Updated results of a phase II study of RC48 in combination with tislelizumab as pre-transurethral resection neoadjuvant therapy for extensive high-risk non–muscle-invasive bladder cancer with HER2 overexpression.

e16596 Background: The combination of antibody-drug conjugates and immune checkpoint inhibitors has shown promising results in patients with advanced and muscle-invasive bladder cancer. However, the efficacy of this combination in high-risk non-muscle invasive bladder cancer (HR-NMIBC) remains unclear. This study aimed to evaluate the safety and efficacy of RC48 in combination with tislelizumab as pre-transurethral resection (pre-TUR) neoadjuvant therapy in patients with extensive HR-NMIBC and HER2 overexpression. Methods: TRUCE-04 is a Phase II, open-label, single-arm trial conducted at the Second Hospital of Tianjin Medical University. From September 2021 to May 2024, 28 patients with extensive HR-NMIBC and HER2 overexpression, whose tumors cannot be completely resected and who were ineligible for or declined radical cystectomy, were enrolled. Patients received intravenous RC48 (120 mg) and tislelizumab (200 mg) every 3 weeks for 3 cycles before TUR. Treatment efficacy was assessed through urine cytology, radiological imaging and pathological examination following transurethral resection and biopsy. The primary endpoint was the complete response rate (CRR), while secondary endpoints included safety and duration of complete response. Results: The safety analysis included all 28 patients, while the efficacy analysis included 26. A complete response (CR) was achieved in 19 patients (73.1%, 95% CI: 54.8–91.3%), and stable disease (SD) was observed in 7 patients (26.9%, 95% CI: 8.7–45.2%), with no progression. The 12-month sustained response rate was 88.9% (95% CI: 75.5–100%), and the 24-month rate was 74.1% (95% CI: 50–100%). Among 12 patients with HER2 IHC 3+, 8 patients (66.7%, 95% CI: 35.4–98.0%) achieved CR. Among 14 patients with HER2 IHC 2+, 11 achieved CR (78.6%, 95% CI: 54.0–100.0%). The most common grade 1–2 treatment-related adverse events (TRAEs) were paresthesia (42.9%), alopecia (39.3%), and pruritus (35.7%). Grade 3–4 TRAEs were reported in 4 patients (14.3%), including fatigue, rash, hypopituitarism, and hyperglycemia. No grade 5 adverse events were observed. Conclusions: Early results from this study suggest that RC48 in combination with tislelizumab shows promising efficacy as pre-TUR neoadjuvant therapy for extensive HR-NMIBC with HER2 overexpression, with a manageable safety profile. Clinical trial information: NCT05495724 .