KEYNOTE-905/EV-303: a major step forward for cisplatin-ineligible MIBC. Perioperative enfortumab vedotin + pembrolizumab (EVP) significantly improved EFS, OS and pCR versus radical cystectomy alone. At 2 years: 🎯 EFS 74.7% vs 39.4% — an absolute difference of 35.3 percentage points. ➡️ Roughly 1 in 3 more patients event-free with perioperative EVP!!! And 57.1% achieved pCR, compared with only 8.6% with surgery (complete TURBT..) alone. Importantly, benefit was broadly consistent across key subgroups in this older, comorbid population, including patients with ECOG PS 2. From my perspective as both a urologist and GU oncologist: if a cisplatin-ineligible patient is considered fit enough for radical cystectomy, the patient can (mostly) also receive at least 3 cycles of neoadjuvant EVP! We finally have the first approved perioperative regimen for cisplatin-ineligible MIBC — and an effective regimen that we should integrate into clinical practice! @Markuseckstein3 @ViktorGruenwald @JoshMeeks @UniklinikBonn @OncoAlert @urotoday @PTarantinoMD @Uroweb @drenriquegrande @PGrivasMDPhD @amerseburger @DrYukselUrun @tompowles1 @Uromigos @OncoBellmunt @montypal @DrChoueiri @neerajaiims @shilpaonc @DrRosenbergMSK @Dr_Aggen

Small cell carcinoma of the bladder: why ADC targets from conventional UC do not simply carry over, and what may work instead 🧵 New in @Histo_Journal: 88 SmCCB from Milan and Erlangen, 79 fully profiled by IHC for ASCL1, NEUROD1, POU2F3, YAP1, HNF4α, NE and tuft cell markers, plus 7 therapeutic targets and NECTIN4 FISH. 🔬 Two phenotypes 🟢 High-NE (57/79): ASCL1-driven, NEUROD1-driven or mixed, diffuse synaptophysin, chromogranin and CD56 🟠 Low-NE (22/79): POU2F3-driven, YAP1-driven or TF-negative, weak or absent NE markers, significantly associated with admixed urothelial, glandular or squamous histology 🎯 ADC and BiTE targets, one by one Nectin-4 (membranous) • Completely negative in 75% (60/80) • Median H-score 0, mean 11.6, max 220 • Higher in Low-NE than High-NE (median 1.5 vs 0, P<0.001), consistent with retained urothelial differentiation NECTIN4 amplification (FISH) • 16/73 (21.9%), a frequency comparable to conventional UC • No difference between High-NE and Low-NE (P=0.835) • No association with membranous protein (P=0.099) TROP2 • Completely negative across the cohort HER2, FOLR1, Claudin 18.2 • Rare and weak expression only DLL3 • Positive in 35/43 evaluable High-NE cases (81%) • Nearly absent in Low-NE (P<0.001) • Relevant for DLL3-directed BiTEs such as tarlatamab and for DLL3 ADCs in development SLFN11 • Median H-score 125, significantly higher in High-NE (P=0.006) • Supports testing DNA-damaging strategies in this group 💡 Key takeaways 1️⃣ High-NE SmCCB is largely Nectin-4 protein negative, yet carries NECTIN4 amplifications at rates similar to conventional UC. The amplification is present, the protein is not. 2️⃣ Our hypothesis: this points to NE transdifferentiation from a urothelial precursor that already harboured the amplification. The gene status is retained, while the urothelial protein program, including Nectin-4, is switched off during lineage change. The equal amplification rate in both phenotypes fits this model. It needs confirmation in paired and clonal analyses. 3️⃣ Practical consequence: NECTIN4 FISH alone should not be read as a surrogate for target presence in SmCCB. Gene status and membranous protein both need to be assessed. 4️⃣ Enfortumab vedotin benefit cannot be assumed in High-NE SmCCB. Low-NE tumours with residual urothelial features remain the more plausible candidates for UC-type ADCs. 5️⃣ High-NE SmCCB behaves biologically like SCLC: DLL3-high, SLFN11-high. This makes it a rational population for SCLC-directed strategies. 6️⃣ A tuft cell-like subset exists: POU2F3-driven tumours co-express POU2AF2 (11/16) and ChAT (13/16), with preclinical mSWI/SNF vulnerabilities. 7️⃣ A simple workflow (NE markers ± TF panel) can stratify SmCCB in routine diagnostics today. ⚠️ Limits: retrospective, TMA-based, no treatment or outcome annotation. Treatment-annotated and paired pre/post-therapy cohorts are the next step. Big shout out to Nazario Tenace from San Raffaele he drove this work as fellow. Bright future for this talented pathologist. Shout out also at great collaborators from Sann Raffaele @AndreaNecchi @Albert0Briganti @F_Montorsi and @mauriziocollechia @maurilioponzoni @claudiodoglioni and @UroMoschini Great collaboration between San Raffaele Milan and UK Erlangen, led by Nazario Tenace, with @andreanecchi 🔗 doi.org/10.1111/his.70284