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When one ADC fails, the next should carry a different kind of poison, not just aim at a different protein.
When one ADC fails, the next should carry a different kind of payload rather than simply aim at a different antigen. Patients progressing on a TOP1-payload ADC are expected to do better on a following ADC with a tubulin, DNA-crosslinker or degrader payload than on a second TOP1 ADC regardless of target, because SLFN11 loss, TOP1 mutations and ABCG2 upregulation are payload-level resistance mechanisms shared by DXd, SN-38 and exatecan derivatives. A randomised sequencing trial in HER2-low or TNBC after T-DXd or sacituzumab govitecan would compare the two strategies and measure SLFN11 and TOP1 status on progression biopsies. With preclinical evidence so far, it addresses the bottlenecks Acquired resistance to every therapy and Too many combinations to test.
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.
Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.
Shares Caution: TOP1 ADC immediately after TOP1 ADC, ADC sequencing, DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group, Too many combinations to test.
Shares TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival, DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer, DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group, Triple-negative breast cancer (TNBC).
Shares Use SLFN11 status to decide which antibody-drug payload to give next, Sequential multiple-assignment randomised trials to find the best order of ADCs, ADC sequencing, Antibody-drug conjugate (ADC).
Shares Sequential multiple-assignment randomised trials to find the best order of ADCs, ADC sequencing, Too many combinations to test, HR-positive / HER2-negative breast cancer.
Shares TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival, DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer, DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group, Triple-negative breast cancer (TNBC).
Shares Dual-payload ADCs in first line to prevent resistance, Dual-payload ADC.
Shares Alpha radioligands after ADC failure, Dual-payload ADCs in first line to prevent resistance, Re-map the tumour's surface proteins before choosing the next antibody drug.
Shares DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group, Antibody-drug conjugate (ADC), Triple-negative breast cancer (TNBC), HR-positive / HER2-negative breast cancer.