# Test alternating drug schedules against giving both drugs at once

Source: https://onco.cc/ideas/idea-tr2-alternating-vs-concurrent/  
OnCo record `idea-tr2-alternating-vs-concurrent` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Two drugs might work better given in turns rather than together, with less toxicity. Almost no trial has tested this.

## Summary

Evolutionary models and mouse studies suggest that alternating two non-cross-resistant agents can delay resistance as well as concurrent dosing at lower cumulative toxicity, and that some pairs are antagonistic when concurrent (for example cytostatic agents that protect cells from cytotoxics). Randomised trials of schedule rather than of drug are rare.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: For at least one common doublet (for example an EGFR TKI plus chemotherapy in EGFR-mutant lung cancer), an alternating schedule achieves non-inferior progression-free survival with at least 30% fewer grade 3 or worse adverse events than concurrent dosing.
- Rationale: FLAURA2 showed concurrent osimertinib plus chemotherapy improves progression-free survival but with substantial added toxicity. Cell-cycle arguments predict that sequence within a cycle matters.
- Proposed test: A randomised phase 2 of concurrent versus alternating osimertinib and platinum-pemetrexed with progression-free survival and toxicity endpoints, plus ctDNA kinetics to compare resistance emergence.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- Bottleneck evidence (Too many combinations to test): Palmer & Sorger, Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy (Cell 2017): https://doi.org/10.1016/j.cell.2017.11.009

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- drugs: [Osimertinib](https://onco.cc/drugs/osimertinib/)
- trials: [FLAURA2](https://onco.cc/trials/flaura2/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)
- key papers: [Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy](https://onco.cc/key-papers/paper-palmer-cell/), [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [FLAURA2: long-term safety of first-line osimertinib plus platinum-pemetrexed in EGFR-mutated advanced lung cancer](https://onco.cc/key-papers/paper-flaura2-long-term-safety-lung-cancer-2026/), [MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-mariposa-nejm-2024/)

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