Background: 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. 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 we reported on CIS Cohort A and report here the full enrollment of CIS (n = 81), interim analysis of Papillary Cohort B (n = 73) and the combined efficacy and safety results in BCG unresponsive NMIBC (n = 154). Methods: All treated patients received intravesical N-803 plus BCG. The primary endpoints for papillary and CIS are disease free rate at 12 months and complete response respectively. Secondary endpoints are duration of response and cystectomy free rate. Results: Cohort A (CIS) Efficacy: Fully enrolled n = 81 with a 20.9 month median follow-up. CR rate 72% (95% CI: 60.5%, 81.1%) with median duration for 3-month responders of 24.1 months and a 60% probability of maintaining this CR for ≥ 18-months (95% CI: 43.1%, 73.5%). 12-month cystectomy free rate is 89% (95% CI: 80.1%, 94.6%), with a 100% cancer specific survival at 24-months. Cohort B (Papillary) Efficacy: To date, 73 patients have enrolled with a median follow-up of 17.3 months. The primary endpoint was met with a disease free rate at 12-months is 57% (95% CI: 43.7%, 68.5%) and at 18-months 53% (95% CI: 38.8%, 64.8%). 12-month cystectomy free rate is 95% (95% CI: 84.7%, 98.3%), with a 98% cancer specific survival at 24-months. Combined Efficacy: In the combined group (n = 154) of BCG unresponsive NMIBC, with a 19.3 months median follow-up, the 12 month cystectomy free rate was 92% (95% CI: 85.5%, 95.3%) and the 24 month OS is 94% (95% CI: 86.9%, 97.1%) with 99.5% cancer specific overall survival. Combined Safety: There were 0% treatment related SAE’s and 0% immune related SAE’s, with 4/ 154 (3%) ≥ TR Grade 3 AEs. 0% treatment related deaths have occurred as of Sept 2021 analysis date. Conclusions: N-803 and BCG was safe and well tolerated with zero percent treatment related or immune related SAEs. The primary end points of both CIS and Papillary disease were met with CR rate of 72% 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 and favorable AE 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. Clinical trial information: NCT03022825.