# Make clonal clearance, not tumour shrinkage, a trial endpoint

Source: https://onco.cc/ideas/idea-bio1-clonal-clearance-endpoint/  
OnCo record `idea-bio1-clonal-clearance-endpoint` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A drug that shrinks a tumour by half but leaves the resistant sub-population untouched will fail. Trials should measure whether every sub-population is cleared, not just overall size.

## Summary

Response criteria (RECIST) measure bulk diameter; ctDNA endpoints measure total variant allele fraction. Neither captures whether all subclones are suppressed. A clonal clearance endpoint, defined as undetectable plasma signal for every baseline-identified subclone at a fixed timepoint, could be validated as a surrogate and used in early-phase trials to distinguish drugs that shrink from drugs that eradicate.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Clonal clearance at 12 weeks predicts progression-free survival better than RECIST response or bulk ctDNA clearance, and drugs that achieve it more often produce longer durations of response in later trials.
- Rationale: Bulk response is dominated by the largest clone; durable benefit depends on the smallest resistant clone. The measurement is now feasible with multi-region baseline tissue and deep plasma sequencing.
- Proposed test: Retrospective validation on serial plasma from two completed targeted-therapy trials with baseline multi-region tissue; if predictive, propose to regulators as an exploratory endpoint for phase 2.
- Maturity: speculative
- Actor: regulator

## Sources

- Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012): https://doi.org/10.1056/NEJMoa1113205

## Connected records

- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/), [RECIST](https://onco.cc/terms/recist/)
- bottlenecks: [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse](https://onco.cc/key-papers/paper-tracerx-evolution-nature-2023/)

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