ADC sequencing
The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload.
Retrospective series (SATEEN, BRE-354, ESMO Breast 2026) show reduced efficacy of a second TOP1-payload ADC given immediately after the first; some suggest interposing chemotherapy. Mechanisms: SLFN11 loss, TOP1 mutations, efflux, antigen downregulation. Prospective trials (TRADE-DXd) are underway.
For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.