# A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer

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

## TL;DR

Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life.

## Summary

Sacituzumab govitecan (SN-38) and datopotamab deruxtecan and trastuzumab deruxtecan (deruxtecan) all deliver topoisomerase I inhibitor payloads; ASCENT-03, ASCENT-04 and TROPION-Breast02 moved the TROP2 conjugates to first line and DESTINY-Breast04 covers the 36.6 percent of triple-negative tumours that are HER2-low. Retrospective series of conjugate after conjugate report short progression-free survival on the second agent, consistent with payload resistance (SLFN11 loss, TOP1 mutation) rather than antigen loss, and the corpus term adc-after-adc-caution records the position. No randomised trial compares TROP2 conjugate then trastuzumab deruxtecan with the reverse, or tests chemotherapy interposition, and the ASCO 2022 biomarker guideline finds no test to guide the choice.

## Fields

- Kind: Idea
- Last checked: 2026-09-24
- Tags: tnbc-evidence
- Hypothesis: In HER2-low metastatic triple-negative breast cancer progressing on a first-line TROP2 antibody-drug conjugate, immediate trastuzumab deruxtecan yields a progression-free survival hazard ratio no better than 0.85 against chemotherapy, and a biomarker of payload resistance (SLFN11 expression or TOP1 alteration in ctDNA) identifies the patients in whom it is inferior.
- Rationale: Shared payload biology predicts cross-resistance; the alternative, chemotherapy between conjugates, is cheap and may restore sensitivity, and the choice is made thousands of times a year without evidence.
- Proposed test: Randomised phase 3 in HER2-low disease after first-line TROP2 conjugate: trastuzumab deruxtecan versus chemotherapy versus chemotherapy then trastuzumab deruxtecan, progression-free survival primary, with mandatory biopsy or ctDNA at progression for payload resistance markers; a parallel cohort in HER2-zero disease comparing the alternate TROP2 conjugate with chemotherapy.
- Maturity: early-clinical
- Actor: industry

## Sources

- TROPION-Breast02 (Ann Oncol 2026): https://europepmc.org/article/MED/41937088
- ASCENT (NEJM 2021): https://europepmc.org/article/MED/33882206

## Connected records

- roadmaps: [ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs](https://onco.cc/roadmaps/adc-generations/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/), [TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET](https://onco.cc/roadmaps/trop2-adc-roadmap/)
- cancers: [HER2-low and HER2-ultralow metastatic breast cancer](https://onco.cc/cancers/her2-low-metastatic-breast-cancer/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Topoisomerase-I inhibitors (and ADC payloads)](https://onco.cc/technologies/topoisomerase-inhibitors/), [TROP2 PET](https://onco.cc/technologies/trop2-pet/)
- targets: [HER2](https://onco.cc/targets/her2/), [TROP2](https://onco.cc/targets/trop2/)
- 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/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Daiichi Sankyo](https://onco.cc/companies/daiichi-sankyo/), [Gilead Sciences (incl. Kite)](https://onco.cc/companies/gilead/)
- terms: [ADC sequencing](https://onco.cc/terms/adc-sequencing/), [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- pairings: [Caution: TOP1 ADC immediately after TOP1 ADC](https://onco.cc/pairings/adc-after-adc-caution/)
- trials: [ASCENT](https://onco.cc/trials/ascent/), [ASCENT-03](https://onco.cc/trials/ascent-03/), [DESTINY-Breast04](https://onco.cc/trials/destiny-breast04/), [TROPION-Breast02](https://onco.cc/trials/tropion-breast02/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- key papers: [ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer](https://onco.cc/key-papers/paper-ascent-nejm-2021/), [Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update](https://onco.cc/key-papers/paper-asco-biomarkers-metastatic-breast-cancer-guideline-jco-2022/), [Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial](https://onco.cc/key-papers/paper-tropion-breast02-ann-oncol-2026/), [DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group](https://onco.cc/key-papers/paper-destiny-breast04-nejm-2022/)

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