ideasIdea
Randomised trials to test whether biomarker-negative patients really do not benefit
Many patients are denied a drug because a test says they will not benefit. For the most important tests, that assumption should itself be tested in a trial.
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.
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.
What would test it
Fund three cooperative-group randomised trials in biomarker-negative populations with overall survival or quality-of-life primary endpoints.
Maturity
early clinical
Who has to act
research
Cost to try
Large (over $50M)
Years to first evidence
5
Bottlenecks it attacks
- Biomarkers are not validated or standardised · Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.
- No one can predict who responds to immunotherapy · Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.