for BCG-unresponsive CIS, according to ImmunityBio, Inc, the developer of N-803.

“The high rates of progression and recurrence for NMIBC make it one of the most expensive cancers to treat. These preliminary data are heartening and provide additional evidence of the potential for ImmunityBio’s [N-803] in treating a serious and potentially fatal cancer, for which the alternative is a highly invasive radical cystectomy,” Patrick Soon-Shiong, MD, chairman and CEO of ImmuntyBio, stated in a press release. “We expect to file a biologics license application following a meeting with the FDA in 2021.”

Interleukin-15 (IL-15) is a key player in the immune system, as it impacts the development, maintenance, and function of the natural killer and T cells. N-803 is an IL-15 superagonist complex which is comprised of IL-15N72D, an IL-15 mutant, which is bound to an IL-15 receptor α/IgG1 Fc fusion protein. N-803 has been designed to have improved pharmacokinetic properties, longer persistence in lymphoid tissues, and stronger clinical activity vs non-complexed IL-15 in vivo.

The open-label, 3-cohort, multicenter phase 2/3 trial evaluated N-803/BCG in patients with unresponsive, high-grade NMIBC. To be eligible for enrollment, patients had to be aged 18 years or older, have histologic confirmation of NMIBC of the translational cell carcinoma high-grade subtype, a histologically confirmed presence of BCG-unresponsive CIS or BCG-unresponsive high-grade Ta or T1 disease, and an ECOG performance status of 0-2.² Patients also needed to have absence of resectable disease following transurethral resection procedures, and those with high-grade Ta and/or T1 disease should have had complete resection prior to treatment.

All participants received N-803 plus BCG via a urinary catheter in the bladder on a weekly basis for 6 consecutive weeks during the initial induction treatment period. Following the first disease assessment, patients were given either a 3-week maintenance course or a 6-week reinduction course, which was the second treatment period, at month 3. For the third treatment period, eligible patients continued to receive maintenance at months 6, 9, 12, and 18. The duration of the study is 24 months.

The primary end points of cohorts A and C included CR, which was evaluated by looking at the incidence of CR of patients with CIS at any time, and disease-free rate, which was examined at 12 months first study treatment. A key secondary end point of the trial was duration of CR in cohorts A and C and disease-free survival in cohort B.

Previously, in December 2019, the FDA granted a breakthrough therapy designation to N-803 for use in combination with BCG in the treatment of this patient population.³ 

The IL-15 superagonist complex is under evaluation in 2 clinical trials in adult patients with NMIBC. In the QUILT 2.005 trial (NCT02138734), investigators are examining N-803 plus BCG in patients with BCG-naïve NMIBC. 

References

1. ImmunityBio announces primary endpoint met of phase 2/3 trial for BCG unresponsive non-muscle invasive bladder cancer CIS with 72% complete response rate. News release. ImmunityBio, Inc. December 21, 2020. Accessed December 22, 2020. http://bit.ly/3hd2uIM.
2. QUILT-3.032: a multicenter clinical trial of intravesical Bacillus Calmette-Guerin (BCG) in combination with ALT-803 in patients with BCG unresponsive high grade non-muscle invasive bladder cancer. ClinicalTrials.gov. Updated December 22, 2020. Accessed December 22, 2020. https://clinicaltrials.gov/ct2/show/NCT03022825.
3. ImmunityBio granted FDA breakthrough therapy designation for N-803 IL-15 superagonist in non-muscle invasive bladder cancer. News release. ImmunityBio, Inc. December 4, 2019. Accessed December 22, 2020. http://bit.ly/37DtLRf.