{"entity":{"id":"b-brain-delivery","kind":"bottleneck","name":"The brain: barrier and sanctuary","aka":[],"tldr":"The blood-brain barrier's tight junctions and efflux pumps keep antibodies, antibody-drug conjugates and most kinase inhibitors out of the brain, so glioblastoma treatment has barely changed since 2005 and brain metastases, which develop in about a fifth of adults with cancer, are usually left to radiotherapy alone.","summary":"The blood-brain barrier excludes most large molecules, and small ones that are actively pumped back out, by tight junctions and efflux transporters, so antibodies, ADCs and a large share of kinase inhibitors reach the brain at a fraction of plasma concentration. Glioblastoma median survival with the Stupp regimen has been about 15 months since 2005 and no drug since has meaningfully moved it; temozolomide, lomustine and tumour-treating fields remain the standard, with vorasidenib the first real advance in a decade for IDH-mutant low-grade glioma. Brain metastases develop in around a fifth of adults with cancer, are excluded or under-represented in most systemic-therapy trials, and are usually managed with radiotherapy alone. Newer agents (tucatinib, osimertinib, lorlatinib, trastuzumab deruxtecan) show that CNS activity is achievable when designed for; focused ultrasound, convection-enhanced delivery, intrathecal cell therapy and receptor-mediated transcytosis are the delivery technologies under test.","asOf":"2026-09-08","links":[{"label":"Stupp et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma (NEJM 2005)","url":"https://doi.org/10.1056/NEJMoa043330"},{"label":"Achrol et al., Brain metastases (Nature Reviews Disease Primers 2019)","url":"https://doi.org/10.1038/s41572-018-0055-y"},{"label":"Arvanitis, Ferraro & Jain, The blood-brain barrier and blood-tumour barrier in brain tumours and metastases (Nature Reviews Cancer 2020)","url":"https://doi.org/10.1038/s41568-019-0205-x"}],"tags":[],"related":["idea-fus-plus-adc-glioma","idea-neoadjuvant-io-glioblastoma","idea-cns-first-adc-strategy","idea-mri-surveillance-replaces-pci","idea-bio2-sonobiopsy","idea-bio2-intraventricular-car-t","idea-bio2-robotic-convection-delivery","idea-bio2-transferrin-shuttle-adc","idea-bio2-implanted-ultrasound-repeat-dosing","idea-bio2-cns-cohort-mandate","idea-bio2-csf-ctdna-monitoring","idea-bio2-brain-exposure-disclosure","idea-bio2-intranasal-delivery","idea-bio2-blood-csf-barrier-model","idea-bio2-fus-for-cell-entry","idea-bio2-brain-penetrant-glue-degraders","idea-moon-brain-delivery-platform"],"cancers":["glioblastoma","breast-her2-positive","nsclc","melanoma","sclc"],"sections":[],"technologies":["bbb-focused-ultrasound","litt","glioma-car-t","ttfields","prophylactic-cranial-irradiation","sbrt","mri"],"targets":["idh","egfr","her2"],"drugs":["temozolomide","vorasidenib","tucatinib","optune","rindopepimut","dordaviprone","tovorafenib"],"companies":["insightec","novocure","servier"],"institutions":["city-of-hope","stanford","mgh","heidelberg-nct"],"pathways":[],"terms":["blood-brain-barrier","her2-brain-metastases","mgmt","egfrviii","h3k27m"],"trials":["eortc-26981","ef-14","indigo","her2climb","destiny-breast12","checkmate-548","act-iv"],"people":[],"bottlenecks":[],"keyPapers":["paper-arvanitis-nat-rev-cancer","paper-achrol-nat-rev-dis-primers"],"journals":[],"dependsOn":[],"notes":[],"stage":"biology","severity":"major","metrics":[{"label":"Median overall survival in newly diagnosed glioblastoma with radiotherapy plus temozolomide (Stupp regimen), still the standard of care","value":"14.6 months","source":"Stupp et al., NEJM 2005","url":"https://doi.org/10.1056/NEJMoa043330"},{"label":"Adults with cancer who develop brain metastases","value":"~20%","source":"Achrol et al., Nature Reviews Disease Primers 2019","url":"https://doi.org/10.1038/s41572-018-0055-y"},{"label":"Median overall survival with tumour-treating fields added to temozolomide (EF-14), the only phase 3 survival gain in glioblastoma since 2005","value":"20.9 vs 16.0 months","source":"Stupp et al., JAMA 2017","url":"https://doi.org/10.1001/jama.2017.18718"}],"causes":["Tight endothelial junctions and P-glycoprotein efflux exclude most antibodies, ADCs and many small molecules.","Glioma cells infiltrate diffusely along white-matter tracts, so surgery and focal radiotherapy cannot remove them all.","Patients with brain metastases are excluded from most trials, so CNS activity is rarely measured until after approval.","Glioma is immunologically cold and the brain has limited lymphatic drainage, blunting immunotherapy.","Tumour heterogeneity in glioblastoma is extreme and single-target agents (EGFRvIII vaccine) have failed."],"currentEfforts":["Insightec's MR-guided focused ultrasound transiently opens the blood-brain barrier and is in trials to deliver chemotherapy and antibodies to glioma.","HER2CLIMB and DESTINY-Breast12 show that tucatinib and trastuzumab deruxtecan have meaningful activity against HER2-positive brain metastases, changing trial eligibility norms.","INDIGO established vorasidenib for IDH-mutant grade 2 glioma, the first targeted therapy to delay progression in diffuse glioma.","Intraventricular and locoregional CAR-T (IL13Ra2, GD2 for H3K27M diffuse midline glioma) at City of Hope and Stanford bypass the barrier entirely.","Novocure's Optune tumour-treating fields device is approved for glioblastoma and is being tested in brain metastases and other sites.","The FDA and ASCO-Friends of Cancer Research recommendations now call for inclusion of patients with treated or stable brain metastases in trials."],"successLooksLike":"Median survival in glioblastoma exceeds three years in a phase 3 trial, and patients with brain metastases are routinely included in systemic-therapy trials with CNS response measured as a standard endpoint."},"route":"/bottlenecks/b-brain-delivery/","neighbours":{"idea":[{"id":"idea-bio2-implanted-ultrasound-repeat-dosing","kind":"idea","name":"A skull ultrasound implant that opens the barrier at every cycle","route":"/ideas/idea-bio2-implanted-ultrasound-repeat-dosing/"},{"id":"idea-moon-brain-delivery-platform","kind":"idea","name":"A standard platform to get drugs into the brain: focused ultrasound plus shuttle-engineered therapeutics","route":"/ideas/idea-moon-brain-delivery-platform/"},{"id":"idea-tr1-brain-mets-default-included","kind":"idea","name":"Brain metastases included by default in every solid-tumour trial","route":"/ideas/idea-tr1-brain-mets-default-included/"},{"id":"idea-bio2-blood-csf-barrier-model","kind":"idea","name":"Build a human model of the barrier that guards the brain fluid","route":"/ideas/idea-bio2-blood-csf-barrier-model/"},{"id":"idea-bio2-intraventricular-car-t","kind":"idea","name":"Deliver CAR-T cells straight into the fluid around the brain","route":"/ideas/idea-bio2-intraventricular-car-t/"},{"id":"idea-bio2-intranasal-delivery","kind":"idea","name":"Deliver drugs and cells to the brain through the nose","route":"/ideas/idea-bio2-intranasal-delivery/"},{"id":"idea-bio2-brain-penetrant-glue-degraders","kind":"idea","name":"Design protein degraders small enough to get into the brain","route":"/ideas/idea-bio2-brain-penetrant-glue-degraders/"},{"id":"idea-fus-plus-adc-glioma","kind":"idea","name":"Focused-ultrasound BBB opening to deliver ADCs and radioligands to glioma","route":"/ideas/idea-fus-plus-adc-glioma/"},{"id":"idea-lung-brain-metastasis-prevention-as-a-primary-endpoint","kind":"idea","name":"Measure brain metastasis prevention as a primary endpoint, not as a secondary one","route":"/ideas/idea-lung-brain-metastasis-prevention-as-a-primary-endpoint/"},{"id":"idea-mri-surveillance-replaces-pci","kind":"idea","name":"MRI surveillance replaces prophylactic cranial irradiation in SCLC","route":"/ideas/idea-mri-surveillance-replaces-pci/"},{"id":"idea-neoadjuvant-io-glioblastoma","kind":"idea","name":"Neoadjuvant immunotherapy with surgical window for glioblastoma","route":"/ideas/idea-neoadjuvant-io-glioblastoma/"},{"id":"idea-bio2-oncolytic-regulated-il12","kind":"idea","name":"Oncolytic viruses that make interleukin-12 only inside the tumour","route":"/ideas/idea-bio2-oncolytic-regulated-il12/"},{"id":"idea-bio2-fus-for-cell-entry","kind":"idea","name":"Open the barrier so engineered immune cells can enter the brain","route":"/ideas/idea-bio2-fus-for-cell-entry/"},{"id":"idea-bio2-brain-met-prevention-trials","kind":"idea","name":"Prevention trials aimed only at brain metastasis","route":"/ideas/idea-bio2-brain-met-prevention-trials/"},{"id":"idea-bio2-csf-ctdna-monitoring","kind":"idea","name":"Read the spinal fluid to track brain tumours without opening the skull","route":"/ideas/idea-bio2-csf-ctdna-monitoring/"},{"id":"idea-bio2-brain-exposure-disclosure","kind":"idea","name":"Require every oncology candidate to publish how much reaches the brain","route":"/ideas/idea-bio2-brain-exposure-disclosure/"},{"id":"idea-bio2-robotic-convection-delivery","kind":"idea","name":"Robot-placed catheters and live imaging for drug infusion into brain tumours","route":"/ideas/idea-bio2-robotic-convection-delivery/"},{"id":"idea-bio2-cns-cohort-mandate","kind":"idea","name":"Stop excluding brain metastases from cancer trials","route":"/ideas/idea-bio2-cns-cohort-mandate/"},{"id":"idea-cns-first-adc-strategy","kind":"idea","name":"Systemic-first management of HER2-positive brain metastases","route":"/ideas/idea-cns-first-adc-strategy/"},{"id":"idea-fund-brain-metastases-programme","kind":"idea","name":"Treat brain metastases as a disease with its own trials programme","route":"/ideas/idea-fund-brain-metastases-programme/"},{"id":"idea-tnbc-brain-metastasis-trials","kind":"idea","name":"Trials that include, and report, brain metastases in triple-negative breast cancer","route":"/ideas/idea-tnbc-brain-metastasis-trials/"},{"id":"idea-bio2-sonobiopsy","kind":"idea","name":"Ultrasound-assisted blood test instead of a brain biopsy","route":"/ideas/idea-bio2-sonobiopsy/"},{"id":"idea-bio2-transferrin-shuttle-adc","kind":"idea","name":"Use the brain's own transport door to carry antibody drugs across","route":"/ideas/idea-bio2-transferrin-shuttle-adc/"}],"cancer":[{"id":"dipg-dmg","kind":"cancer","name":"Diffuse midline glioma, H3 K27-altered (including DIPG)","route":"/cancers/dipg-dmg/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"breast-her2-positive","kind":"cancer","name":"HER2-positive breast cancer","route":"/cancers/breast-her2-positive/"},{"id":"her2-positive-breast-brain-metastases","kind":"cancer","name":"HER2-positive breast cancer with brain metastases","route":"/cancers/her2-positive-breast-brain-metastases/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"glioma-car-t","kind":"technology","name":"CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)","route":"/technologies/glioma-car-t/"},{"id":"bbb-focused-ultrasound","kind":"technology","name":"Focused-ultrasound blood-brain barrier opening","route":"/technologies/bbb-focused-ultrasound/"},{"id":"litt","kind":"technology","name":"Laser interstitial thermal therapy (LITT)","route":"/technologies/litt/"},{"id":"mri","kind":"technology","name":"MRI","route":"/technologies/mri/"},{"id":"prophylactic-cranial-irradiation","kind":"technology","name":"Prophylactic cranial irradiation vs MRI surveillance","route":"/technologies/prophylactic-cranial-irradiation/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"ttfields","kind":"technology","name":"Tumour treating fields (TTFields)","route":"/technologies/ttfields/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"idh","kind":"target","name":"IDH1 / IDH2","route":"/targets/idh/"}],"drug":[{"id":"dordaviprone","kind":"drug","name":"Dordaviprone","route":"/drugs/dordaviprone/"},{"id":"optune","kind":"drug","name":"Optune / Optune Pax (TTFields)","route":"/drugs/optune/"},{"id":"rindopepimut","kind":"drug","name":"Rindopepimut","route":"/drugs/rindopepimut/"},{"id":"temozolomide","kind":"drug","name":"Temozolomide","route":"/drugs/temozolomide/"},{"id":"tovorafenib","kind":"drug","name":"Tovorafenib","route":"/drugs/tovorafenib/"},{"id":"tucatinib","kind":"drug","name":"Tucatinib","route":"/drugs/tucatinib/"},{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/"}],"company":[{"id":"insightec","kind":"company","name":"Insightec","route":"/companies/insightec/"},{"id":"novocure","kind":"company","name":"Novocure","route":"/companies/novocure/"},{"id":"servier","kind":"company","name":"Servier","route":"/companies/servier/"}],"institution":[{"id":"city-of-hope","kind":"institution","name":"City of Hope","route":"/institutions/city-of-hope/"},{"id":"duke-cancer-institute","kind":"institution","name":"Duke Cancer Institute","route":"/institutions/duke-cancer-institute/"},{"id":"hug-geneva","kind":"institution","name":"Geneva University Hospitals (HUG)","route":"/institutions/hug-geneva/"},{"id":"heidelberg-nct","kind":"institution","name":"Heidelberg University Hospital / NCT / DKFZ","route":"/institutions/heidelberg-nct/"},{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"},{"id":"northwestern-lurie","kind":"institution","name":"Robert H. Lurie Comprehensive Cancer Center of Northwestern University","route":"/institutions/northwestern-lurie/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"},{"id":"sunnybrook-odette","kind":"institution","name":"Sunnybrook Odette Cancer Centre","route":"/institutions/sunnybrook-odette/"},{"id":"uf-health-cancer-center","kind":"institution","name":"University of Florida Health Cancer Center","route":"/institutions/uf-health-cancer-center/"}],"term":[{"id":"blood-brain-barrier","kind":"term","name":"Blood-brain barrier (BBB)","route":"/terms/blood-brain-barrier/"},{"id":"egfrviii","kind":"term","name":"EGFRvIII","route":"/terms/egfrviii/"},{"id":"h3k27m","kind":"term","name":"H3 K27M (diffuse midline glioma)","route":"/terms/h3k27m/"},{"id":"her2-brain-metastases","kind":"term","name":"HER2-positive brain metastases","route":"/terms/her2-brain-metastases/"},{"id":"mgmt","kind":"term","name":"MGMT promoter methylation","route":"/terms/mgmt/"}],"trial":[{"id":"act-iv","kind":"trial","name":"ACT IV","route":"/trials/act-iv/"},{"id":"action-dmg","kind":"trial","name":"ACTION","route":"/trials/action-dmg/"},{"id":"checkmate-548","kind":"trial","name":"CheckMate 548","route":"/trials/checkmate-548/"},{"id":"destiny-breast12","kind":"trial","name":"DESTINY-Breast12","route":"/trials/destiny-breast12/"},{"id":"ef-14","kind":"trial","name":"EF-14","route":"/trials/ef-14/"},{"id":"eortc-26981","kind":"trial","name":"EORTC 26981 / NCIC CE.3 (Stupp trial)","route":"/trials/eortc-26981/"},{"id":"her2climb","kind":"trial","name":"HER2CLIMB","route":"/trials/her2climb/"},{"id":"indigo","kind":"trial","name":"INDIGO","route":"/trials/indigo/"},{"id":"prima-cns","kind":"trial","name":"PRIMA-CNS","route":"/trials/prima-cns/"}],"paper":[{"id":"paper-peters-alex-alectinib-crizotinib-nejm-2017","kind":"paper","name":"Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/"},{"id":"paper-kwak-crizotinib-alk-nsclc-nejm-2010","kind":"paper","name":"Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer","route":"/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/"},{"id":"paper-achrol-nat-rev-dis-primers","kind":"paper","name":"Brain metastases","route":"/key-papers/paper-achrol-nat-rev-dis-primers/"},{"id":"paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","kind":"paper","name":"First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer","route":"/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/"},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-indigo-nejm-2023","kind":"paper","name":"INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma","route":"/key-papers/paper-indigo-nejm-2023/"},{"id":"paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999","kind":"paper","name":"Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission","route":"/key-papers/paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999/"},{"id":"paper-lin-tnbc-cns-metastases-dfci-cancer-2008","kind":"paper","name":"Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases","route":"/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/"},{"id":"paper-stupp-temozolomide-nejm-2005","kind":"paper","name":"Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma","route":"/key-papers/paper-stupp-temozolomide-nejm-2005/"},{"id":"paper-arvanitis-nat-rev-cancer","kind":"paper","name":"The blood-brain barrier and blood-tumour barrier in brain tumours and metastases","route":"/key-papers/paper-arvanitis-nat-rev-cancer/"}],"roadmap":[{"id":"devices-roadmap","kind":"roadmap","name":"Devices and physical therapies roadmap: heat and light → electric fields and focused sound → drug-releasing implants","route":"/roadmaps/devices-roadmap/"},{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"},{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"}],"pathway":[{"id":"blood-brain-barrier-metastasis","kind":"pathway","name":"The blood-brain barrier & brain metastasis","route":"/pathways/blood-brain-barrier-metastasis/"}]}}