HER3 imaging, and why three tracers stalled
HER3 sits on most lung cancers and there are drugs aimed at it, so a scan showing which tumours carry it looks obvious. Three attempts were made and all three stopped, largely because the drug's own trials could not show that how much HER3 a tumour has predicts whether the drug works.
Overview
HER3 is the textbook crossover case: expressed in around 80% of non-small cell lung cancers, targeted by patritumab deruxtecan and other antibody-drug conjugates, with no radioligand in routine use. Three antibody PET tracers were built (64Cu-patritumab, 89Zr-GSK2849330, 89Zr-lumretuzumab) and all three belong to drug programmes that lost momentum or were discontinued. Only one HER3 imaging trial is currently recruiting: 89Zr-patritumab deruxtecan at the Netherlands Cancer Institute with Daiichi Sankyo as collaborator, 16 patients, on the explicit rationale that HER3 expression can be assessed non-invasively including at sites that are difficult to biopsy.
The honest problem is not the tracer. Patritumab deruxtecan's own biomarker analyses report no relationship between efficacy and HER3 protein expression by immunohistochemistry, and the SOLTI TOT-HER3 work found activity across a wide range of ERBB3 mRNA and HER3 protein levels, suggesting limited predictive value. One published tracer study could determine no correlation between tumour uptake and ex-vivo immunohistochemistry. The drug itself received a complete response letter in June 2024 on a third-party manufacturing finding, and the BLA was withdrawn in May 2025 after HERTHENA-Lung02 missed its overall survival endpoint.
This record exists as a worked negative: the crossover lens will keep producing targets like this, and the discipline it needs is to ask whether expression predicts benefit before assuming a companion diagnostic has a market.
There is no non-invasive way to measure HER3 across all of a patient's disease, including its rise after EGFR-inhibitor therapy, but it is also not established that knowing HER3 expression changes who benefits from a HER3-directed drug.
- The predictive premise may simply be false: if HER3 level does not determine benefit, no measurement of it will.
- The tracer is tied to a therapeutic asset whose regulatory path has already failed once.
- Antibody format and isotope choice make routine delivery expensive relative to the information gained.
- Results from NCT06222489, especially any relationship between uptake and response rather than uptake and staining.
- Whether any HER3 drug programme re-files and, if so, whether a selection biomarker appears on its label.
- Publication of a validated, standardised HER3 tissue assay, which would either remove the need for imaging or give it a comparator worth beating.
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.
HER3 has been reported in 83% of non-small cell lung cancers and estimated at up to 80% depending on stage; overexpression occurred in 42% of a 45-patient cohort, more often than HER2.
Three antibody tracers were built and all sit in stalled or discontinued drug programmes; one active trial of 16 patients is recruiting. No imaging agent has reported a relationship to outcome.
For 64Cu-patritumab, no correlation between tumour uptake and ex-vivo immunohistochemistry could be determined, and the drug's own analyses report no relationship between HER3 protein expression and efficacy.
Antibody-based HER3 tracers have been given to humans without reported safety signals in small series, but no dosimetry figure worth quoting has been published for the current agent.
Receptor-status PET has a precedent: fluoroestradiol F-18 was approved in May 2020 as an adjunct to biopsy for detecting oestrogen-receptor-positive lesions, judged on reader concordance against biopsy rather than a drug-selection claim.
Red, amber or green on each review category, each with its reason, so an obvious no-go takes seconds rather than a meeting.
Antibody kinetics again: the only active agent is a zirconium-89 labelled antibody-drug conjugate, which images days after injection.
The clinical need is unproven, not merely unmet: the sponsor's own trials found no relationship between HER3 expression and benefit, so a test that measures expression may change nothing.
Every clinical HER3 tracer is derived from a specific therapeutic antibody owned by its sponsor, so an independent programme would need a new binder.
Companion-only, and the lead therapy's BLA was withdrawn in May 2025 after a failed overall-survival endpoint, so the market it would serve is not currently approved.
Zirconium-89 and copper-64 are available but cyclotron-dependent and less widely distributed than gallium-68 or fluorine-18.
Nobody is competing, which in this case reflects the weak predictive case rather than an opening.
- Netherlands Cancer Institute with Daiichi Sankyorecruiting
89Zr-patritumab deruxtecan PET/CT, 16 patients, recruiting; the only active HER3 imaging trial found.
https://clinicaltrials.gov/study/NCT06222489 - Historical programmesdiscontinued
64Cu-patritumab, 89Zr-GSK2849330 and 89Zr-lumretuzumab, all attached to drug programmes that were discontinued or lost momentum.
https://apps.dtic.mil/sti/pdfs/AD1050824.pdf
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