# Sequencing HER2 ADCs by payload after T-DXd

Source: https://onco.cc/ideas/idea-her2-adc-sequencing-payload/  
OnCo record `idea-her2-adc-sequencing-payload` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-07
- 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.
- Proposed 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

## Sources

- DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer (New England Journal of Medicine 2022): https://doi.org/10.1056/NEJMoa2115022
- DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group (New England Journal of Medicine 2022): https://doi.org/10.1056/NEJMoa2203690

## Connected records

- cancers: [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/)
- drugs: [ARX788](https://onco.cc/drugs/arx788/), [Disitamab vedotin](https://onco.cc/drugs/disitamab-vedotin/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Trastuzumab emtansine](https://onco.cc/drugs/trastuzumab-emtansine/)
- terms: [ADC sequencing](https://onco.cc/terms/adc-sequencing/)
- key papers: [KATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatment](https://onco.cc/key-papers/paper-katherine-nejm-2019/), [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](https://onco.cc/key-papers/paper-kristine-lancet-oncol-2018/), [Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer](https://onco.cc/key-papers/paper-trastuzumab-deruxtecan-breast-her2-positive-n-engl-j-med-2020/)
- ideas: [Sequential multiple-assignment randomised trials to find the best order of ADCs](https://onco.cc/ideas/idea-tr2-smart-sequencing-adc/), [Use SLFN11 status to decide which antibody-drug payload to give next](https://onco.cc/ideas/idea-bio1-slfn11-payload-guidance/)

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