Meningioma: future developments · • VEGF pathway inhibitors sunitinib, vatalinib, bevacizumab...
Transcript of Meningioma: future developments · • VEGF pathway inhibitors sunitinib, vatalinib, bevacizumab...
Meningioma: future developments
Matthias Preusser, MDDepartment of Medicine I
Comprehensive Cancer Center ViennaMedical University of Vienna
Disclosures
MP has received research support from Böhringer-Ingelheim,GlaxoSmithKline, Merck Sharp & Dome and Roche and honoraria for lectures,consultation or advisory board participation from Bristol-Myers Squibb,Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline,Mundipharma, Roche, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo,Merck Sharp & Dome.
Preusser M. Tertialbuch Innere Medizin. Facultas, 9th Edition, 2015
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 rateBrain edema
Bevacizumab in meningioma
Franke et al, SNI 2018
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
Trial data to expect
Trabectedin
Ecteinascidia turbinate
Trabectedin (Yondelis)
• Tetrahydroisoquinoline originally isolated from the sea squirt Ecteinascidia turbinate
• Approved for advanced sarcoma and recurrent ovarian cancer; trials in breast, prostate, endometrial, pancreatic cancer
• Binds to the minor groove of the DNA and induces apoptosis in tumor cells, TAM depletion, anti-angiogenesis
• Application: i.v. via central venous catheter (Port-a-cath)• 1.5mg/m2 over 24h every three weeks• Toxicity: hepatotoxicity, myelosuppression, nausea, necrosis
after extravasation, rare: rhabdomyolysis; improved tolerability by dexamethasone pretreatment
Cancer 2012
Primary endpoint: Progression-free survival
Secondary endpoints: Objective response rate (CR, PR), OS, safety, HRQoL
Recurrent WHO II or III meningioma, no more local therapy options, measurable disease
Trabectedinn=57
EORTC-1320-BTG: Trabectedin for recurrent grade II or III meningioma: a randomized phase II study of the EORTC Brain Tumor Group
Best investigators choicen=29
R
EORTC-1320-BTG: Sites
10 Countries 49 Centers
EORTC-1320-BTG: Accrual
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 trialPrincipIe Investigator: M. Preusser
SMO/AKT/FAK Inhibitor trial (NCT02523014)
• Alliance, NCI (+EORTC?)• Patients with residual, recurrent or progressive
meningiomas• Screening of tumor samples for AKT1, SMO and
NF2 mutations• Mutation-bearing tumors treated with AKT, SMO
or FAK inhibitor, respectively• Co-primary endpoint: Response rate and 6-month
PFS • Trial status: accruing
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!