Payload-class switching as the rule for ADC sequencing
When one ADC fails, the next should carry a different kind of poison, not just aim at a different protein.
Cross-resistance among TOP1-payload ADCs is emerging as a clinical reality. The field's instinct to switch antigen (HER2 → TROP2) may be less important than switching payload mechanism (TOP1 → tubulin, DNA crosslinker, or degrader).
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.
Pages like this
not linked directly; found by shared links- IdeaSequencing HER2 ADCs by payload after T-DXd
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).
- PersonSeock-Ah Im
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).
- PersonBinghe Xu
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).
- IdeaRegistry-embedded randomisation of treatment order in routine care
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.
- CompanyMersana Therapeutics
Shares ADC sequencing, Acquired resistance to every therapy, Antibody-drug conjugate (ADC), Triple-negative breast cancer (TNBC).
- ProductRinatabart sesutecan
Shares Sequence folate-receptor ADCs by payload class, Topoisomerase-I inhibitors (and ADC payloads), Antibody-drug conjugate (ADC).
- TargetTROP2
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, TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival.
- TermT030 (belotecan derivative)
Shares Drug efflux pumps (ABC transporters), Topoisomerase-I inhibitors (and ADC payloads), Antibody-drug conjugate (ADC).