# Sequential multiple-assignment randomised trials to find the best order of ADCs

Source: https://onco.cc/ideas/idea-tr2-smart-sequencing-adc/  
OnCo record `idea-tr2-smart-sequencing-adc` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- 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): https://doi.org/10.1016/j.cell.2017.11.009

## Connected records

- ideas: [Combination baskets defined by resistance mechanism rather than by cancer type](https://onco.cc/ideas/idea-tr2-resistance-mechanism-baskets/), [Payload-class switching as the rule for ADC sequencing](https://onco.cc/ideas/idea-payload-switching/), [Registry-embedded randomisation of treatment order in routine care](https://onco.cc/ideas/idea-tr2-pragmatic-sequence-randomisation/), [Sequencing HER2 ADCs by payload after T-DXd](https://onco.cc/ideas/idea-her2-adc-sequencing-payload/)
- pairings: [Caution: TOP1 ADC immediately after TOP1 ADC](https://onco.cc/pairings/adc-after-adc-caution/)
- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/)
- drugs: [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Sacituzumab govitecan](https://onco.cc/drugs/sacituzumab-govitecan/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- terms: [ADC sequencing](https://onco.cc/terms/adc-sequencing/), [Drug efflux pumps (ABC transporters)](https://onco.cc/terms/efflux-pump/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)
- key papers: [Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy](https://onco.cc/key-papers/paper-palmer-cell/)

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