A retrospective real-world study of disitamab vedotin combined with tislelizumab versus chemotherapy in patients with previously untreated metastatic urothelial carcinoma.

733 Background: Eligible patients with metastatic urothelial carcinoma (mUC) typically receive platinum-based chemotherapy as first-line therapy. Recently, antibody-drug conjugates (ADCs) combined with PD-1 antibody have shown good efficacy and safety in metastatic urothelial carcinoma (mUC). And HER2-positive thought to be an unfavorable prognostic factor and associated with poor outcomes but can benefit from anti-HER2 ADCs such as Disitamab Vedotin (RC48-ADC). The aim of this retrospective study is to evaluate the efficacy and safety of RC48-based therapy in real-world untreated mUC, especially in comparison to standard chemotherapy. Methods: We retrospectively collected data from 70 consecutive patients with mUC who received routine care between July 2022 and December 2023 including 30 received RC48-ADC plus Tislelizumab (DT-group) and 40 received the conventional regimen of Gemcitabine plus Cisplatin (GC-group). Last follow-up on 30 March 2024. The primary endpoints were objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: The median age of the DT-group and GC-group patients were 67-y and 64-y, with 66.7% (n=20) and 82.5% (n=33) HER-2 negative (identified as IHC 0 or 1+). Baseline characteristics of the two groups, including age, gender, pathological grading, ECOG score, tumour location, metastasis and HER-2 expression showed no statistically difference (P > 0.05). The ORR in DT-group was 1.5 times higher than in GC-group, reaching 73.3% (22/30) versus 47.5% (19/40) with a higher CR rate (20% vs 0%). Even in HER-2 negative subgroup from DT-group, the RC48-ADC plus Tislelizumab therapy achieved impressive outcomes (ORR 55% (11/20)) comparable to chemotherapy. For survival analyses, PFS was longer in the DT-group than in GC-group (median, 10.98 months vs. 7.67 months; P<0.005), as was OS (median, not reached vs. 11.34 months). Two groups showed a similar safety profile (p > 0.05). The most reported TRAEs were bone marrow suppression, gastrointestinal and hepatobiliary disorders, malaise, alopecia and rash, and no ≥ grade 3 TRAEs or treatment-related deaths were reported. Conclusions: This retrospective study of patients with treatment-naïve mUC demonstrated administration of RC48 for real-world patients is both effective and safe. Several global clinical trials (DV-001, RC48-G001) evaluating efficacy and safety of RC48-ADC in combination with immunotherapy are ongoing. These data further solidify the benefit of anti-HER2 ADC combined with checkpoint inhibitors for frontline treatment of patients with mUC.