{"entity":{"id":"idea-tr2-biomarker-negative-arms","kind":"idea","name":"Randomised trials to test whether biomarker-negative patients really do not benefit","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Biomarkers are not validated or standardised): Fernandez et al., Examination of low ERBB2 protein expression in breast cancer tissue (JAMA Oncology 2022)","url":"https://doi.org/10.1001/jamaoncol.2021.7239"}],"tags":[],"related":["her2-low","idea-tr2-marker-stratified-default"],"cancers":[],"sections":[],"technologies":[],"targets":["pdl1"],"drugs":["trastuzumab-deruxtecan"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["destiny-breast06"],"people":[],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response"],"keyPapers":["paper-destiny-breast06-nejm-2024","paper-fernandez-jama-oncol"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"large","horizonYears":5},"route":"/ideas/idea-tr2-biomarker-negative-arms/","neighbours":{"term":[{"id":"her2-low","kind":"term","name":"HER2-low and HER2-ultralow","route":"/terms/her2-low/"}],"idea":[{"id":"idea-tr2-marker-stratified-default","kind":"idea","name":"Test the drug in biomarker-negative patients too, so the biomarker can be validated","route":"/ideas/idea-tr2-marker-stratified-default/"}],"target":[{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"drug":[{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"}],"trial":[{"id":"destiny-breast06","kind":"trial","name":"DESTINY-Breast06","route":"/trials/destiny-breast06/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"}],"paper":[{"id":"paper-destiny-breast06-nejm-2024","kind":"paper","name":"DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer","route":"/key-papers/paper-destiny-breast06-nejm-2024/"},{"id":"paper-fernandez-jama-oncol","kind":"paper","name":"Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue","route":"/key-papers/paper-fernandez-jama-oncol/"}]}}