# Randomised trials to test whether biomarker-negative patients really do not benefit

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

## TL;DR

Patients are denied a drug when a test says they will not benefit, but that restriction is usually inferred from enrichment trials rather than tested. For high-stakes markers with weak evidence in the negative group, such as PD-L1 and HER2 0, randomised trials in biomarker-negative patients should test the assumption itself.

## Summary

Label restrictions based on biomarkers are often inferred from enrichment trials or subgroup analyses rather than from tests of the biomarker-negative population. For high-stakes markers with weak evidence in the negative group (PD-L1 in several tumours, HER2-ultralow and HER2 0, HRD-negative for PARP inhibitors), academic randomised trials in the biomarker-negative population with pragmatic endpoints would either open access to a denied group or firmly justify the restriction.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: At least one of three trials in biomarker-negative populations will demonstrate clinically meaningful benefit, changing a label or guideline within five years.
- Rationale: T-DXd showed activity in HER2-ultralow and possibly HER2 0 populations excluded by the original biomarker, and PD-1 blockade benefits some PD-L1-negative patients in several tumour types.
- Proposed test: Fund three cooperative-group randomised trials in biomarker-negative populations with overall survival or quality-of-life primary endpoints.
- Maturity: early-clinical
- Actor: research

## Sources

- Bottleneck evidence (Biomarkers are not validated or standardised): Fernandez et al., Examination of low ERBB2 protein expression in breast cancer tissue (JAMA Oncology 2022): https://doi.org/10.1001/jamaoncol.2021.7239

## Connected records

- terms: [HER2-low and HER2-ultralow](https://onco.cc/terms/her2-low/)
- ideas: [Test the drug in biomarker-negative patients too, so the biomarker can be validated](https://onco.cc/ideas/idea-tr2-marker-stratified-default/)
- targets: [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- trials: [DESTINY-Breast06](https://onco.cc/trials/destiny-breast06/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- key papers: [DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer](https://onco.cc/key-papers/paper-destiny-breast06-nejm-2024/), [Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue](https://onco.cc/key-papers/paper-fernandez-jama-oncol/)

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