Our NECTIN4 scoring system for predicting enfortumab vedotin response in urothelial carcinoma is just published in @CCR_AACR 🔬 The short version: NECTIN4 is not a failed biomarker. It has been measured in the wrong compartment. 📊 179 EV-treated mUC patients, multicenter, FISH plus IHC, benchmarked against EV-301 EPAR data. Why NECTIN4 looked ubiquitous 🧠 EV-301: median H-score 250, 82.6% ≥150. Our cohort: membranous 160, cytoplasmic 200, combined 260 with 78.2% ≥150. The trial numbers most likely reflect membranous plus cytoplasmic staining. Only the membrane predicts 🎯 ✅ Membranous 2+/3+ vs 0/1+: ORR 55.1% vs 25.5% (p<0.001), mPFS 7.1 vs 2.9 mo (HR 0.45), mOS 12.3 vs 6.9 mo (HR 0.57) ❌ Cytoplasmic: ORR 49.6% vs 39.5% (p=0.4), no PFS or OS signal ❌ Bulk NECTIN4 mRNA: no association Adding cytoplasm drops negativity from 12% to 3.4%. More positives, less information. 📉 The score 🔬 Four tiers (0, 1+, 2+, 3+) adapted from the ASCO/CAP HER2 gastric algorithm, which accounts for incomplete membranous staining. Blinded testing, 44 cases, 3 raters: Fleiss' κ 0.749 across four tiers, 0.874 for 0/1+ vs 2+/3+. Genomics on top 🧬 NECTIN4 amplification in 25.1%: ORR 76.2% vs 36.6%, mPFS 12.2 vs 3.9 mo (HR 0.40), mOS 30.1 vs 8.5 mo (HR 0.33). Restricting FISH to 2+/3+ captures 97.8% of amplified cases and spares 29.1% of patients any molecular testing. ⚡ Integrated three-tier model 1️⃣ Amplified: ORR 76.2%, mOS 30.1 mo 2️⃣ Non-amplified, membranous high: ORR 42.9%, mOS 8.8 mo 3️⃣ Non-amplified, membranous low: ORR 26.1%, mOS 6.9 mo Both markers independent in multivariable models. OS C-index rises from 0.557 to 0.621 when combined. Where this lands 🎯 Not (!) an argument for testing every patient today. With EV+P as first-line standard and few alternatives, a negative result rarely changes management. But with HER2, TROP2 and HER3/EGFR ADCs, NECTIN4 radioligands and T-cell engagers coming, the question shifts from "does the target matter" to "which target first." Unlike HER2-low, EV-301 showed an attenuated effect in NECTIN4-low disease (PFS HR ~0.9, CI crossing 1). ⚠️ Prospective validation running: EVOKE (DRKS00034745) Immense thanks to @niklas_kluemper and Jonas Saal, to Thomas Büttner, Sebastian Rauch and Fabienne Lange, and to every centre and biobank within the GUARDIANS and BRIDGE Consortium 🙏 🔗 doi.org/10.1158/1078-0432.CC…