# Add a drug when the blood test turns, without stopping the one that works

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

## TL;DR

When a resistance mutation first appears in the blood, the current drug is often still controlling most of the tumour. Adding a second drug rather than swapping may keep both under control.

## Summary

Most ctDNA-guided strategies switch therapy at molecular progression. Because the resistant clone is usually a minority at that point, switching abandons control of the sensitive majority. An additive strategy keeps the backbone and adds a mechanism-matched agent when a specific resistance alteration crosses a threshold in plasma, with the aim of suppressing both populations.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Mechanism-matched addition at molecular progression yields longer time to radiographic progression than either continuing alone or switching, in patients with a single dominant emergent mechanism.
- Rationale: Combination at the point of minimal resistant burden is when the added agent has the best chance of eradicating the emergent clone, and the backbone still suppresses the dominant population.
- Proposed test: Three-arm randomised phase 2 at molecular progression on osimertinib with detectable MET amplification: continue, switch, or add a MET inhibitor; primary endpoint time to radiographic progression.
- Maturity: speculative
- Actor: clinic

## 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

- ideas: [Molecular-progression switching beyond ESR1](https://onco.cc/ideas/idea-ctdna-switch-generalised/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [MET](https://onco.cc/targets/met/)
- drugs: [Amivantamab](https://onco.cc/drugs/amivantamab/), [Osimertinib](https://onco.cc/drugs/osimertinib/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- key papers: [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer](https://onco.cc/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2017/), [Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC](https://onco.cc/key-papers/paper-osimertinib-nsclc-n-engl-j-med-2020/)

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