PUNCH03: Preliminary results from a phase II study of disitamab vedotin combined with tislelizumab and Bacillus Calmette-Guerin (BCG) in Her2-positive high-risk non-muscle-invasive bladder cancer (HR NMIBC).

4597 Background: Disitamab vedotin (RC48) was a novel antibody drug conjugate that targets the Her2 protein. The KEYNOTE-057 study has supported the benefits of PD-1 inhibitor in HR NMIBC patients (pts). Our study was established to evaluate the efficacy and safety of RC48 combined with tislelizumab and BCG as a bladder-preserving treatment for Her2-positive HR NMIBC pts. Methods: This open-label phase II study enrolled BCG-naïve HR NMIBC pts with multiple papillary tumors (high-grade Ta or T1 tumors), and all pts were Her2-positive (IHC 2+ or 3+). Firstly, the papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Secondly, pts were administered RC48 (2.0 mg/kg, ivgtt), every 2 weeks for 1 cycle, and were administered tislelizumab (200 mg, ivgtt), every 3 weeks for 1 cycle. Then, pts received second TURBT. Finally, pts received at least 1 year of tislelizumab (200 mg, Q3W, ivgtt). Meanwhile, pts were administered 3 - 5 cycles of RC48 (2.0 mg/kg, Q2W, ivgtt) and received 18 instillations of BCG. Specifically, pts were started on an induction course of BCG with 6 instillations every week, followed by maintenance with 3 instillations every 2 weeks and 9 instillations every 4 weeks. The primary end point was recurrence-free survival (RFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary end points were bladder-preservation rate, OS and safety. Our study estimated a RFS rate at 12 months was no less than 85% and the study would enroll 38 pts. Results: By Aug. 2025, 24 eligible pts were enrolled and analyzed (male 87.5%; median age 63 years (38-85); IHC 2+ =58.3%, IHC 3+ =41.7%; tumor size≥3 cm (50%); cT1=100.0%; 75.0% multiple papillary tumours. Median follow-up was 6.1 months (3.1-14.2), the median number of tislelizumab cycles was 10 (4-16) and RC48 cycles was 6 (4-8). All pts completed tislelizumab and RC48 treatment during the induction therapy. During the follow-up, only two pts showed reappearance and one pt received radical cystectomy. The bladder-preservation rate was 95.8% (95%CI, 90.7%-100%). The common treatment related adverse events (TRAEs) of any grade were fatigue (54.2%), alopecia (33.0%), anorexia (33.0%) and peripheral neuropathy (16.8%). None 3-5 grade of TRAEs were observed. Conclusions: Our preliminary results supported the use of disitamab vedotin combined with tislelizumab and BCG as a bladder-preserving therapy for Her2-positive HR NMIBC pts. Clinical trial information: ChiCTR2400093839.