Man on the ladder, Berlin

The recent debate around trastuzumab deruxtecan (T-DXd) resistance has quietly split into two camps: those who argue the payload has stopped working, and those who believe the tumour has simply disengaged from the target.

Both positions are supported by credible data, and both are partly right.

The real question is not which mechanism dominates in the abstract, rather it’s which one is operating in any given patient?

If we want to think about climbing on and navigating resistance to T-DXd, then we have several possibilities to consider.

The answer determines whether the rational next step is another HER2 ADC, a different payload, a combination strategy, or something altogether outside the HER2 axis…

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