ideasIdea
Pause a failed drug so the tumour becomes sensitive to it again
Resistant cancer cells sometimes come to depend on the very drug they resisted. Stopping the drug for a while can make them vulnerable to it once more.
Drug addiction has been demonstrated for BRAF-inhibitor-resistant melanoma in mice and reported anecdotally in patients rechallenged after a break. Intermittent dosing prevented resistance in those models. A prospective trial would formalise rechallenge: after progression and a defined washout with an intervening therapy, patients are rechallenged with the original agent and monitored with ctDNA for the resistance allele's decline during the holiday.
Hypothesis
The resistant clone fraction measured in plasma falls during a drug holiday, and rechallenge after a defined interval produces objective responses in a clinically meaningful minority of patients.
Rationale
The fitness cost of resistance mutations is a general evolutionary principle and is directly measurable in plasma, which makes the holiday duration optimisable rather than arbitrary.
What would test it
Phase 2 rechallenge study with serial ctDNA during the holiday in BRAF-mutant melanoma or EGFR-mutant lung cancer; endpoints response rate on rechallenge and correlation with clone decay kinetics.
Maturity
early clinical
Who has to act
clinic
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
- Tumour heterogeneity and clonal evolution · A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.