{"entity":{"id":"idea-tr2-resistance-mechanism-baskets","kind":"idea","name":"Combination baskets defined by resistance mechanism rather than by cancer type","aka":[],"tldr":"Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.","summary":"Progression biopsies and ctDNA now reveal resistance mechanisms (SLFN11 loss for topoisomerase-1 payloads, MET amplification for EGFR inhibitors, RB loss for CDK4/6 inhibitors). A basket trial enrolling by mechanism would test the matched rescue combination (for example ATR inhibitor plus the same ADC for SLFN11-low tumours) across histologies, converting a resistance hypothesis into a trial in months.","asOf":"2026-09-08","links":[{"label":"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)","url":"https://doi.org/10.1016/j.cell.2017.11.009"}],"tags":[],"related":["idea-payload-switching","idea-tr2-smart-sequencing-adc"],"cancers":[],"sections":[],"technologies":["adc","cdk46-inhibitor"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tumour-agnostic","efflux-pump"],"trials":[],"people":[],"bottlenecks":["b-combination-space","b-resistance"],"keyPapers":["paper-palmer-cell"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Mechanism-defined baskets will achieve objective response rates at least twice those of unselected post-progression combination cohorts of the same agents.","rationale":"Histology-agnostic approvals (NTRK, MSI-high) proved that biology can define a population; resistance mechanisms are the same idea applied after progression.","test":"A three-cohort basket: SLFN11-low after a TOP1 ADC, MET-amplified after EGFR TKI, and RB1-loss after CDK4/6 inhibitor, each with a pre-specified rescue combination and a Simon two-stage design.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":4},"route":"/ideas/idea-tr2-resistance-mechanism-baskets/","neighbours":{"idea":[{"id":"idea-payload-switching","kind":"idea","name":"Payload-class switching as the rule for ADC sequencing","route":"/ideas/idea-payload-switching/"},{"id":"idea-tr2-smart-sequencing-adc","kind":"idea","name":"Sequential multiple-assignment randomised trials to find the best order of ADCs","route":"/ideas/idea-tr2-smart-sequencing-adc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"}],"term":[{"id":"efflux-pump","kind":"term","name":"Drug efflux pumps (ABC transporters)","route":"/terms/efflux-pump/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"}],"paper":[{"id":"paper-palmer-cell","kind":"paper","name":"Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy","route":"/key-papers/paper-palmer-cell/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}