A liver-cleared Nectin-4 tracer for urothelial cancer
An approved bladder cancer drug works by latching onto a protein called Nectin-4, and half of patients lose that protein as the disease spreads. The one scan built to show it is cleared through the kidneys, so the bladder and the nearby lymph nodes glow with waste tracer and are the hardest places to read.
Overview
Enfortumab vedotin, a Nectin-4-directed antibody-drug conjugate, has been approved since December 2019 and now reaches into the perioperative setting: in November 2025 the FDA approved pembrolizumab with enfortumab vedotin as neoadjuvant then adjuvant treatment for cisplatin-ineligible muscle-invasive bladder cancer, on a trial of 344 patients that reported a hazard ratio of 0.40 for recurrence, progression or death. Selection does not require a Nectin-4 assay, yet Nectin-4 expression falls in more than half of cases during metastatic progression and more than a third of metastases are Nectin-4-negative.
The imaging work is almost entirely Chinese and academic. The bicyclic peptide tracer 68Ga-N188, from Peking University, has a published first-in-human study in 14 patients with advanced urothelial cancer plus two healthy volunteers, and a 62-patient head-to-head study against FDG across 16 tumour types. It is registered in three Chinese trials. Its published limitation is decisive for the indication that matters most: the tracer is excreted in urine, and a 2025 review states plainly that this poses challenges for in-situ bladder cancer detection because of high background activity in the urinary tract.
So the opportunity is not a target in search of a tracer, nor a tracer in search of a target, but a pharmacokinetic specification: a Nectin-4 ligand cleared hepatobiliary rather than renally, which could read the bladder wall and the pelvic nodes where staging and surgical decisions are actually made.
Before radical cystectomy or before starting enfortumab vedotin, no test shows whether the bladder tumour and the pelvic nodes still express Nectin-4, because the only human Nectin-4 tracer is renally excreted and urinary activity obscures exactly that region.
- Clearance engineering may not survive contact with affinity: a hepatobiliary-cleared analogue could lose the binding that makes the peptide work.
- Hepatic background could simply move the problem, since the liver is a common site of urothelial metastasis.
- If NECTIN4 amplification on tissue turns out to predict benefit reliably, the selection half of the case weakens and only the staging use remains.
- Results from the three registered 68Ga-N188 trials, particularly any per-lesion comparison against nodal pathology.
- Any published Nectin-4 ligand with a hepatobiliary clearance profile, which would be the first direct competitor for this specification.
- Whether the perioperative approval shifts practice toward pre-cystectomy target confirmation, which is where a readable pelvis pays.
The five domains of a radiopharmaceutical due-diligence review, adapted from the Fryback-Thornbury hierarchy of diagnostic efficacy. Each carries the state of the public evidence and the fact behind it, not a score out of five: a single total hides the reason and stops telling candidates apart. Domains marked as carrying most weight are the ones that decide the case at this asset's stage.
Nectin-4 is reported in 83% of 524 bladder cancers by tissue microarray and over 97% in another series, against 67% in upper-tract disease; expression falls in more than 50% of cases during metastatic progression, with over a third of metastases negative.
68Ga-N188 has a published first-in-human study of 14 patients with advanced urothelial cancer and a 62-patient head-to-head study against FDG, all single-country and academic.
No study reports sensitivity or specificity against nodal histopathology, and the published review states that urinary excretion challenges in-situ bladder detection because of urinary-tract background.
No adverse events are reported in the published first-in-human cohorts, but the series are small and no formal dosimetry figure for a pelvis-readable construct exists because no such construct has been made.
No Nectin-4 imaging agent has any filing anywhere, but 68Ga-PSMA-11 set the precedent for a pelvic-nodal claim: its initial-staging trial used sensitivity and specificity for pelvic nodal metastases against prostatectomy pathology as the primary endpoint.
Red, amber or green on each review category, each with its reason, so an obvious no-go takes seconds rather than a meeting.
The known human tracer is renally excreted and its own literature says this obstructs in-situ bladder detection; the opportunity requires re-engineering clearance, which is unproven for this ligand class.
Nodal staging before cystectomy is weak on CT and target loss in metastatic disease is documented in over half of cases, so both the staging and the selection question are live.
The bicyclic peptide scaffold behind 68Ga-N188 derives from a therapeutic programme, and the leading published work sits with Chinese academic centres; freedom to operate for a new clearance-engineered ligand is unexamined in public sources.
A pelvis-readable tracer has a staging use of its own in muscle-invasive disease as well as a selection use alongside an approved antibody-drug conjugate now moving into perioperative treatment.
Gallium-68 already works for the peptide, and a fluorine-18 version would suit distribution.
Three registered Chinese trials of 68Ga-N188 are running and the field is publishing quickly, but nobody has disclosed a hepatobiliary-cleared construct.
- Peking University Cancer Hospital and Peking University First Hospitalearly clinical
68Ga-N188, the only Nectin-4 tracer with published human data; three registered trials (NCT05321316, NCT05593107, NCT06648317).
https://pubmed.ncbi.nlm.nih.gov/37093191/ - Astellas and Pfizerapproved
Enfortumab vedotin, the approved Nectin-4 antibody-drug conjugate that creates the selection question; no Nectin-4 assay is required on the label.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer - Mayo Clinic Laboratoriesin clinical use
A commercially available Nectin-4 immunohistochemistry assay reporting percent positive cells and H-score, the incumbent test.
https://www.mayocliniclabs.com/test-catalog/Overview/622259
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