# ctDNA-guided dose holidays for lung cancer targeted therapy

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

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## 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

- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [EGFR](https://onco.cc/targets/egfr/)
- drugs: [Osimertinib](https://onco.cc/drugs/osimertinib/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- key papers: [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](https://onco.cc/key-papers/paper-egfr-nsclc-lancet-oncol-2012/), [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR](https://onco.cc/key-papers/paper-egfr-nsclc-n-engl-j-med-2010/)
- roadmaps: [Hormonal therapy roadmap: removing the ovaries → tamoxifen → oral degraders switched by a blood test](https://onco.cc/roadmaps/hormonal-therapy-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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