Daniele Raggi

Consultant Medical Oncologist in Genito-Urinary tumours @RoyalMarsdenNHS

[Niklas Klümper @niklas_kluemper]

Happy to share our new paper in Clinical Cancer Research on NECTIN4 as a biomarker for enfortumab vedotin in urothelial cancer! @CCR_AACR @AACR

An important clue was already present in EV-301: patients with higher NECTIN4 IHC (H-score >150) had an ORR of 45.8% vs 20.0% with lower expression.

We now take this one step further and show that localization matters:

🎯 Membranous NECTIN4 correlates with EV response — cytoplasmic NECTIN4 does not.

This makes biological sense for an ADC: EV needs to bind its target on the tumor-cell surface to internalize and deliver its payload.

We further integrate NECTIN4 amplification + membranous protein expression, moving toward a more precise biomarker framework for EV.

For ADC biomarkers, it is not simply whether a target is expressed — but how much, where, and in which tumor lesion.

Hopefully another step toward precision ADC therapy in urothelial cancer.

Thanks to a great team and my collaborators! @Markuseckstein3 @KuppeChristoph @braegelmannlab @JoshMeeks @HolzelMichael

https://t.co/e1IhJTy2ij

@OncoAlert @weoncologists @DrChoueiri

@Uroweb @AmerUrological @ASCO @PathSoc @OncoAlert @Histo_Journal @andreanecchi @emanuele_crupi @danieleraggi83 @raffcolo @Dr_Aggen @DrRosenbergMSK @h_alahmadie @PGrivasMDPhD @shilpaonc @drenriquegrande @amerseburger @brookmans76 @DrYukselUrun @onkowissen @imedverse @UroDocAsh @urotoday @EUplatinum @JCO_ASCO @CCR_AACR @niklas_kluemper @DrRosenbergMSK @Dr_Aggen @Uromigos @tompowles1 @shilpaonc @PGrivasMDPhD

[Daniele Raggi @DanieleRaggi83]

@DrSACooper @TylerSbrt @DeepOnco 💯

[Daniele Raggi @DanieleRaggi83]

@gbanna74 Thanks for an amazing #IUCS26! It was a real pleasure to be part of it. See you at #IUCS27! 🙌

[Sumanta K. Pal, MD, FASCO @montypal]

Great to see progress in #testicularcancer as reported by @DanieleRaggi83 @royalmarsdenNHS. Compelling data for miR-371a-3p via studies done through @SWOG/@CDNCancerTrials. Excited to see EU-grant funded work in TRANSCEND-XR. @gbanna74 @ravikanesvaran #IUCS26

[Alison Tree 💙 @alison_tree]

Great talk @urologysummit by @DanieleRaggi83 @royalmarsdenNHS on germ cell tumours. Who needs more treatment? Who needs less? Can we stratify and minimise follow up scans after completing the OTIS-S trial? #IUCS26

[Yüksel Ürün @DrYukselUrun]

With EV+pembrolizumab broadly effective, do we now need biomarkers to identify who benefits most, or who can safely receive less?

The key question is no longer only “who is high risk?” but “who still has disease?”

ctDNA may help move bladder cancer from static risk groups toward real-time treatment decisions.

Excellent presentation by @PGrivasMDPhD at #IUCS26

@neerajaiims @gbanna74 @Sebastiano_Buti @CinziaConted @dralishadamani @nataliagandur @amg120395 @ravikanesvaran @koshkin85 @MicheleMaffezz @ManiamAkash @ParamMariappan @dmukherji @VanitaNoronha @montypal @DanieleRaggi83 @PasRescigno @jteoh_hk @alison_tree @yekeduz_emre @ONCOassist

[Yüksel Ürün @DrYukselUrun]

Science by day, friendship by the lake. 🌿
@gbanna74 @Sebastiano_Buti @CinziaConted @dralishadamani @nataliagandur @amg120395 @PGrivasMDPhD @ravikanesvaran @koshkin85 @MicheleMaffezz @ManiamAkash @dmukherji @VanitaNoronha @montypal @DanieleRaggi83 @PasRescigno @jteoh_hk @alison_tree @yekeduz_emre @ONCOassist

[Markus Eckstein @Markuseckstein3]

🚨 Out now in European Urology Oncology: our real-world landscape of actionable alterations in advanced urothelial carcinoma. Open access. 🔬

Short version: actionable findings are the rule. Acting on them is the exception.

📊 MIER cohort (n=233 MIBC/mUC, TSO500, expert-annotated):

🧬 97% carried at least one pathogenic or likely pathogenic variant (226/233).
🎯 Actionable FGFR3 alterations in 11%, mostly S249/R248 hotspots, all PCR-confirmed.
🧪 40% harboured alterations in 24 biomarkers linked to FDA-approved therapies. PIK3CA 20%, ATM 6.4%, KRAS 5.2%.
📈 ERBB2 amplification in 15% (36/233), HER2 IHC 3+ in 15 patients.
⚠️ MSI-high by NGS in 4.2%, but only 4 of 9 showed MMR protein loss on IHC. Orthogonal validation is not optional.
🧩 Pathway level: cell cycle 82% (TP53 73%, RB1 25%), RTK/Ras/PI3K 42%, histone modifiers 47% (KDM6A 25%), SWI/SNF 27%.
📉 Then the MTB cohort (n=40, routine diagnostics, CCC Erlangen-EMN):
55% had actionable alterations. 5% on-label, 50% off-label.
One patient received the recommended therapy. 🩺
ERBB2 amplification plus PIK3CA mutation, off-label alpelisib, stable disease and pain improvement for 4 months, then progression and skin toxicity. A second patient qualified for trastuzumab deruxtecan on cooccurring ERBB2 amplification and IHC 3+, but died before treatment could start.
Retrospectively, 80% of the MIER cohort would have had an indication. 10% on-label, 70% off-label.

That gap is the finding. 🧠

Four things I take from it:

1️⃣ The bottleneck has moved. We are no longer short of targets. We are short of access, evidence, and workable pathways. Cost coverage, comorbidity, and patient deterioration between recommendation and administration prevented most indications. Discovery papers keep counting alterations; almost nobody counts what happens next.

2️⃣ Off-label is not a free option. Seventy percent theoretical eligibility sounds impressive until you ask what the evidence behind each recommendation actually is. Much of it is early-phase or preclinical. Advancing those cautiously is not timidity, it is the correct reading of the data.

3️⃣ Genomics without protein-level validation has limits. Not every alteration translates into an expressed, targetable protein on the cell surface. For ADCs that distinction is everything, which is why membranous target assessment belongs alongside sequencing rather than after it.

4️⃣ Timing decides relevance. In Germany, MTB referral typically happens after progression on EV(P) and, per FDA label, trastuzumab deruxtecan. By then Nectin-4 and HER2 testing no longer changes anything. That pushes interest toward TROP2, HER3/EGFR and newer constructs. Most of these agents are inaccessible outside trials, which makes trial referral one of the most valuable things an MTB can offer.

Our turnaround is 6 to 40 days, median 11 to 18. That is fast enough. The delay is not analytical. It is structural. 🔬

With the German Model Project Genome Sequencing now underway, this is exactly the moment to measure implementation, not just actionability.

Huge credit to first author Maria Giulia Carta and to Fulvia Ferrazzi, co-senior with me, and to the whole Erlangen team. @FulviaFerrazzi

🔗 https://t.co/nOaujvVIle

@Uroweb @AmerUrological @ASCO @PathSoc @OncoAlert @Histo_Journal @niklas_kluemper @andreanecchi @emanuele_crupi @danieleraggi83 @raffcolo @Dr_Aggen @DrRosenbergMSK @h_alahmadie @PGrivasMDPhD @shilpaonc @drenriquegrande @amerseburger @brookmans76 @DrYukselUrun @onkowissen @imedverse @UroDocAsh @IBCG_BladderCA @AndreaNecchi @apolo_andrea @PGrivasMDPhD

#Uropathology #urothelial #BladderCancer #PrecisionOncology #pathtwitter

[Alison Tree 💙 @alison_tree]

Very sad to be saying goodbye to the very lovely and hard working @drmaneesh_singh after a year @royalmarsdenNHS. We have loved working with you, come back soon! Thanks to @VedangMurthy and @docpriyamvada for letting us borrow him ❤️

[Syed A Hussain @ProfSyedHussain]

@PGrivasMDPhD @DanieleRaggi83 @koshkin85

[Sumanta K. Pal, MD, FASCO @montypal]

Please consider registering for this amazing meeting hosted by @gbanna74 & @ravikanesvaran! A terrific faculty including @dmukherji, @ProfSyedHussain, @alison_tree, @DrDarrenPoon, @ParamMariappan, @neerajaiims, @PGrivasMDPhD, @koshkin85, @DanieleRaggi83, @VanitaNoronha, @amg120395 & @MariaBarbu128! Always an amazing time w great learning. New this year - oral presentations, one of which will be delivered by my former research fellow @NickSalgia @RoswellPark!

[Liang Cheng, MD @LiangChengMD]

Congratulations to Drs. Emanuele Crupi, @emanuele_crupi Daniele Raggi @DanieleRaggi83 and colleagues on the publication of this timely article last month in Nature Reviews Urology @NatRevUrol

HER2-directed antibody - drug conjugates (ADCs) are rapidly transforming the treatment landscape of urothelial carcinoma. Landmark clinical trials have established HER2-targeted therapy as a new therapeutic pillar. However, there is urgent need for urothelial carcinoma–specific HER2 testing and interpretation criteria. Current HER2 scoring systems are largely adapted from breast and gastroesophageal cancers, despite important differences in tumor biology, staining patterns, specimen types, and intratumoral heterogeneity. These limitations can substantially influence HER2 classification, patient selection, clinical trial eligibility, and ultimately access to life-extending therapies.

 The authors provide a compelling framework highlighting the need for standardized HER2 assessment, consideration of spatial and temporal heterogeneity, and future integration of dynamic biomarkers such as liquid biopsy. As HER2 ADCs become increasingly central to precision medicine in bladder cancer, achieving diagnostic clarity will be essential to fully unlocking the potential of these breakthrough therapies.

Full article link: https://t.co/dp8R3LALM6

[Raffaele Colombo @raffcolo]

More than 40 bispecific ADCs in the clinic!

Figure from https://t.co/Ajv7tjT2EF

@BarbaraPistill2 @FerMosele

1 now approved by China NMPA
7 with reported clinical data thus far
3 discontinued (one more after publication)
3 additional in clinical development (not in the table)

[Eleni Efstathiou @EfstathiouEleni]

Another win for precision medicine in prostate cancer ! Molecular / Genomic testing is a requirement for good clinical practice !
No excuses no delays and no patient left behind.
It takes a lot of such wins to stack and move the needle in our field and they are coming🙌🏻 @oncodaily @neerajaiims @scserendipity1 @OncoAlert #prostatecancer #precisionmedicine

[Nick James @Prof_Nick_James]

Delighted that our STAMPEDE paper on abiraterone therapy selection with MMAI in high risk M0 HSPC now out. https://t.co/5TF3nHt0DZ

[Pavlos Msaouel @PavlosMsaouel]

@emanuele_crupi presenting #ASCO26 the phase 2 study results of the GemFLP regimen in urinary tract adenocarcinoma. @ASCO @DocMattCampbell @PGrivasMDPhD @neerajaiims @glovedoc @SGoswamiMDPhD @mjmoussa_ @OncHahn @OAlhalabiMD

[Emanuele Crupi, MD @emanuele_crupi]

Same target, different warhead: LY4052031 hits Nectin-4 with ORR 33% and DCR 75% in pretreated UC. #ASCO26 @DanieleRaggi83 @niklas_kluemper @Markuseckstein3 @urologysummit @oncodaily #Nectin4

[Daniel Castellano @cdanicas]

🎯 #ASCO26 @ASCO NEXUS-01 @gopaiyer study in mUC with a new nectin4 ADC (camptho payload) MTD 3.6 mg/k?
ORR 42% (pretreated EV-Pembro)
👉 well tolerated (low diarrhea and > hematologic toxicity) @PGrivasMDPhD @OncoAlert @tompowles1 @DrChoueiri @GuardConsortium @UroTarget

[Linghua Wang, MD, PhD @IamLinghua]

1/ Thrilled to share our new paper, out today in @ScienceMagazine! We built a pan-cancer spatial atlas of tertiary lymphoid structures (TLSs) and developed computation and AI frameworks to study TLS biology at scale.
https://t.co/zgcBnnm7Rl

[Daniele Raggi @DanieleRaggi83]

@emanuele_crupi @ConquerCancerFd @UTMDAnderson Very well done, Emanuele, hugely deserved. Proud of you!