The Phase II single-arm multicenter trial targeted BCG unresponsive high grade NMIBC patients who refused radical cystectomy. Two cohorts were enrolled: cohort A included patients with CIS with or without Ta or T1 tumors while cohort B only had Ta and/or T1 disease. Patients were then treated with intravesical N-803 + BCG in an induction schedule of weekly treatments for 6 weeks. At 3 months, patients were re-evaluated by cystoscopy and biopsy and either treated with a second induction course or a 3-week maintenance course consisting of weekly treatments for 3 weeks. Maintenance courses continued at 6, 9, 12, and 18 months for eligible patients.
N-803 (also known as ALT-803) is an IL-15 immunostimulatory protein complex (IL-15RαFc) that can promote activation and proliferation of NK (natural killer) cells and CD8+ T cells without recruiting regulatory T cells. It was initially evaluated in a phase Ib trial as an intravesical agent in combination with BCG (NCT02138734) for BCG-naïve patients. Remarkably, all patients on the trial remained disease-free at 24 months; however, as a single arm study, the responses could have been due to the BCG. Therefore, a randomized trial is underway in BCG-naïve patients. In preclinical experiments, the combination of N-803 and BCG reduced tumor burden and recruited cytotoxic T lymphocytes. This led to the combination of intravesical N-803 and BCG being evaluated in BCG unresponsive, high grade NMIBC. Initial findings of this study were just reported at the AUA annual meeting.
The primary endpoint was complete response (CR) rate of CIS at any time point in cohort A and the disease-free rate at 12 months in cohort B.
This trial is limited for many reasons mainly because this is an early analysis with accrual still ongoing and analysis being limited to few patients. Nevertheless, important takeaways from this interim analysis are that 1) CIS patients had a high CR rate (with some CRs as long as 12-18 months) and 2) patients with papillary only disease had a 77% 6-month disease-free survival rate. CIS is historically difficult to treat when unresponsive to BCG and so the high CR rate in cohort A is extremely encouraging. Furthermore, the use of intravesical N-803 in combination with BCG may emerge to be a less toxic, less cumbersome, and less costly approach to BCG unresponsive disease than systemic immunotherapies that are now under evaluation.
62 patients have been enrolled to date on this trial with 35 patients with CIS (cohort A) and 27 patients with papillary tumor only (cohort B). In cohort A, of 18 evaluable patients, 16 (89%) have achieved CR. In cohort B, of 13 evaluable patients, 10 (77%) demonstrated no disease at their 3-month and 6-month assessment. Of the 8 patients evaluated beyond this time point, no recurrences have been noted. Three treatment-related adverse events (AEs) were reported (infection, anemia, and bacteremia) ranging grades 2-3. None of the patients experienced immune-related AEs.