meningioma: future developments...meningioma (who grade ii) based on the 2016 who criteria age ≥...
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Meningioma: future developments
Matthias Preusser, MD
Department of Medicine I
Comprehensive Cancer Center Vienna
Medical University of Vienna
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Disclosures
MP has received honoraria for lectures, consultation or advisory boardparticipation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen.
The following for-profit companies have supported clinical trials andcontracted research conducted by MP with payments made to his institution: Böhringer-Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie.
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Andreas Vesalius, 1534
Meningioma
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Meningioma classification
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Histopathological classificationMeningiothelial Fibroblastic
Secretory Clear cell
Atypical Malignant
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Histopathological classification
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Mutational profiles
Clark et al, Science 2013
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Mutations and site
Preusser et al, Nature Rev Neurol 2018
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Mutations and site
Clark et al, Science 2013
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Mutations and histology
Brastianos et al, Nature Genetics 2013
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Secretory meningioma: TRAF7 and KLF4
Reuss, Acta Neuropathol 2013
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Clear cell meningioma: SMARCE1
Meninges, SMARCE1-pos Clear cell meningioma
Clear cell meningiomaSMARCE1-mutatedSMARCE1-negative
Clear cell meningiomaSMARCE1-wild typeSMARCE1-positive
Smith et al, Nature Genetics 2012
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Rhabdoid meningioma: BAP1 mutations
Shankar et al, Neuro-Oncol 2016
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Meningioma subtypes and molecular subtypes
Preusser et al, Nature Rev Neurol 2018
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TERT promoter mutations as prognostic factor
Sahm, JNCI 2015
TERT hotsposts C228T and C250T: 6.4% overall, 1.7% grade I, 5.7% grade II, 20% grade III
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Sahm F et al. Lancet Oncol 2017
Methylation profiles of meningioma
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Novel therapy approaches
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Potential indications for systemictherapies of meningiomas
• Recurent or progressive WHO I, II, III mengingiomas not treatable (anymore) by surgery or radiotherapy
• Surgically inaccessible (e.g. skull base)
• Multiple meningioma
• En plaque
• Metastatic meningioma
• Clinical trial
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Possible targets for future therapies
Potential drug / drug class
Molecular target / biomarker
AKT inhibitor AKT1 (p.Glu17Lys) mutation
Hedgehog inhibitor SMO (p.Trp535Leu) mutation
FAK inhibitor NF2/merlin loss
Immune checkpoint inhibitor
PD1-/PD-L1
VEGF or VEGFR inhibitor
VEGF/VEGFR2
Trabectedin DNA, tumor-associated macrophages, angiogenesis
Goldbrunner et al, EANO Guidelines , Lancet Oncol 2016Preusser et al, Nature Rev Neurol 2018
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Challenges
• Lack of clinical trials
• Available data mainly from case reports, retrospective series or small uncontrolled trials, often with soft inclusion criteria
• Lack of data on natural course -> availableinformation difficult to interpret
• No accepted radiological response criteria
• WHO I versus WHO II versus III?
• Little knowledge on biology and biomarkers
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Targeted drugs that (probably) don´t work
• Interferon-alpha• Octreotide analogues: sandostatin LAR, pasireotide
LAR• Mifepristone• Megestrol acetate• Imatinib• Erlotinib and gefitinib
• Cave: low level-of-evidence, biomarkers may select responding tumors
Kaley et al, Neuro-Oncol 2014
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Targeted drugs that may work
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Bevacizumab
- Monoclonal antibody against VEGF-A
- Approved for colorectal cancer, breast cancer, kidney cancer, ovarian cancer, glioblastoma
- Toxicity: hypertension, bleeding, thrombo-embolic events, GI perforation, proteinuria
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Angiogenesis and VEGF in meningioma
Preusser et al, Clin Neuropathol 2012
CD34
VEGF VEGF-R2
CD34
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Growth rate
Brain edema
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Bevacizumab in meningioma
Franke et al, SNI 2018
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EORTC-1320: OS by LOC treatment
Bevacizumab, median OS: 13.54 monthsTrabectedin, median OS: 11.37 monthsHydroxyurea, median OS: 7.39 months
n=9
n=57
n=11
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Sunitinib
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- Tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, FLT, CSF, RET
- Approved for renal cellcarcinoma, GIST, pancreaticNET
- Toxicity: fatigue, hypertension, thromboembolic events, leukopenia, GI perforaton
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Positive correlation of VEGF-R2 with PFS
Kaley et al, Neuro-Oncol 2014
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Clark, Science 2013Abedalthagafi, Neuro-Oncol 2016Preusser et al, in preparation
Targeting mutations in meningioma
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2012
SMO: - 5% of cases, mainly meningothelial
meningiomas- Mainly skull base- Hedgehog pathway activation- Smoothended inhibitor Vismodegib approved
for basal cell carcinoma, under investigation in CRC, SCLC, medulloblastoma
AKT1:- 13% of cases, mainly meningothelial and
transitional meningiomas- Mainly skull base- PI3K-AKT-mTOR pathway activation- Oncogenic in breast, colorectal and lung
cancers - Several pathway inhibitors available
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Baseline +6 monthsWeller et al, JNCI 2016
AKT inhibitor in meningioma
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AKT inhibitor
Hedgehog inhibitor
PI3K inhibitor
MEningioma taRGEted therapy: the MERGE trial
PrincipIe Investigator: M. Preusser
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Recurrent or progressive meningiomas
Progressive disease or
significant toxicity:
Off study
Complete response, partial
response or stable disease:
Continue on therapy
AKT mutationSMO mutation
SMO inhibitor:
Vismodegib
AKT inhibitor:
AZD5363
Brain MRI every
2 months
n = 24 (n = 12 Gr1;
n = 12 Gr2/3)
Phase II trial of SMO/AKT1/FAK inhibitors in progressive meningiomas with SMO/AKT1/NF2 mutations
FAK inhibitor:
GSK2256098
n = 36 (n = 12 Gr1;
n = 24 Gr2/3)
NF2 mutation
n = 24 (n = 12 Gr1;
n = 12 Gr2/3)
CDK inhibitor:
Ribociclib
n = 24 Gr2/3
NF2, CDKN2A loss
PI: P. Brastianos, Boston
Courtesy of Priscilla Brastianos
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Goldbrunner et al. Lancet Oncol 2016
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ROAM trial
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Histologically confirmed newly diagnosed solitary atypical meningioma (WHO grade II) based on the 2016 WHO criteria
Age ≥ 18 years
All anatomical locations allowed except optic nerve sheath tumor
Complete resection (Simpson 1, 2 or 3) as assessed by the surgeon
No neurofibromatosis type II (NF-2), no optic nerve sheath tumors, no multiple meningiomas, no radiation-induced meningiomas
ROAM trial: main eligibility criteria
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Conclusions and Clinical Perspectives
• Surgery and radiotherapy established treatments, but nostandard treatment of recurrent/progressive meningiomas, unmet clinical need
• Growing insight nto molecular pathology of meningiomas
• Correlation of genetic subtypes with histology and site
• TERT as potential strong prognosti markers
• VEGF pathway inhibitors sunitinib, vatalinib, bevacizumab showed potential activity in small and uncontrolled studies, confirmation needed
• Randomized trial in recurrent high-grade meningioma withtrabectedin (EORTC-BTG-1320) ongoing
• Oncogenic SMO and AKT1 mutations may representactionable targets in a small fraction of cases, trial ongoing
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Thank you!