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The open question of whether a second ADC works after the first one fails, especially when both carry the same type of payload.
ADC sequencing is the open question of whether a second antibody-drug conjugate works after the first one fails, especially when both carry the same class of payload. Retrospective series including SATEEN, BRE-354 and data at ESMO Breast 2026 show reduced efficacy when a second TOP1-payload ADC follows immediately after the first; proposed mechanisms are SLFN11 loss, TOP1 mutations, efflux and antigen downregulation. Prospective trials such as TRADE-DXd are under way. The term is attached to Triple-negative breast cancer (TNBC) and HR-positive / HER2-negative breast cancer and to the Antibody-drug conjugate (ADC) technology, and it is referenced by Mersana Therapeutics, the pairing cautioning against TOP1 ADC after TOP1 ADC and the idea of payload-class switching.
Showing the technology this term belongs to: Antibody-drug conjugate (ADC).
The first-line overall survival result that made an antibody-drug conjugate the standard for PD-L1-negative or immunotherapy-ineligible metastatic triple-negative disease, and the reason the sequencing question (which TROP2 drug first, what after it) is now urgent.
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.
Shares Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial, TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival, A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer, TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET.
Shares Payload-class switching as the rule for ADC sequencing, TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET, ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs, Too many combinations to test.
Shares Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial, A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer, TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET, Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem.
Shares Exatecan (and derivatives), Topoisomerase-I inhibitor payloads, TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET, ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs.
Shares Sequential multiple-assignment randomised trials to find the best order of ADCs, Payload-class switching as the rule for ADC sequencing, Too many combinations to test, Acquired resistance to every therapy.
Shares Caution: TOP1 ADC immediately after TOP1 ADC, Sequential multiple-assignment randomised trials to find the best order of ADCs, Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial, Topoisomerase-I inhibitor payloads.
Shares Sequential multiple-assignment randomised trials to find the best order of ADCs, Payload-class switching as the rule for ADC sequencing, Topoisomerase-I inhibitor payloads, Drug efflux pumps (ABC transporters).
Shares Payload-class switching as the rule for ADC sequencing, Too many combinations to test, Acquired resistance to every therapy, Antibody-drug conjugate (ADC).