ASCO GU 2021: Phase II/III Clinical Results of IL-15RαFc Superagonist N-803 With BCG in BCG-Unresponsive NMIBC Carcinoma In Situ Patients

(UroToday.com) Most patients newly diagnosed with bladder cancer have non-muscle invasive disease (NMIBC). For patients with intermediate or high-risk NMIBC and those with carcinoma in situ (CIS), adjuvant treatment with BCG is guideline-recommended on the basis of proven benefits in disease recurrence. While BCG is efficacious, many patients eventually develop BCG-unresponsive disease. For many years, there have been very limited options for these patients. A novel treatment option is N-803 (Anktiva), a mutant IL-15-based immunostimulatory fusion protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells.

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Preliminary data from a phase Ib trial among BCG-naive patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response without recurrence over 24 months of follow-up. Thus, the QUILT 3.032 study was designed as an open-label, 3 cohort multicenter phase II/III study of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825). In a plenary abstract presentation in the Rapid Abstract Session: Urothelial Carcinoma and Rare Tumors session at the 2021 ASCO GU Cancers Symposium, Dr. Karim Chamie, and colleagues report the interim results of this trial in cohort A, with BCG-unresponsive CIS [with or without Ta or T1 disease].

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Among patients with BCG-unresponsive CIS [with or without Ta or T1 disease], all patients in the cohort received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. For this analysis, the primary endpoint in this cohort (A) is the incidence of complete response (CR) of CIS at any time.

As of a data cut-off of December 2020, to date, 80 patients have enrolled in cohort A. Enrolled patients are generally in keeping with a BCG-refractory NMIBC cohort with a mean age of 73 years, a preponderance of men (86%), most being white (90%), and generally good performance status (ECOG PS = 0 in 82%). Further, most patients had CIS at the time of first recurrence (69%) while 21% had CIS and Ta disease and 9% had CIS and T1 disease. Patients were enrolled at a median of 6.2 months from the last BCG dose and 2.3 months from the first detected recurrence. Notably, the median time from the last BCG dose to the first detected recurrence was 2.7 months.

Dr. Chamie noted that this was a heavily pre-treated cohort with a median of 5 prior TURBTs and a median of 16 prior BCG instillations. All patients had received prior BCG. In addition, 78% of patients received additional therapy beyond BCG including checkpoint inhibitors in 3%, chemotherapy in 59%, interferon in 13%, and vicinium in 3%.

Treatment was generally well-tolerated with low-grade treatment-related AEs including dysuria (18%), hematuria 915%), and pollakiuria (14%), urgency (8%), bladder spasm (5%), fatigue (8%), chills (6%), and pyrexia (5%). All other AEs were seen at 6% or less. Treatment-emergent severe adverse events were noted in 9 subjects with a rate of 1% for any given AE. Notably, none of these were deemed treatment-related and no immune-related serious AEs have been noted. Further, there have been no treatment-related discontinuations or treatment-related Grade 5 events.

At this time (with a median follow-up of 10.7 months), a complete response at any time was noted in 51 of 72 evaluable patients (72%). As a result, the primary endpoint was met. To date, 10/80 (12.5%) patients proceeded to cystectomy in this BCG unresponsive population.

Among those who achieved CR, the probability of maintaining a CR for 12 months was 56%, with a median duration of CR of 19.2 (7.6 to not reached) months.

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In comparison to other agents in this disease space, Dr. Chamie emphasized that these data appear to be favorable for N-803.

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Thus, the authors conclude that, in this cohort of the QUILT 3.032 trial, treatment has met the primary endpoint with a CR rate of 72% and a 56% probability of CR patients maintaining CR for at least 12 months. Further, there were no treatment-related serious adverse events and this treatment was well tolerated. This represents a new treatment approach in this rapidly changing disease space.


Presented by: Karim Chamie, MD, Associate Professor of Urology David Geffen School of Medicine at UCLA University of California, Los Angeles

Co-Authors: Sam Chang, Mark L. Gonzalgo, Eugene V. Kramolowsky, Wade J. Sexton, Sandeep K. Reddy, Paul Bhar, Chad Garner, Patrick Soon-Shiong

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Twitter @WallisCJD during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021
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