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

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

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed test: 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
- Actor: industry

## Sources

- Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018): https://doi.org/10.1056/NEJMoa1713137

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- targets: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/)
- drugs: [Amivantamab](https://onco.cc/drugs/amivantamab/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Sotorasib](https://onco.cc/drugs/sotorasib/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- trials: [ADAURA](https://onco.cc/trials/adaura/), [FLAURA](https://onco.cc/trials/flaura/), [FLAURA2](https://onco.cc/trials/flaura2/), [MARIPOSA](https://onco.cc/trials/mariposa/), [RTOG 0617](https://onco.cc/trials/rtog-0617/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [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/)

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