Combo of N-803 and BCG shows promise in BCG-unresponsive bladder cancer
USA: A combo treatment of IL15RaFc superagonist N-803 (VesAnktiva) and Bacillus Calmette-Guerin (BCG) led to "a clinically meaningful benefit" in patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), according to findings from QUILT-3-032 study. The findings were presented virtually at the 2022 American Urological Association annual meeting held in New Orleans.
Most patients with newly diagnosed bladder cancer have a non-muscle invasive disease and this is a disease space in which there is a significant unmet need. Adjuvant treatment with guideline-recommended is based on proven benefits in disease recurrence for patients with intermediate or high-risk NMIBC and those with carcinoma in situ (CIS).
While BCG is efficacious, many patients eventually develop BCG-unresponsive disease and are at significant risk for progression, recurrence, and mortality. For these patients, there have been minimal options for many years. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that facilitates the proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells.
Intravesical N-803 with BCG was shown to induce complete response in all durable patients for 24 months in phase 1b trials of BCG-naïve patients with NMIBC. Thus, Karim Chamie, the University of California Los Angeles, and colleagues further explored this treatment approach in an open-label, 3 cohort multicenter study (QUILT 3.032) in patients with BCG-unresponsive high-grade NMIBC.
The study included160 subjects who received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. Patients were categorized into two cohorts with differing primary outcomes: for patients with CIS (Cohort A) the primary outcome was the incidence of complete response (CR) at any time while the primary endpoint for those with papillary disease (Cohort B) was the disease-free rate (DFS) at 12 months.
Of the 160 patients, 83 patients had CIS (Cohort A) and 77 had papillary disease (Cohort B). The median age is 72.3 years and 81% are men.
Based on the study, the researchers found the following:
- The mean number of prior TURBTs before enrollment was a median of 12 prior BCG doses.
- Low grade treatment-related AEs (grade 1-2) include dysuria (22%), pollakiuria (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at rates of 7% or less.
- No treatment-related grade 4 or 5 AE was seen.
- No treatment-emergent SAEs were considered treatment-related.
- No immune-related SAEs have been seen.
- Among patients in Cohort A, patients with CIS had a CR rate of 71% (59/83). Among those that responded, the median duration of complete response was 24.1 months. In this group, 91% avoided cystectomy, and 24-month bladder cancer-specific progression-free survival (defined as progression to MIBC) was 96%. The authors further demonstrated favorable outcomes for other survival endpoints.
- The authors further demonstrated complete remission rates in this cohort were consistent across subgroups defined based on numerous stratification criteria.
- In cohort B, patients with papillary disease had disease-free survival of 57% at 12 months and 48% at 24 months. In this group, 95% avoided cystectomy during the observation period. Even among those undergoing cystectomy, this was delayed among responders (N=4) with a median time to surgery of 12.9 months versus 7.8 in non-responders (N=8).
- Pharmacokinetic data show no systemic levels of N-803, confirming that this intravesical therapy is not absorbed.
To conclude, among 160 patients with BCG-unresponsive NMIBC after treatment with intravesical N-803 plus BCG, there is a 99% bladder cancer-specific overall survival at 2 years. In CIS patients, a 71% CR rate was seen with 24.1 months median duration of response and 96% absence of progression to MIBC at 24 months. A 53% DFS rate at 18 months was seen in those with papillary disease.
"Together, these results show that the efficacy and safety profile of N-803+BCG exceeds other available intravesical and systemic options," the authors concluded.
Reference:
American Urological Association. Chamie K, et al "Final clinical results of pivotal trial of IL-15R&[alpha]Fc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) CIS and papillary cohorts" AUA 2022; Abstract PLLBA-01.
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