IL-15RαFc superagonist SHR-1501 with or without bacille Calmette Guerin (BCG) for high-risk non-muscle invasive bladder cancer (NMIBC): A phase 1/2 study.

4606 Background: BCG is the standard therapy after transurethral resection of bladder tumor for high-risk NMIBC. IL-15 agonists can enhance the immune response induced by BCG via stimulating the proliferation and activation of natural killer cells and CD8+ cytotoxic T cells, without inducing regulatory T cells. SHR-1501 is an IL-15 agonist fusion protein, composed of a humanized antibody Fc region fused with IL-15 and IL-15Rα sushi domain. In this phase 1/2 study, we assessed the safety, tolerability, and efficacy of SHR-1501 in patients (pts) with high-risk NMIBC. Methods: The study comprised dose-escalation phase 1a and 1b parts of SHR-1501 alone or in combination with BCG in pts with high-risk NMIBC, followed by a phase 2 part of SHR-1501 plus BCG in multiple cohorts, including pts with BCG-naive NMIBC (cohort A), BCG-unresponsive NMIBC carcinoma in situ (CIS; cohort B), and BCG-unresponsive high-grade Ta/T1 NMIBC without CIS (cohort C). All pts received intravesical study treatment weekly for 6 weeks during induction period. During maintenance period, instillations occurred weekly for the first 3 weeks at 3, 6, 12, 18, and 24 months after the initial induction instillation. Primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose in phase 1a and 1b parts; and was complete response (CR) rate for cohort B and 12-mo disease-free survival (DFS) rate for cohorts A and C in phase 2 part. Results: As of Sep 7, 2024, 84 pts were enrolled (n = 8 in phase 1a; n = 6 in phase 1b; n = 29, 17, and 24 in cohorts A, B, and C in phase 2). In phase 1a part of SHR-1501 alone (200, 400, and 600 μg) and phase 1b part of SHR-1501 (600 μg) plus BCG (120 mg), no DLTs were observed, and MTD was not reached. Thus, 600 μg of SHR-1501 plus 120 mg of BCG was used in phase 2 part. Treatment-related adverse events (TRAEs) occurred in 4 (50.0%) of 8 pts with SHR-1501 and 53 (69.7%) of 76 pts with SHR-1501 + BCG. Grade 3 TRAEs were reported in 1 (12.5%) pt with SHR-1501 (urinary tract infection) and 7 (9.2%) pts with SHR-1501 + BCG (urinary tract infection and hypertension occurred in > 1 pt). No grade 4 or 5 TRAEs were reported. No serious TRAEs occurred. Of the efficacy evaluable pts in cohort B, the CR rate at 3 or 6 months was 90.9% (10/11). In cohorts A and C, the 12-month DFS rate was not reached. The 9-month DFS rate was 94.4% (95% CI, 66.6-99.2) in cohort A and 53.9% (95% CI, 15.5-81.4) in cohort C. Conclusions: SHR-1501 alone or in combination with BCG was well-tolerable and demonstrated a favorable efficacy in BCG-naive and BCG-unresponsive high-risk NMIBC pts, supporting further investigations. Clinical trial information: NCT05410730 .