HER2-directed TKIs (like zongertinib) and ADCs (trastuzumab-deruxtecan/TDXD) have different mechanisms, and clinical data shows they are effective when used sequentially. Zongertinib works post-TDXD, and vice-versa. However, there is no evidence to support using one HER2 TKI after another has failed.

The TROPION-PanTumor01 study showed that patients who progressed on the TROP2-ADC sacituzumab govitecan still achieved responses to a second TROP2-ADC, Dato-DXD. This suggests that targeting the same antigen with a different payload can overcome initial resistance, informing future treatment sequencing.

When sequencing antibody-drug conjugates (ADCs), the critical factor for efficacy may not be switching the antibody target, but rather switching the cytotoxic payload. For example, using an ADC with a different payload (like tizotumab vedotin’s MMAE) after one with a topoisomerase inhibitor (like TDXD) could overcome resistance, shifting the paradigm from 'ADC after ADC' to 'payload after payload'.

Most approved ADCs for breast cancer utilize a topoisomerase-1 inhibitor payload. This common mechanism raises a critical question about cross-resistance, making the sequencing of these agents a significant clinical challenge without clear data to guide decisions on their subsequent use after progression.

A subtle finding in the DESTINY-Breast11 trial, where TDXD alone underperformed TDXD followed by THP, suggests that taxane-based chemotherapy might remain effective even after a patient's HER2-positive cancer becomes resistant to the antibody-drug conjugate TDXD.

In the evolving landscape of antibody-drug conjugates (ADCs), the critical factor for sequencing is likely the cytotoxic payload, not just the target antigen. A patient could respond to an ADC with a different payload after progressing on another, even if both target the same protein.

Contrary to concerns about cross-resistance between HER2 antibody-drug conjugates (ADCs), retrospective data shows TDM-1 remains effective after progression on TDXD. This suggests the different cytotoxic payloads are key, allowing for effective sequencing and challenging the assumption that progression on one ADC class member precludes using another.

As multiple effective Antibody-Drug Conjugates (ADCs) become available, the primary clinical challenge is no longer *if* they work, but *how* to use them best. Key unanswered questions involve optimal sequencing, dosing for treatment versus maintenance, and overall length of therapy, mirroring issues already seen in breast cancer.

Clinicians should be cautious not to conflate the remarkable CNS activity of trastuzumab deruxtecan (T-DXd) in HER2-positive disease with that of other ADCs, like TROP2-ADCs, in HER2-low or negative settings. Data is emerging for TROP2-ADCs, but their CNS activity is expected to be much more modest.