{"entity":{"id":"glioblastoma","kind":"indication","name":"Glioma & glioblastoma","aka":[],"tldr":"Gliomas are now diagnosed by molecular class, and three classes got their first targeted drugs in 2024-25 (vorasidenib for IDH-mutant glioma, tovorafenib for BRAF-altered paediatric glioma, dordaviprone for H3 K27M). Glioblastoma itself is the hardest to treat and has kept the same standard since 2005; CAR-T delivered into the brain and focused-ultrasound drug delivery are the live directions.","summary":"Gliomas are classified by the WHO 2021 system on molecular grounds: IDH-wild-type glioblastoma (grade 4, ~50% of gliomas, median age 65, median survival ~15 months with maximal therapy), IDH-mutant astrocytoma (grades 2-4) and 1p/19q-codeleted oligodendroglioma (better prognosis, decades of survival possible), and paediatric-type tumours including H3 K27M-mutant diffuse midline glioma (median survival ~11 months) and BRAF-altered low-grade glioma (the commonest childhood brain tumour, rarely life-threatening but chronically disabling). The two shared barriers are the blood-brain barrier, which excludes most drugs, and diffuse infiltration, which makes complete resection impossible.\n\nGlioblastoma treatment has been static since 2005: maximal safe resection (improved by 5-ALA fluorescence, intraoperative MRI, and awake mapping; the extent of resection is itself prognostic and is now graded by the RANO resect classes), radiotherapy with concurrent and adjuvant temozolomide (Stupp), and tumour treating fields (EF-14). MGMT promoter methylation predicts temozolomide benefit; unmethylated tumours gain less, though not nothing, and how much remains debated (in the elderly trials NOA-08 and Nordic, unmethylated tumours did better with radiotherapy than with temozolomide alone). Every major systemic trial since has failed: bevacizumab (PFS only), rindopepimut (ACT IV), nivolumab (CheckMate 143, 498, 548), depatuxizumab mafodotin (INTELLANCE-1), and many more. At recurrence, lomustine, re-resection, re-irradiation, LITT, and bevacizumab for oedema are the options, with median survival under a year. DCVax-L's externally controlled phase 3 remains contested.\n\nProgress has come at the edges. Vorasidenib (INDIGO, approved 2024) is the first targeted therapy for grade 2 IDH-mutant glioma, delaying radiation and chemotherapy by years. Dabrafenib with trametinib (2023) was the first targeted therapy approved for BRAF V600E paediatric low-grade glioma; tovorafenib (2024) followed for relapsed or refractory BRAF-altered tumours, including BRAF fusions. Dordaviprone (August 2025) is the first drug approved for H3 K27M diffuse midline glioma. Methylation-based classification and intraoperative nanopore sequencing have transformed diagnosis. For glioblastoma itself the most promising directions are locoregional CAR-T (IL13Rα2, GD2, multi-target), focused-ultrasound and LITT-based barrier opening to deliver ADCs, radioconjugates, and chemotherapy, neoadjuvant immunotherapy with window designs, personalised neoantigen vaccines (NeoVax), and combinations built on the unmethylated-MGMT population where temozolomide adds nothing.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Glioblastoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Glioblastoma"}],"tags":["cns","spike"],"related":["meningioma"],"indications":[],"sections":[],"technologies":[],"targets":["b7h3"],"drugs":[],"companies":["bms"],"institutions":["penn-abramson","heidelberg-nct"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"central nervous system","burden":"About 300,000 CNS tumours occur per year, most of them not glioblastoma; IDH-mutant and paediatric low-grade gliomas can be lived with for decades and now have targeted drugs. Median survival for glioblastoma with maximal therapy is about 15 months.","subtypes":["Glioblastoma, IDH-wild-type (WHO grade 4; TERT promoter, EGFR amplification, +7/−10)","Astrocytoma, IDH-mutant (grades 2-4; CDKN2A/B deletion defines grade 4)","Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (grades 2-3)","Diffuse midline glioma, H3 K27M-altered (including DIPG)","Paediatric low-grade glioma (BRAF fusion or V600E, NF1)","Diffuse hemispheric glioma H3 G34-mutant; infant-type hemispheric glioma (NTRK/ALK/ROS1 fusions)"],"biomarkers":["IDH1/2","1p/19q codeletion","MGMT methylation","H3K27M","EGFR amplification","Methylation class","IDH1/2 mutation (vorasidenib eligibility)","MGMT promoter methylation (temozolomide benefit)","H3 K27M (dordaviprone eligibility)","BRAF fusion / V600E (tovorafenib, dabrafenib-trametinib)","TERT promoter, EGFR amplification, +7/−10 (molecular glioblastoma)","CDKN2A/B homozygous deletion (grade 4 astrocytoma)","DNA methylation class (Heidelberg classifier)","NTRK/ALK/ROS1 fusions (infant gliomas)","TMB / mismatch repair (rare hypermutant, IO-responsive)"],"standardOfCare":[{"setting":"Glioblastoma","approach":"Resection → RT + temozolomide → TTFields; lomustine/bevacizumab at relapse.","refs":[],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"IDH-mutant grade 2","approach":"Resection → vorasidenib or observation; RT/PCV for high-risk.","refs":[],"guideline":{"version":"NCCN Guidelines: Central Nervous System Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425"}},{"setting":"Diagnosis","approach":"MRI with contrast; maximal safe resection with 5-ALA and intraoperative mapping, with early postoperative MRI to measure the extent of resection; integrated histo-molecular diagnosis with methylation classification where available.","refs":[]},{"setting":"Glioblastoma, newly diagnosed","approach":"Radiotherapy 60 Gy in 30 fractions with concurrent and 6 cycles adjuvant temozolomide; from age 65, short-course radiotherapy (40 Gy in 15 fractions) with temozolomide (CCTG CE.6); for older patients unfit for combined treatment, temozolomide alone or hypofractionated radiotherapy alone, chosen by MGMT status (Nordic, NOA-08); TTFields with maintenance temozolomide; trials for MGMT-unmethylated patients.","refs":["temozolomide"]},{"setting":"Glioblastoma, recurrent","approach":"Re-resection or LITT if feasible; lomustine; bevacizumab for oedema/steroid sparing; re-irradiation; clinical trial (CAR-T, FUS-BBB, vaccines) strongly preferred.","refs":[]},{"setting":"IDH-mutant grade 2 glioma","approach":"Maximal resection; vorasidenib for residual/recurrent disease (INDIGO); radiotherapy plus PCV or temozolomide for high-risk or progressive disease.","refs":[]},{"setting":"Oligodendroglioma grade 3 / astrocytoma grade 3","approach":"Radiotherapy plus PCV (RTOG 9402, EORTC 26951) or temozolomide (CATNON).","refs":["temozolomide"]},{"setting":"H3 K27M diffuse midline glioma","approach":"Radiotherapy; dordaviprone at progression (2025); GD2 CAR-T and ONC201 first-line trials.","refs":[]},{"setting":"Paediatric low-grade glioma","approach":"Resection where safe; chemotherapy (carboplatin/vincristine) or tovorafenib / dabrafenib-trametinib for BRAF-altered relapsed disease; avoid radiation in young children.","refs":[]}],"stateOfArt":["Vorasidenib in low-grade glioma.","Methylation-based diagnosis.","TTFields.","Three first-in-class targeted approvals for glioma subtypes in 2024-25: vorasidenib (IDH-mutant), tovorafenib (BRAF paediatric), dordaviprone (H3 K27M).","Molecular classification (WHO 2021, methylation classifier, intraoperative nanopore) now defines diagnosis.","Locoregional CAR-T produces objective responses in recurrent glioblastoma and DIPG, though transient.","Focused ultrasound opens the blood-brain barrier in humans with 4-6x higher drug delivery; efficacy trials underway."],"history":[{"year":1926,"title":"Bailey and Cushing classify gliomas","note":"Histologic classification that lasted, in essence, until 2016.","refs":[]},{"year":1978,"title":"Radiotherapy proven to extend survival (BTSG)","note":"Whole-brain then involved-field radiation becomes standard.","refs":[]},{"year":1999,"title":"Temozolomide approved (anaplastic astrocytoma)","refs":["temozolomide"]},{"year":2005,"title":"Stupp regimen: temozolomide + RT","refs":[]},{"year":2008,"title":"IDH1 mutations discovered in glioma","note":"Parsons/Vogelstein glioblastoma genome sequencing; reclassification follows.","refs":[]},{"year":2009,"title":"Bevacizumab accelerated approval at recurrence","note":"Radiographic response without survival benefit.","refs":[]},{"year":2014,"title":"AVAglio / RTOG 0825: bevacizumab no OS benefit; 5-ALA and methylation classifier emerge","refs":[]},{"year":2015,"title":"TTFields improves OS (EF-14)","refs":[]},{"year":2016,"title":"WHO 2016 integrates molecular markers; ACT IV vaccine fails","refs":[]},{"year":2017,"title":"Short-course radiotherapy plus temozolomide extends survival from age 65 (CCTG CE.6)","refs":[]},{"year":2020,"title":"CheckMate 143: immunotherapy fails at recurrence","note":"CheckMate 548 (2022) and CheckMate 498 (2023) follow in newly diagnosed disease; all three negative.","refs":[]},{"year":2021,"title":"WHO 2021: IDH-wild-type glioblastoma defined molecularly","refs":[]},{"year":2022,"title":"GD2 CAR-T responses in DIPG (Stanford)","refs":[]},{"year":2023,"title":"INDIGO: vorasidenib in grade 2 IDH-mutant glioma; DCVax-L contested publication","refs":[]},{"year":2024,"title":"Vorasidenib approved","refs":[]},{"year":2025,"title":"Dordaviprone approved for H3 K27M diffuse midline glioma","note":"6 August 2025; first systemic therapy for the disease.","refs":[]},{"year":2026,"title":"ASCO 2026: NeoVax personalised vaccine immune responses; multi-target CAR-T; tovorafenib EU approval","refs":[]}],"pipeline":[],"openProblems":["Blood-brain barrier.","Immunologically cold, heterogeneous, infiltrative.","Glioblastoma: no systemic drug has beaten the 2005 standard; getting drugs across the blood-brain barrier is the crux.","Glioblastoma's standard has not changed since 2005: every phase 3 systemic agent since temozolomide has failed, so median survival has not moved in 20 years.","MGMT-unmethylated glioblastoma (~60%) gains almost nothing from chemotherapy and has no approved alternative.","Blood-brain barrier and diffuse infiltration limit delivery and resection; imaging cannot distinguish progression from pseudoprogression reliably.","Immunotherapy failure: low TMB, T-cell exclusion, dexamethasone, and treatment-induced lymphopenia; neoadjuvant approaches are the only signal.","Antigen heterogeneity and loss (EGFRvIII, IL13Rα2) undermine single-target vaccines, ADCs, and CAR-T.","Paediatric tumours (DIPG) have one approved drug with 22% response; durable control remains out of reach.","Trial design: single-arm and external-control comparisons (DCVax-L, historical vaccine data) have repeatedly misled the field."]},"route":"/indications/glioblastoma/","neighbours":{"indication":[{"id":"meningioma","kind":"indication","name":"Meningioma","route":"/indications/meningioma/"}],"target":[{"id":"b7h3","kind":"target","name":"B7-H3","route":"/targets/b7h3/"},{"id":"bradykinin-b1-receptor","kind":"target","name":"Bradykinin B1 receptor (B1R)","route":"/targets/bradykinin-b1-receptor/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"institution":[{"id":"penn-abramson","kind":"institution","name":"Abramson Cancer Center, University of Pennsylvania","route":"/institutions/penn-abramson/"},{"id":"erasmus-mc","kind":"institution","name":"Erasmus MC Cancer Institute","route":"/institutions/erasmus-mc/"},{"id":"heidelberg-nct","kind":"institution","name":"Heidelberg University Hospital / NCT / DKFZ","route":"/institutions/heidelberg-nct/"},{"id":"inselspital-bern","kind":"institution","name":"Inselspital, Bern University Hospital / University Cancer Center Inselspital","route":"/institutions/inselspital-bern/"},{"id":"usz-zurich","kind":"institution","name":"University Hospital Zurich / Comprehensive Cancer Center Zurich","route":"/institutions/usz-zurich/"},{"id":"uppsala-akademiska","kind":"institution","name":"Uppsala University Hospital / Uppsala University","route":"/institutions/uppsala-akademiska/"}],"drug":[{"id":"f-18-fet","kind":"drug","name":"Floretyrosine F-18 (FET)","route":"/drugs/f-18-fet/"},{"id":"fluciclovine-f18","kind":"drug","name":"Fluciclovine F-18","route":"/drugs/fluciclovine-f18/"},{"id":"f-18-fdopa","kind":"drug","name":"Fluorodopa F-18","route":"/drugs/f-18-fdopa/"},{"id":"f-18-fluorothymidine","kind":"drug","name":"Fluorothymidine F-18 (FLT)","route":"/drugs/f-18-fluorothymidine/"},{"id":"temozolomide","kind":"drug","name":"Temozolomide","route":"/drugs/temozolomide/"}],"term":[{"id":"radiation-necrosis","kind":"term","name":"Radiation necrosis (brain)","route":"/terms/radiation-necrosis/"}],"section":[{"id":"f-neuro-imaging","kind":"section","name":"Neuro-imaging","route":"/fronts/f-neuro-imaging/"}],"roadmap":[{"id":"neuro-imaging-roadmap","kind":"roadmap","name":"Neuro-oncology imaging roadmap: FDG PET → amino acid PET → SSTR2 theranostics in meningioma","route":"/roadmaps/neuro-imaging-roadmap/"}]}}