{"entity":{"id":"idea-tr2-smart-sequencing-adc","kind":"idea","name":"Sequential multiple-assignment randomised trials to find the best order of ADCs","aka":[],"tldr":"Patients are randomised at each decision point, not just at the start, so one trial can compare whole treatment sequences rather than single drugs.","summary":"SMART designs, standard in behavioural science, randomise patients again at progression. In metastatic breast cancer where three ADCs (T-DXd, sacituzumab, Dato-DXd) and multiple payload classes compete, a SMART would compare sequences (A then B versus B then A, payload switch versus antigen switch) with a primary endpoint of time to failure of the second line or overall survival.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Too many combinations to test): Palmer & Sorger, Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy (Cell 2017)","url":"https://doi.org/10.1016/j.cell.2017.11.009"}],"tags":[],"related":["idea-payload-switching","idea-her2-adc-sequencing-payload","adc-after-adc-caution"],"cancers":["breast-hr-positive","tnbc"],"sections":[],"technologies":["adc"],"targets":[],"drugs":["trastuzumab-deruxtecan","sacituzumab-govitecan","datopotamab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":["adc-sequencing","efflux-pump"],"trials":[],"people":[],"bottlenecks":["b-combination-space","b-resistance"],"keyPapers":["paper-palmer-cell"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A SMART in HER2-low metastatic breast cancer identifies a sequence with at least four months longer overall survival than the most common real-world sequence.","rationale":"Sequences are almost never randomised, so guidelines are built from single-line trials with different populations. Cross-resistance among topoisomerase-1 payload ADCs makes order a plausibly large effect.","test":"A cooperative-group SMART with two re-randomisation points, 600 patients, embedding SLFN11 and TOP1 biomarker sampling at each progression.","maturity":"speculative","actor":"research","cost":"large","horizonYears":5},"route":"/ideas/idea-tr2-smart-sequencing-adc/","neighbours":{"idea":[{"id":"idea-tr2-resistance-mechanism-baskets","kind":"idea","name":"Combination baskets defined by resistance mechanism rather than by cancer type","route":"/ideas/idea-tr2-resistance-mechanism-baskets/"},{"id":"idea-payload-switching","kind":"idea","name":"Payload-class switching as the rule for ADC sequencing","route":"/ideas/idea-payload-switching/"},{"id":"idea-tr2-pragmatic-sequence-randomisation","kind":"idea","name":"Registry-embedded randomisation of treatment order in routine care","route":"/ideas/idea-tr2-pragmatic-sequence-randomisation/"},{"id":"idea-her2-adc-sequencing-payload","kind":"idea","name":"Sequencing HER2 ADCs by payload after T-DXd","route":"/ideas/idea-her2-adc-sequencing-payload/"}],"pairing":[{"id":"adc-after-adc-caution","kind":"pairing","name":"Caution: TOP1 ADC immediately after TOP1 ADC","route":"/pairings/adc-after-adc-caution/"}],"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"}],"drug":[{"id":"datopotamab-deruxtecan","kind":"drug","name":"Datopotamab deruxtecan","route":"/drugs/datopotamab-deruxtecan/"},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"}],"term":[{"id":"adc-sequencing","kind":"term","name":"ADC sequencing","route":"/terms/adc-sequencing/"},{"id":"efflux-pump","kind":"term","name":"Drug efflux pumps (ABC transporters)","route":"/terms/efflux-pump/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"}],"paper":[{"id":"paper-palmer-cell","kind":"paper","name":"Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy","route":"/key-papers/paper-palmer-cell/"}]}}