# Randomise the next line of treatment before the first one fails

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

## TL;DR

Trials usually study one treatment at a time, so nobody knows the best order. Deciding the next step in advance, by lottery, answers the sequencing question at little extra cost.

## Summary

Sequencing questions are almost never answered because patients leave the trial at progression. A pre-randomised design assigns the second-line option at the time of first-line enrolment, keeps patients within the protocol at progression, and collects the progression biopsy. Total sample size increases modestly, but the design yields a real strategy comparison rather than isolated line-by-line results.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Strategy-randomised sequencing trials detect clinically meaningful differences in overall survival between drug orders that line-by-line trials cannot detect, in at least one common setting.
- Rationale: Overall survival depends on the whole sequence, not the first agent; oncology has repeatedly discovered that ordering matters (for example in metastatic colorectal and prostate cancer) only through retrospective analysis.
- Proposed test: Add pre-randomised second-line assignment to two ongoing first-line trials and compare information gained per patient with a matched conventional design.
- Maturity: speculative
- Actor: research

## 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

- terms: [ADC sequencing](https://onco.cc/terms/adc-sequencing/), [Overall survival (OS)](https://onco.cc/terms/os/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)

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