Responses to trastuzumab deruxtecan (T-Dxd) in HER2 IHC spectrum 2+ versus 3+ urothelial carcinoma across lines of therapy.

4581 Background: The role of HER2 as a therapeutically actionable target has been validated with the DESTINY-PanTumor02 trial demonstrating meaningful clinical benefit to T-DXd across HER2-expressing bladder malignancies leading to the FDA approval in the immunohistochemical (IHC) 3+ population. We explore the clinical outcome of real-world patients with urothelial carcinoma (UCa) on T-DXd and its correlation with molecular and pathological findings across all the HER-2 IHC scores (e.g., 0 to 3+). Methods: We reviewed the clinical, pathologic, and molecular data of 29 patients with UCa, who received T-DXd between April 2024 and November 2025. Baseline clinical variables included age, sex, ECOG performance status, visceral metastases, line of therapy, and HER2 IHC score (adapted from gastric cancer scoring). Available genomic data included tumor mutational burden (TMB ≥10 mut/Mb), ERBB2 amplification and mutation, DNA damage response (DDR), FGFR alterations, and microsatellite instability (MSI) status. Outcomes of interest included Objective Response Rate (ORR), Disease Control Rate (DCR), and progression-free survival (PFS) and overall survival (OS) which were estimated using Kaplan–Meier methods and compared across groups using the log-rank test. Cox proportional hazards models were used to estimate hazard ratios. Results: Higher HER2 IHC scores were associated with greater clinical activity and higher ORR in IHC 2+ (n=7; 42.9; 95% CI = 9.9–81.6%) tumors and HER2 IHC 3+ (n=20; 55.0; 95% CI =31.5–76.9%). However, no response was seen in HER2 IHC 1+ (n=2). Median duration of response was 15.6 months in HER2 IHC 2+ and 11.6 months in HER2 IHC 3+ (15/30 patients received T-DXd in ≥3 lines). PFS and OS appeared comparable between HER2 2+ and HER2 3+ tumors, with no statistically significant difference by log-rank test (p = 0.67, p = 0.79 respectively). Elevated TMB was observed in 6/12 cases. ERBB2 amplification was detected in 3/10 of cases and ERBB2 mutation in 5/13 of cases. Alterations in DDR related genes and FGFR were identified in patients 2/11 and 1/12 respectively, while MSI-H was not observed in any case. Responses were numerically higher when T-DXd was given in 2 nd line (53.3%, 95% CI 26.6–78.7%) than in further lines (42.9%, 95% CI 17.7–71.1%) and so was DCR 93% (95% CI 68.1–99.8%) in 2 nd line than 71.4% (95% CI 41-91.6%) in further (≥3) lines. Conclusions: T-DXd demonstrated meaningful clinical activity not only in IHC 3+ but in IHC 2+ tumors as well, which is consistent with the results of the DESTINY-PanTumor02 trial. In this limited sample size, there was no statistically significant association between genomic features and patient outcomes. Larger studies are needed to further find predictors across different levels of IHC expression. HER2 IHC Score n Responders (CR/PR) ORR (%) 95% CI 1+ 2 0 0.0 0.0–84.2% 2+ 7 3 42.9 9.9–81.6% 3+ 20 11 55.0 31.5–76.9%