{"entity":{"id":"idea-her2-adc-sequencing-payload","kind":"idea","name":"Sequencing HER2 ADCs by payload after T-DXd","aka":[],"tldr":"When Enhertu stops working, the next ADC should probably carry a different kind of payload, such as the tubulin inhibitors in Kadcyla or ARX788, rather than another topoisomerase drug.","summary":"The idea is to choose the next HER2 antibody-drug conjugate after trastuzumab deruxtecan by payload class: a tubulin-inhibitor ADC such as trastuzumab emtansine, ARX788 or disitamab vedotin rather than another topoisomerase 1 payload. T-DXd is now used first line and in early disease, so most later HER2 ADC use will follow it; resistance often spares HER2 expression but involves TOP1 or SLFN11 changes, and TOP1 payloads show cross-resistance. The hypothesis is that a tubulin-payload ADC gives a higher response rate and longer progression-free survival than a second TOP1-payload ADC when HER2 is retained. The test is a randomised phase 2 stratified by HER2 immunohistochemistry on a progression biopsy, measuring SLFN11 and TOP1; the evidence is preclinical.","asOf":"2026-09-07","links":[{"label":"DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer (New England Journal of Medicine 2022)","url":"https://doi.org/10.1056/NEJMoa2115022"},{"label":"DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group (New England Journal of Medicine 2022)","url":"https://doi.org/10.1056/NEJMoa2203690"}],"tags":[],"related":[],"cancers":["breast-her2-positive"],"sections":[],"technologies":["adc"],"targets":[],"drugs":["trastuzumab-deruxtecan","trastuzumab-emtansine","arx788","disitamab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["adc-sequencing"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-katherine-nejm-2019","paper-trastuzumab-deruxtecan-breast-her2-positive-n-engl-j-med-2020","paper-kristine-lancet-oncol-2018"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"After T-DXd progression with retained HER2 expression, a tubulin-payload HER2 ADC produces a higher ORR and longer PFS than a second TOP1-payload HER2 ADC.","rationale":"Cross-resistance among TOP1 payloads has been observed in breast cancer retrospective series; HER2 remains expressed in most T-DXd-resistant tumours.","test":"Randomised phase 2 of T-DM1 or ARX788 versus a TOP1-payload HER2 ADC after T-DXd, stratified by HER2 IHC on progression biopsy; measure SLFN11 and TOP1 status.","maturity":"preclinical-evidence"},"route":"/ideas/idea-her2-adc-sequencing-payload/","neighbours":{"cancer":[{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","route":"/cancers/breast-her2-positive/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"}],"drug":[{"id":"arx788","kind":"drug","name":"ARX788","route":"/drugs/arx788/"},{"id":"disitamab-vedotin","kind":"drug","name":"Disitamab vedotin","route":"/drugs/disitamab-vedotin/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"},{"id":"trastuzumab-emtansine","kind":"drug","name":"Trastuzumab emtansine","route":"/drugs/trastuzumab-emtansine/"}],"term":[{"id":"adc-sequencing","kind":"term","name":"ADC sequencing","route":"/terms/adc-sequencing/"}],"paper":[{"id":"paper-katherine-nejm-2019","kind":"paper","name":"KATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatment","route":"/key-papers/paper-katherine-nejm-2019/"},{"id":"paper-kristine-lancet-oncol-2018","kind":"paper","name":"Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial","route":"/key-papers/paper-kristine-lancet-oncol-2018/"},{"id":"paper-trastuzumab-deruxtecan-breast-her2-positive-n-engl-j-med-2020","kind":"paper","name":"Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer","route":"/key-papers/paper-trastuzumab-deruxtecan-breast-her2-positive-n-engl-j-med-2020/"}],"idea":[{"id":"idea-tr2-smart-sequencing-adc","kind":"idea","name":"Sequential multiple-assignment randomised trials to find the best order of ADCs","route":"/ideas/idea-tr2-smart-sequencing-adc/"},{"id":"idea-bio1-slfn11-payload-guidance","kind":"idea","name":"Use SLFN11 status to decide which antibody-drug payload to give next","route":"/ideas/idea-bio1-slfn11-payload-guidance/"}]}}