ASCO GU 2022: Positive Efficacy and Safety Phase 3 Results in Both CIS and Papillary Cohorts BCG-Unresponsive NMIBC After IL-15RαFc Superagonist N-803 (Anktiva) and BCG Infusion

( The 2022 GU ASCO Annual meeting featured a session on demystifying next-generation sequencing in urothelial carcinoma, including a presentation by Dr. Sam Chang and colleagues reporting results of a phase 3 trial assessing IL-15RαFc superagonist N-803 (Anktiva) and BCG for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Dr. Chang notes that BCG induces (aka primes) trained immunity in the treatment of superficial bladder cancer by activating NK and T cell killing of bladder cancer cells. Furthermore, innate immune memory results in a prolonged durable complete response. Thus, the question is whether we can potentiate this innate immune response, perhaps through BCG + N-803.

 N-803, a high affinity IL-15 immunostimulatory fusion protein, promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not T reg cells. N-803 has unique mechanisms of action:

  • IL-15 N72D mutation enhances binding to IL-2Rbeta driving proliferation and activation of NK and T cells
  • Allows transpresentation selectively to only the IL-2RBeta/gamma chain of NK and CD8+ T cells without binding to Tregs
  • Increases the half-life and lymphoid recycling and homing, with specific binding to NK, CD8+ T cells, dendritic cells and macrophages


As such, there is a synergistic mechanism of action of BCG (priming) and N-803 (boosting) to induce innate immune memory with prolonged duration of response. 

ASCOGU 2022_Chang_0 

A phase 1b trial demonstrated that intravesical N-803 with BCG induced complete response in all BCG-naïve NMIBC patients, without recurrences for 24 months. An open-label, multicenter phase 3 study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) with CIS and papillary disease is reported. At ASCO GU 2021 results were reported on the CIS Cohort A and at GU ASCO 2022 Dr. Chang now reports the full enrollment of CIS cohort (n = 83) and interim analysis of papillary Cohort B (n = 77) in BCG unresponsive NMIBC (n = 154).

 All treated patients in this trial received intravesical N-803 plus BCG. The primary endpoints for papillary and CIS were disease free rate at 12 months and complete response, respectively. Secondary endpoints included duration of response and cystectomy free rate. Of note, it is important to highlight that these patients were heavily pretreated with a median of 12 BCG doses before enrolment.

Among Cohort A (CIS), there were 83 patients enrolled. With a 23.9 month median follow-up, the complete response rate was 71% (95% CI 60.1%, 80.5%), with median duration for 3-month responders of 24.1 months and a 55% probability of maintaining this complete response for ≥ 18-months (95% CI 40.1%, 67.3%). The cystectomy free rate in responders was 93%, with a 100% cancer specific survival at 24-months. The 12 month (62%) and 24 month (52%) durable complete response in Cohort A is as follows:


ASCOGU 2022_Chang_1 


Importantly, this benefit was seen across all subgroups examined.

Among Cohort B (Papillary), to date, there were 77 patients enrolled. With a median follow-up of 20.7 months, the primary endpoint was met with a disease-free rate at 12-months of 57% (95% CI 44%, 68%) and 53% at 18-months (95% CI 40%, 65%). The cystectomy free rate was 95%, with a 99% cancer-specific survival at 24-months. The 12 month (57%) and 24 month (48%) durable complete response in Cohort B was similar to Cohort A. Again, this benefit was seen across all subgroups examined. With regards to adverse events in cohorts A (CIS) and B (papillary), there were no treatment-related grade 4/5 adverse events, no serious treatment-related adverse events and no immune-related adverse events: 

ASCOGU 2022_Chang_2 

Dr. Chang concluded this presentation of this phase 3 trial assessing IL-15RαFc superagonist N-803 and BCG for patients with BCG-unresponsive NMIBC with the following take-home messages: 

  • N-803 and BCG was safe and well-tolerated with no treatment-related or immune-related serious adverse events
  • The primary endpoints of both CIS and papillary disease were met with a complete response rate of 71% and 12-month disease-free rate of 57%, respectively
  • Durable responses were noted in both cohorts and the therapy resulted in significant avoidance of cystectomy with a cystectomy free rate of 92% and a 24-month cancer-specific survival of 99.5%
  • Given the observed strong efficacy, favorable adverse event profile, and mode of administration, N-803 represents a significant advance in the treatment option compared to existing therapies for BCG unresponsive CIS and papillary NMIBC


Presented By: Sam S. Chang, MD, MBA, Vanderbilt University Medical Center, Nashville, TN

Co-Authors: Karim Chamie, Mark L. Gonzalgo, Eugene V. Kramolowsky, Wade J. Sexton, Sandeep K. Reddy, Paul Bhar, Megan Huang, Patrick Soon-Shiong

Affiliations: University of California Los Angeles, Los Angeles, CA, Department of Urology, University of Miami Miller School of Medicine, Miami, FL, Virginia Urology Center PC, Richmond, VA, Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, ImmunityBio, Culver City, CA, ImmunityBio, Inc, Morrisville, NC


Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022  

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