# Switch drugs at maximum response, not at relapse

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

## TL;DR

Species go extinct when a second disaster hits a population already shrunk by a first one. Apply the same logic: hit the tumour with a different kind of drug when it is smallest, rather than waiting for it to grow back.

## Summary

The first-strike, second-strike model from extinction biology proposes that a therapy switch at nadir, when the residual population is small and less diverse, exploits stochastic extinction and pre-empts the expansion of resistant clones. Current practice continues the first drug until progression, when the population is large and resistant. A trial would randomise patients at best response to a mechanistically distinct second strike versus continuation.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: In patients achieving deep response on a targeted agent, a time-limited switch to a non-cross-resistant agent at nadir increases the rate of durable remission at three years compared with continuing the first agent to progression.
- Rationale: Small populations are more vulnerable to extinction; the mechanism is well established in ecology and is implicit in consolidation strategies in leukaemia, but has never been tested in solid tumours.
- Proposed test: Phase 2 in ALK-positive lung cancer or BRAF melanoma: at confirmed best response, randomise to three months of a different mechanism (for example chemotherapy or an ADC) followed by original therapy, versus continuation; endpoint durable remission at 36 months.
- Maturity: speculative
- Actor: research

## Sources

- Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012): https://doi.org/10.1056/NEJMoa1113205

## Connected records

- cancers: [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- drugs: [Lorlatinib](https://onco.cc/drugs/lorlatinib/)
- institutions: [Moffitt Cancer Center](https://onco.cc/institutions/moffitt/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)

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