Efficacy and safety of RC48 alone or combined with PD-1 inhibitors in high-risk non-muscle invasive bladder cancer.

High-risk non-muscle invasive bladder cancer (HR-NMIBC) presents a significant therapeutic challenge due to its high recurrence and progression rates, particularly in patients with human epidermal growth factor receptor 2 (HER2) expression who are unresponsive to or ineligible for Bacillus Calmette–Guérin (BCG) therapy. This study aimed to evaluate the efficacy and safety of the HER2-targeted antibody-drug conjugate (ADC), Disitamab Vedotin (RC48), alone or in combination with PD-1 inhibitors, as a systemic bladder-sparing approach in a real-world HR-NMIBC cohort. We conducted a multicenter, retrospective, real-world study involving 32 patients with HR-NMIBC who received RC48 alone (n = 3) or in combination with PD-1 inhibitors (n = 29) between June 2022 and December 2024. Eligibility criteria included BCG-unresponsive (n = 7) or BCG-ineligible (n = 25). Data were collected on demographics, clinical characteristics, treatment responses, and adverse events. The primary endpoint was complete response rate (CRR). Secondary endpoints included event-free survival (EFS), duration of complete response (DoCR), 6-month bladder preservation rate, and safety. At a median follow-up of 13.3 months, the overall CRR was 71.9% (23/32; 95% CI: 53.3%–86.3%). In the BCG-unresponsive and BCG-ineligible subgroups, CRRs were 85.7% (6/7) and 68.0% (17/25), respectively. The median EFS for the overall cohort was 22.1 months (95% CI: 16.7–27.4), with no significant difference between the BCG subgroups (P = 0.98). Among the 23 responders, the median DoCR was 16.9 months (95% CI: 13.1–20.7). Treatment-related adverse events (TRAEs) occurred in 53.1% of patients, primarily Grade 1–2 peripheral neuropathy (21.9%) and rash (21.9%). Grade ≥ 3 TRAEs were rare (6.3%). In this real-world study, RC48-based systemic therapy, particularly in combination with PD-1 inhibitors, demonstrates promising preliminary activity and a manageable safety profile in BCG-unresponsive or BCG-ineligible HR-NMIBC. Large prospective trials are required to confirm long-term durability and the optimal role of this systemic approach.