OnCo
ideasIdea

ctDNA-guided dose holidays for lung cancer targeted therapy

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.

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.

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.
What would test it
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
Who has to act
clinic
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks

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