780 Background: Nectin-4 is the primary target of enfortumab vedotin (EV), an antibody-drug conjugate approved for metastatic urothelial carcinoma (mUC). Nectin-4 frequently co-expresses with HER2 (ERBB2) in urothelial tumors, suggesting overlapping molecular phenotypes. HER2 IHC adequately stratifies EV/EVP outcomes remains unclear. This study evaluates whether HER2 IHC reliably predicts response to EV versus EVP in mUC. Methods: We retrospectively abstracted all treatment lines receiving EV or EVP (2021–2024). The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were PFS/OS from treatment start using a 42-day landmark Kaplan–Meier analysis. Prespecified IHC splits were 2-group (IHC 2/3 vs 0/1) and 3-group (0/1 vs 2 vs 3). Exploratory SISH-integrated schemas were: two-tier (IHC3 or IHC2/SISH+ vs IHC2/SISH− or 0/1) and three-tier (HER2-high: IHC3 or IHC2/SISH+; intermediate: IHC2/SISH−; negative: IHC0/1). Fisher’s exact test compared ORR; log-rank compared survival. Analyses were EV, EVP, and pooled. Results: Among 64 evaluable lines with HER2 IHC and response, IHC 2/3 vs 0/1 enriched for response: EVP 83.3% (20/24) vs 40.0% (4/10), p =0.034; EV 50.0% (12/24) vs 16.7% (1/6), p =0.196 (same direction, underpowered); pooled 66.7% (32/48) vs 31.3% (5/16), p =0.019. The 3-group IHC model showed a graded increase in ORR (3 > 2 > 0/1) with global significance in pooled ( p =0.037) and EVP ( p =0.018) cohorts (EV non-significant, p =0.305). Landmark PFS mirrored ORR: pooled median 7.42 vs 2.92 months (IHC2/3 vs 0/1; p =0.129); EVP 8.31 vs 4.30 ( p =0.234); EV 4.83 vs 1.35 ( p =0.308). OS was not interpretable due to insufficient events. Adding SISH did not change the clinical signal: SISH-integrated two-/three-tier schemas reproduced the same gradients and did not outperform IHC-only; defining HER2-positivity by SISH alone likewise failed to exceed the simple IHC 2/3 vs 0/1 split. Conclusions: In real-world mUC, HER2 IHC alone—independent of SISH—reliably enriches for benefit with EV-based therapy, with the clearest separation in EVP. A pragmatic IHC-only approach using 2-group or 3-group stratification is readily implementable. Prospective validation is warranted. ORR and landmark PFS by IHC 2/3 vs 0/1. Cohort IHC 2/3 ORR (k/n) IHC 0/1 ORR (k/n) Fisher p PFS, mo (2/3 vs 0/1) Log-rank p EVP 83.3% (20/24) 40.0% (4/10) 0.034 8.31 vs 4.30 0.234 EV 50.0% (12/24) 16.7% (1/6) 0.196 4.83 vs 1.35 0.308 EV+EVP pooled 66.7% (32/48) 31.3% (5/16) 0.019 7.42 vs 2.92 0.129
Jo et al. (2026) studied this question.