# The brain: barrier and sanctuary

Source: https://onco.cc/bottlenecks/b-brain-delivery/  
OnCo record `b-brain-delivery` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: biology
- Severity: major
- Metrics: Median overall survival in newly diagnosed glioblastoma with radiotherapy plus temozolomide (Stupp regimen), still the standard of care: 14.6 months (Stupp et al., NEJM 2005); Adults with cancer who develop brain metastases: ~20% (Achrol et al., Nature Reviews Disease Primers 2019); Median overall survival with tumour-treating fields added to temozolomide (EF-14), the only phase 3 survival gain in glioblastoma since 2005: 20.9 vs 16.0 months (Stupp et al., JAMA 2017)
- 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.

## Sources

- Stupp et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma (NEJM 2005): https://doi.org/10.1056/NEJMoa043330
- Achrol et al., Brain metastases (Nature Reviews Disease Primers 2019): https://doi.org/10.1038/s41572-018-0055-y
- Arvanitis, Ferraro & Jain, The blood-brain barrier and blood-tumour barrier in brain tumours and metastases (Nature Reviews Cancer 2020): https://doi.org/10.1038/s41568-019-0205-x

## Connected records

- ideas: [A skull ultrasound implant that opens the barrier at every cycle](https://onco.cc/ideas/idea-bio2-implanted-ultrasound-repeat-dosing/), [A standard platform to get drugs into the brain: focused ultrasound plus shuttle-engineered therapeutics](https://onco.cc/ideas/idea-moon-brain-delivery-platform/), [Brain metastases included by default in every solid-tumour trial](https://onco.cc/ideas/idea-tr1-brain-mets-default-included/), [Build a human model of the barrier that guards the brain fluid](https://onco.cc/ideas/idea-bio2-blood-csf-barrier-model/), [Deliver CAR-T cells straight into the fluid around the brain](https://onco.cc/ideas/idea-bio2-intraventricular-car-t/), [Deliver drugs and cells to the brain through the nose](https://onco.cc/ideas/idea-bio2-intranasal-delivery/), [Design protein degraders small enough to get into the brain](https://onco.cc/ideas/idea-bio2-brain-penetrant-glue-degraders/), [Focused-ultrasound BBB opening to deliver ADCs and radioligands to glioma](https://onco.cc/ideas/idea-fus-plus-adc-glioma/), [Measure brain metastasis prevention as a primary endpoint, not as a secondary one](https://onco.cc/ideas/idea-lung-brain-metastasis-prevention-as-a-primary-endpoint/), [MRI surveillance replaces prophylactic cranial irradiation in SCLC](https://onco.cc/ideas/idea-mri-surveillance-replaces-pci/), [Neoadjuvant immunotherapy with surgical window for glioblastoma](https://onco.cc/ideas/idea-neoadjuvant-io-glioblastoma/), [Oncolytic viruses that make interleukin-12 only inside the tumour](https://onco.cc/ideas/idea-bio2-oncolytic-regulated-il12/), [Open the barrier so engineered immune cells can enter the brain](https://onco.cc/ideas/idea-bio2-fus-for-cell-entry/), [Prevention trials aimed only at brain metastasis](https://onco.cc/ideas/idea-bio2-brain-met-prevention-trials/), [Read the spinal fluid to track brain tumours without opening the skull](https://onco.cc/ideas/idea-bio2-csf-ctdna-monitoring/), [Require every oncology candidate to publish how much reaches the brain](https://onco.cc/ideas/idea-bio2-brain-exposure-disclosure/), [Robot-placed catheters and live imaging for drug infusion into brain tumours](https://onco.cc/ideas/idea-bio2-robotic-convection-delivery/), [Stop excluding brain metastases from cancer trials](https://onco.cc/ideas/idea-bio2-cns-cohort-mandate/), [Systemic-first management of HER2-positive brain metastases](https://onco.cc/ideas/idea-cns-first-adc-strategy/), [Treat brain metastases as a disease with its own trials programme](https://onco.cc/ideas/idea-fund-brain-metastases-programme/), [Trials that include, and report, brain metastases in triple-negative breast cancer](https://onco.cc/ideas/idea-tnbc-brain-metastasis-trials/), [Ultrasound-assisted blood test instead of a brain biopsy](https://onco.cc/ideas/idea-bio2-sonobiopsy/), [Use the brain's own transport door to carry antibody drugs across](https://onco.cc/ideas/idea-bio2-transferrin-shuttle-adc/)
- cancers: [Diffuse midline glioma, H3 K27-altered (including DIPG)](https://onco.cc/cancers/dipg-dmg/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/), [HER2-positive breast cancer with brain metastases](https://onco.cc/cancers/her2-positive-breast-brain-metastases/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- technologies: [CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)](https://onco.cc/technologies/glioma-car-t/), [Focused-ultrasound blood-brain barrier opening](https://onco.cc/technologies/bbb-focused-ultrasound/), [Laser interstitial thermal therapy (LITT)](https://onco.cc/technologies/litt/), [MRI](https://onco.cc/technologies/mri/), [Prophylactic cranial irradiation vs MRI surveillance](https://onco.cc/technologies/prophylactic-cranial-irradiation/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Tumour treating fields (TTFields)](https://onco.cc/technologies/ttfields/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [HER2](https://onco.cc/targets/her2/), [IDH1 / IDH2](https://onco.cc/targets/idh/)
- drugs: [Dordaviprone](https://onco.cc/drugs/dordaviprone/), [Optune / Optune Pax (TTFields)](https://onco.cc/drugs/optune/), [Rindopepimut](https://onco.cc/drugs/rindopepimut/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Tovorafenib](https://onco.cc/drugs/tovorafenib/), [Tucatinib](https://onco.cc/drugs/tucatinib/), [Vorasidenib](https://onco.cc/drugs/vorasidenib/)
- companies: [Insightec](https://onco.cc/companies/insightec/), [Novocure](https://onco.cc/companies/novocure/), [Servier](https://onco.cc/companies/servier/)
- institutions: [City of Hope](https://onco.cc/institutions/city-of-hope/), [Duke Cancer Institute](https://onco.cc/institutions/duke-cancer-institute/), [Geneva University Hospitals (HUG)](https://onco.cc/institutions/hug-geneva/), [Heidelberg University Hospital / NCT / DKFZ](https://onco.cc/institutions/heidelberg-nct/), [Massachusetts General Hospital Cancer Center](https://onco.cc/institutions/mgh/), [Robert H. Lurie Comprehensive Cancer Center of Northwestern University](https://onco.cc/institutions/northwestern-lurie/), [Stanford Health Care / Stanford Cancer Institute](https://onco.cc/institutions/stanford/), [Sunnybrook Odette Cancer Centre](https://onco.cc/institutions/sunnybrook-odette/), [University of Florida Health Cancer Center](https://onco.cc/institutions/uf-health-cancer-center/)
- terms: [Blood-brain barrier (BBB)](https://onco.cc/terms/blood-brain-barrier/), [EGFRvIII](https://onco.cc/terms/egfrviii/), [H3 K27M (diffuse midline glioma)](https://onco.cc/terms/h3k27m/), [HER2-positive brain metastases](https://onco.cc/terms/her2-brain-metastases/), [MGMT promoter methylation](https://onco.cc/terms/mgmt/)
- trials: [ACT IV](https://onco.cc/trials/act-iv/), [ACTION](https://onco.cc/trials/action-dmg/), [CheckMate 548](https://onco.cc/trials/checkmate-548/), [DESTINY-Breast12](https://onco.cc/trials/destiny-breast12/), [EF-14](https://onco.cc/trials/ef-14/), [EORTC 26981 / NCIC CE.3 (Stupp trial)](https://onco.cc/trials/eortc-26981/), [HER2CLIMB](https://onco.cc/trials/her2climb/), [INDIGO](https://onco.cc/trials/indigo/), [PRIMA-CNS](https://onco.cc/trials/prima-cns/)
- key papers: [Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/), [Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer](https://onco.cc/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/), [Brain metastases](https://onco.cc/key-papers/paper-achrol-nat-rev-dis-primers/), [First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer](https://onco.cc/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/), [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma](https://onco.cc/key-papers/paper-indigo-nejm-2023/), [Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission](https://onco.cc/key-papers/paper-auperin-prophylactic-cranial-irradiation-sclc-nejm-1999/), [Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases](https://onco.cc/key-papers/paper-lin-tnbc-cns-metastases-dfci-cancer-2008/), [Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma](https://onco.cc/key-papers/paper-stupp-temozolomide-nejm-2005/), [The blood-brain barrier and blood-tumour barrier in brain tumours and metastases](https://onco.cc/key-papers/paper-arvanitis-nat-rev-cancer/)
- roadmaps: [Devices and physical therapies roadmap: heat and light → electric fields and focused sound → drug-releasing implants](https://onco.cc/roadmaps/devices-roadmap/), [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](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- pathways: [The blood-brain barrier & brain metastasis](https://onco.cc/pathways/blood-brain-barrier-metastasis/)

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