{"entity":{"id":"idea-bio1-ctdna-adaptive-tki","kind":"idea","name":"ctDNA-guided dose holidays for lung cancer targeted therapy","aka":[],"tldr":"Use tumour DNA in the blood as the signal to pause and restart a lung cancer pill, keeping the tumour in check while slowing the rise of resistant cells.","summary":"Adaptive therapy needs a fast, quantitative burden marker. In EGFR- and ALK-driven lung cancer, ctDNA falls to undetectable within weeks of TKI and rises before scans show progression. The proposal is a rules-based algorithm: pause the TKI when ctDNA has been undetectable for two consecutive draws, restart at reappearance, and compare with continuous dosing.","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":["nsclc"],"sections":[],"technologies":["liquid-biopsy","kinase-inhibitors"],"targets":["egfr"],"drugs":["osimertinib"],"companies":[],"institutions":[],"pathways":[],"terms":["ctdna"],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-resistance","b-dose-optimisation"],"keyPapers":["paper-flaura-nejm-2018","paper-egfr-nsclc-lancet-oncol-2012","paper-egfr-nsclc-n-engl-j-med-2010"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"ctDNA-guided intermittent osimertinib yields non-inferior progression-free survival to continuous dosing with fewer resistance mutations at progression and lower cumulative toxicity and cost.","rationale":"Intermittent dosing delayed resistance in BRAF melanoma models by exploiting drug-addiction of resistant cells; ctDNA provides the missing real-time burden signal for tumours that do not have a serum marker.","test":"Randomised phase 2 of 150 patients with EGFR-mutant NSCLC in deep molecular response on osimertinib: ctDNA-guided intermittent versus continuous; endpoints PFS, mechanism spectrum at progression, drug-free months.","maturity":"speculative","actor":"clinic","cost":"medium","horizonYears":4},"route":"/ideas/idea-bio1-ctdna-adaptive-tki/","neighbours":{"cancer":[{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","route":"/cancers/alk-positive-nsclc/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"drug":[{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"paper":[{"id":"paper-egfr-nsclc-lancet-oncol-2012","kind":"paper","name":"Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial","route":"/key-papers/paper-egfr-nsclc-lancet-oncol-2012/"},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-egfr-nsclc-n-engl-j-med-2010","kind":"paper","name":"Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR","route":"/key-papers/paper-egfr-nsclc-n-engl-j-med-2010/"}],"roadmap":[{"id":"hormonal-therapy-roadmap","kind":"roadmap","name":"Hormonal therapy roadmap: removing the ovaries → tamoxifen → oral degraders switched by a blood test","route":"/roadmaps/hormonal-therapy-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}