{"entity":{"id":"idea-bio1-first-strike-second-strike","kind":"idea","name":"Switch drugs at maximum response, not at relapse","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":[],"cancers":["nsclc","melanoma"],"sections":[],"technologies":[],"targets":[],"drugs":["lorlatinib"],"companies":[],"institutions":["moffitt"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-resistance"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":5},"route":"/ideas/idea-bio1-first-strike-second-strike/","neighbours":{"cancer":[{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"drug":[{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"}],"institution":[{"id":"moffitt","kind":"institution","name":"Moffitt Cancer Center","route":"/institutions/moffitt/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}]}}