Test intermittent dosing of targeted drugs to delay resistance, with honest priors
Giving a targeted drug in pulses rather than continuously might slow the emergence of resistant cells and reduce side effects. Early results are mixed, so this needs careful trials with clear rules for when to try it.
Randomised trials of intermittent versus continuous dosing of targeted agents, selected by biology: intermittent schedules are favoured where preclinical data show drug-addicted resistant clones (as in some BRAF-mutant melanoma models) or where toxicity is exposure-driven; disfavoured where continuous suppression is needed. The SWOG S1320 trial found intermittent BRAF/MEK inhibition did not improve PFS in melanoma, so the proposal targets settings with stronger mechanistic support (e.g., some hormonal and ALK-driven settings) and uses ctDNA to define pulse timing.
- Wrong doses · Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.