OnCo
ideasIdea

Sequencing HER2 ADCs by payload after T-DXd

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.

T-DXd is now used first line and in early disease, so most later-line HER2 ADC use will follow T-DXd. Resistance often spares HER2 expression but involves TOP1/SLFN11 changes; tubulin-payload ADCs (T-DM1, ARX788, disitamab vedotin) or HER2 TKIs may retain activity.

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.
What would test it
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

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