{"entity":{"id":"opp-her3-imaging-crossover","kind":"opportunity","name":"HER3 imaging, and why three tracers stalled","aka":["HER3 PET"],"tldr":"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.","summary":"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.\n\nThe 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drug itself received a complete response letter in June 2024 on a third-party manufacturing finding, and the BLA was withdrawn in May 2025 after HERTHENA-Lung02 missed its overall survival endpoint.\n\nThis record exists as a worked negative: the crossover lens will keep producing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.","asOf":"2026-09-23","links":[{"label":"NCT06222489: 89Zr-patritumab deruxtecan PET/CT","url":"https://clinicaltrials.gov/study/NCT06222489"},{"label":"No relationship between HER3-DXd efficacy and HER3 immunohistochemistry, Nature Communications 2024","url":"https://www.nature.com/articles/s41467-024-50056-y"},{"label":"Complete response letter for patritumab deruxtecan, June 2024","url":"https://daiichisankyo.us/press-releases/-/article/patritumab-deruxtecan-bla-submission-receives-complete-response-letter-from-fda-due-to-inspection-findings-at-third-party-manufacturer"},{"label":"No validated HER3 immunohistochemistry assays or thresholds (review)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12758208/"},{"label":"Fluoroestradiol F-18 label, the receptor-imaging precedent","url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212155s000lbl.pdf"}],"tags":["target crossover","worked negative","lung","companion diagnostic"],"related":["zr-89","cu-64"],"indications":["nsclc"],"sections":[],"technologies":["immuno-pet","pet-ct"],"targets":["her3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"lens":"target-crossover","unmetNeed":"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.","useCase":"In its plausible form, a HER3 tracer is a pharmacodynamic and trial-enrichment tool rather than a clinical test: measuring target engagement and the change in HER3 after EGFR-inhibitor therapy inside a drug-development programme. A clinical selection use would require a predictive relationship that the drug's own trials have so far failed to demonstrate.","hypothesis":"Whole-body HER3 quantification will predict response to a HER3-directed antibody-drug conjugate where single-site immunohistochemistry does not, because the failure of tissue testing reflects sampling and assay variability rather than the absence of a true dose-response relationship.","rationale":"HER3 is expressed in the great majority of lung cancers and rises after EGFR-inhibitor treatment, so there is a real biological signal to measure, and imaging is the only way to measure it everywhere at once. Against that, the published record is discouraging in a specific and informative way: there are no validated HER3 immunohistochemistry assays and no standardised scoring thresholds, the sponsor found no relationship between expression and efficacy, and one tracer study could not correlate uptake with tissue staining. The hypothesis above is testable but currently unsupported.","test":"A trial-embedded study in patients receiving a HER3-directed antibody-drug conjugate, imaging before treatment and after one cycle, powered to relate baseline tracer uptake and its change to objective response. The question it must answer is not whether the tracer binds HER3 but whether tracer uptake separates responders from non-responders where immunohistochemistry did not.","maturity":"early-clinical","verdict":"companion-only","mostAdvanced":"89Zr-patritumab deruxtecan PET/CT at the Netherlands Cancer Institute with Daiichi Sankyo, 16 patients, recruiting under NCT06222489; the only active HER3 imaging trial found.","dueDiligence":[{"domain":"target-biology","state":"strong","why":"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.","source":"Published NSCLC series","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12393064/"},{"domain":"clinical-evidence","state":"thin","why":"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.","source":"NCT06222489","url":"https://clinicaltrials.gov/study/NCT06222489"},{"domain":"diagnostic-performance","state":"none","why":"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.","source":"Sponsor biomarker analyses and tracer report","url":"https://www.nature.com/articles/s41467-024-50056-y","weighted":true},{"domain":"safety-dosimetry","state":"thin","why":"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."},{"domain":"regulatory-path","state":"moderate","why":"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.","source":"FDA review, fluoroestradiol F-18","url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212155s000lbl.pdf"}],"flags":[{"category":"technical","flag":"amber","why":"Antibody kinetics again: the only active agent is a zirconium-89 labelled antibody-drug conjugate, which images days after injection."},{"category":"unmet-need","flag":"red","why":"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."},{"category":"ip","flag":"red","why":"Every clinical HER3 tracer is derived from a specific therapeutic antibody owned by its sponsor, so an independent programme would need a new binder."},{"category":"commercial","flag":"red","why":"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."},{"category":"isotope","flag":"amber","why":"Zirconium-89 and copper-64 are available but cyclotron-dependent and less widely distributed than gallium-68 or fluorine-18."},{"category":"competition","flag":"green","why":"Nobody is competing, which in this case reflects the weak predictive case rather than an opening."}],"competition":[{"name":"Netherlands Cancer Institute with Daiichi Sankyo","what":"89Zr-patritumab deruxtecan PET/CT, 16 patients, recruiting; the only active HER3 imaging trial found.","stage":"recruiting","url":"https://clinicaltrials.gov/study/NCT06222489"},{"name":"Historical programmes","what":"64Cu-patritumab, 89Zr-GSK2849330 and 89Zr-lumretuzumab, all attached to drug programmes that were discontinued or lost momentum.","stage":"discontinued","url":"https://apps.dtic.mil/sti/pdfs/AD1050824.pdf"}],"differentiation":"HER3 immunohistochemistry exists but is unvalidated: reviews state there are no validated assays and no standardised scoring thresholds for predicting benefit, and an mRNA alternative developed by the SOLTI group was also not predictive. Imaging would differ by sampling every lesion, but it inherits the underlying problem that no measure of HER3 has yet predicted response.","metrics":[{"label":"Non-small cell lung cancers reported to express HER3","value":"83%","source":"Published NSCLC series","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12393064/"},{"label":"Patients randomised in HERTHENA-Lung02, whose overall-survival miss preceded BLA withdrawal","value":"586","source":"HERTHENA-Lung02 reporting","url":"https://www.nature.com/articles/s41467-024-50056-y"}],"risks":["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."],"watch":["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."]},"route":"/opportunities/opp-her3-imaging-crossover/","neighbours":{"isotope":[{"id":"cu-64","kind":"isotope","name":"Copper-64","route":"/isotopes/cu-64/"},{"id":"zr-89","kind":"isotope","name":"Zirconium-89","route":"/isotopes/zr-89/"}],"indication":[{"id":"nsclc","kind":"indication","name":"Non-small cell lung cancer","route":"/indications/nsclc/"}],"technology":[{"id":"immuno-pet","kind":"technology","name":"Immuno-PET","route":"/technologies/immuno-pet/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"}],"target":[{"id":"her3","kind":"target","name":"HER3 (ERBB3)","route":"/targets/her3/"}]}}