{"entity":{"id":"idea-bio1-clonal-clearance-endpoint","kind":"idea","name":"Make clonal clearance, not tumour shrinkage, a trial endpoint","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["liquid-biopsy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["recist","ctdna","pfs"],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-trial-design"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":4},"route":"/ideas/idea-bio1-clonal-clearance-endpoint/","neighbours":{"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"},{"id":"recist","kind":"term","name":"RECIST","route":"/terms/recist/"}],"bottleneck":[{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"paper":[{"id":"paper-tracerx-evolution-nature-2023","kind":"paper","name":"TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse","route":"/key-papers/paper-tracerx-evolution-nature-2023/"}]}}