# Payload-class switching as the rule for ADC sequencing

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

## TL;DR

When one ADC fails, the next should carry a different kind of poison, not just aim at a different protein.

## Summary

When one ADC fails, the next should carry a different kind of payload rather than simply aim at a different antigen. Patients progressing on a TOP1-payload ADC are expected to do better on a following ADC with a tubulin, DNA-crosslinker or degrader payload than on a second TOP1 ADC regardless of target, because SLFN11 loss, TOP1 mutations and ABCG2 upregulation are payload-level resistance mechanisms shared by DXd, SN-38 and exatecan derivatives. A randomised sequencing trial in HER2-low or TNBC after T-DXd or sacituzumab govitecan would compare the two strategies and measure SLFN11 and TOP1 status on progression biopsies. With preclinical evidence so far, it addresses the bottlenecks Acquired resistance to every therapy and Too many combinations to test.

## Fields

- Kind: Idea
- Last checked: 2026-09-04
- Hypothesis: In patients progressing on a TOP1-payload ADC, a next ADC with a non-TOP1 payload yields longer PFS than a second TOP1-payload ADC regardless of antigen.
- Rationale: SLFN11 loss, TOP1 mutations, and ABCG2 upregulation are payload-level resistance mechanisms shared by DXd, SN-38, and exatecan derivatives.
- Proposed test: A randomised sequencing trial in HER2-low/TNBC after T-DXd or sacituzumab: MMAE- or non-TOP1-payload ADC vs alternate TOP1 ADC; measure SLFN11 and TOP1 status on progression biopsies as predictive biomarkers.
- Maturity: preclinical-evidence

## Sources

- ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer (New England Journal of Medicine 2021): https://doi.org/10.1056/NEJMoa2028485
- DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer (New England Journal of Medicine 2022): https://doi.org/10.1056/NEJMoa2115022

## Connected records

- 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/), [Dual-payload ADC](https://onco.cc/technologies/dual-payload-adc/), [Topoisomerase-I inhibitors (and ADC payloads)](https://onco.cc/technologies/topoisomerase-inhibitors/)
- terms: [ADC sequencing](https://onco.cc/terms/adc-sequencing/), [Drug efflux pumps (ABC transporters)](https://onco.cc/terms/efflux-pump/)
- ideas: [Alpha radioligands after ADC failure](https://onco.cc/ideas/idea-alpha-after-adc/), [Combination baskets defined by resistance mechanism rather than by cancer type](https://onco.cc/ideas/idea-tr2-resistance-mechanism-baskets/), [Dual-payload ADCs in first line to prevent resistance](https://onco.cc/ideas/idea-dual-payload-first/), [Re-map the tumour's surface proteins before choosing the next antibody drug](https://onco.cc/ideas/idea-bio1-antigen-mapping-at-progression/), [Sequence folate-receptor ADCs by payload class](https://onco.cc/ideas/idea-fra-adc-sequencing-ovarian/), [Sequential multiple-assignment randomised trials to find the best order of ADCs](https://onco.cc/ideas/idea-tr2-smart-sequencing-adc/), [Use SLFN11 status to decide which antibody-drug payload to give next](https://onco.cc/ideas/idea-bio1-slfn11-payload-guidance/)
- 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: [DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer](https://onco.cc/key-papers/paper-destiny-breast03-nejm-2022/), [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/), [TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival](https://onco.cc/key-papers/paper-tropion-breast01-jco-2024/)

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