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!