Meningioma: future developments...meningioma (WHO grade II) based on the 2016 WHO criteria Age ≥...
Transcript of Meningioma: future developments...meningioma (WHO grade II) based on the 2016 WHO criteria Age ≥...
Meningioma: future developments
Matthias Preusser, MD
Department of Medicine I
Comprehensive Cancer Center Vienna
Medical University of Vienna
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.
Andreas Vesalius, 1534
Meningioma
Meningioma classification
Histopathological classificationMeningiothelial Fibroblastic
Secretory Clear cell
Atypical Malignant
Histopathological classification
Mutational profiles
Clark et al, Science 2013
Mutations and site
Preusser et al, Nature Rev Neurol 2018
Mutations and site
Clark et al, Science 2013
Mutations and histology
Brastianos et al, Nature Genetics 2013
Secretory meningioma: TRAF7 and KLF4
Reuss, Acta Neuropathol 2013
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
Rhabdoid meningioma: BAP1 mutations
Shankar et al, Neuro-Oncol 2016
Meningioma subtypes and molecular subtypes
Preusser et al, Nature Rev Neurol 2018
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
Sahm F et al. Lancet Oncol 2017
Methylation profiles of meningioma
Novel therapy approaches
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
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
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
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
Targeted drugs that may work
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
Angiogenesis and VEGF in meningioma
Preusser et al, Clin Neuropathol 2012
CD34
VEGF VEGF-R2
CD34
Growth rate
Brain edema
Bevacizumab in meningioma
Franke et al, SNI 2018
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
Sunitinib
- 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
Positive correlation of VEGF-R2 with PFS
Kaley et al, Neuro-Oncol 2014
Clark, Science 2013Abedalthagafi, Neuro-Oncol 2016Preusser et al, in preparation
Targeting mutations in meningioma
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
Baseline +6 monthsWeller et al, JNCI 2016
AKT inhibitor in meningioma
AKT inhibitor
Hedgehog inhibitor
PI3K inhibitor
MEningioma taRGEted therapy: the MERGE trial
PrincipIe Investigator: M. Preusser
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
Goldbrunner et al. Lancet Oncol 2016
ROAM trial
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
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
Thank you!