{"entity":{"id":"idea-tr1-intermittent-dosing-to-delay-resistance","kind":"idea","name":"Test intermittent dosing of targeted drugs to delay resistance, with honest priors","aka":[],"tldr":"Giving a targeted drug in pulses rather than continuously might slow the emergence of resistant cells and reduce side effects. Early results are mixed, so this needs careful trials with clear rules for when to try it.","summary":"Randomised trials of intermittent versus continuous dosing of targeted agents, selected by biology: intermittent schedules are favoured where preclinical data show drug-addicted resistant clones (as in some BRAF-mutant melanoma models) or where toxicity is exposure-driven; disfavoured where continuous suppression is needed. The SWOG S1320 trial found intermittent BRAF/MEK inhibition did not improve PFS in melanoma, so the proposal targets settings with stronger mechanistic support (e.g., some hormonal and ALK-driven settings) and uses ctDNA to define pulse timing.","asOf":"2026-09-08","links":[{"label":"SWOG S1320 (intermittent vs continuous dabrafenib and trametinib) on ClinicalTrials.gov","url":"https://clinicaltrials.gov/study/NCT02196181"}],"tags":[],"related":[],"cancers":["melanoma","nsclc"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["braf","alk"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["resistance","ctdna"],"trials":["alex","cobrim","columbus","combi-ad","combi-d"],"people":[],"bottlenecks":["b-dose-optimisation","b-resistance"],"keyPapers":["paper-chapman-vemurafenib-nejm-2011","paper-braf-melanoma-n-engl-j-med-2015","paper-alk-nsclc-n-engl-j-med-2013"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"In biologically selected settings, intermittent schedules will achieve non-inferior PFS with reduced toxicity and cost, and in a subset will delay resistance; in unselected settings they will not.","rationale":"Resistance is an evolutionary process sensitive to dosing schedule; preclinical models show schedule-dependent outcomes, but the one large clinical test was negative, so selection criteria matter.","test":"Two randomised phase 2 trials in settings with preclinical support for drug-addicted resistance, with ctDNA-guided pulse timing and PFS non-inferiority plus toxicity as endpoints.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":4},"route":"/ideas/idea-tr1-intermittent-dosing-to-delay-resistance/","neighbours":{"cancer":[{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"trial":[{"id":"alex","kind":"trial","name":"ALEX","route":"/trials/alex/"},{"id":"cobrim","kind":"trial","name":"coBRIM","route":"/trials/cobrim/"},{"id":"columbus","kind":"trial","name":"COLUMBUS","route":"/trials/columbus/"},{"id":"combi-ad","kind":"trial","name":"COMBI-AD","route":"/trials/combi-ad/"},{"id":"combi-d","kind":"trial","name":"COMBI-d","route":"/trials/combi-d/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"paper":[{"id":"paper-chapman-vemurafenib-nejm-2011","kind":"paper","name":"BRIM-3: improved survival with vemurafenib in melanoma with BRAF V600E mutation","route":"/key-papers/paper-chapman-vemurafenib-nejm-2011/"},{"id":"paper-alk-nsclc-n-engl-j-med-2013","kind":"paper","name":"Crizotinib versus chemotherapy in advanced ALK-positive lung cancer","route":"/key-papers/paper-alk-nsclc-n-engl-j-med-2013/"},{"id":"paper-braf-melanoma-n-engl-j-med-2015","kind":"paper","name":"Nivolumab in previously untreated melanoma without BRAF mutation","route":"/key-papers/paper-braf-melanoma-n-engl-j-med-2015/"}]}}