ideasIdea

Add the second drug on day one when the escape route is predictable

If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.

For several targeted agents the dominant bypass is known in advance: MET amplification after EGFR inhibition, RTK and MAPK reactivation after KRAS G12C inhibition, and MEK reactivation after BRAF inhibition (which is why BRAF and MEK inhibitors are combined). Extending upfront combination logic requires tolerability, so intermittent scheduling or lower-dose partner agents should be part of the design.

Hypothesis

Upfront combination against the dominant predicted bypass extends progression-free survival by more than 50 percent relative to sequential addition at progression, at acceptable added toxicity.

Rationale

BRAF plus MEK inhibition proved the principle, converting a short-lived response into a durable one; the same logic has not been systematically applied to other classes because tolerability was assumed prohibitive without testing schedules.

What would test it

Randomised phase 2 of upfront versus at-progression addition of a bypass-directed agent in a setting with a well-documented dominant mechanism, with dose-optimised intermittent schedules.

Maturity

early clinical

Who has to act

industry

Cost to try

Medium ($1M to $50M)

Years to first evidence

Bottlenecks it attacks

Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
Too many combinations to test · There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.
Wrong doses · Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.

Connected

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Pages like this

not linked directly; found by shared links

Idea
Add a drug when the blood test turns, without stopping the one that works
Shares Amivantamab, MET, Osimertinib, Acquired resistance to every therapy.
Person
Dae Ho Lee
Shares Amivantamab, MET, Osimertinib, EGFR.
Idea
ctDNA-guided dose holidays for lung cancer targeted therapy
Shares Osimertinib, Wrong doses, Acquired resistance to every therapy, EGFR.
Pairing
Amivantamab + lazertinib (first-line EGFR NSCLC)
Shares Amivantamab, MET, Osimertinib, EGFR.
Term
MET amplification (bypass resistance)
Shares Amivantamab, MET, Acquired resistance to every therapy, EGFR.
Idea
Test alternating drug schedules against giving both drugs at once
Shares Osimertinib, Too many combinations to test, Acquired resistance to every therapy, Non-small-cell lung cancer.
Idea
Design drug pairs where resisting one makes you vulnerable to the other
Shares BRAF, Too many combinations to test, RAS / RAF / MEK / ERK (MAPK), Acquired resistance to every therapy.
Person
John V. Heymach
Shares Osimertinib, KRAS, EGFR, Non-small-cell lung cancer.

Add the second drug on day one when the escape route is predictable

Connected

Pages like this

cancers

targets

drugs

pathways

bottlenecks