Michael WellerDepartment of NeurologyUniversity Hospital Zurich

Switzerland

SAMO Masterclass 2015CNS Tumors

Berne, 18 September, 2015

„Brain“ tumors curable by surgery alone

(Vestibular) schwannomas

Meningiomas (WHO grade I, ? II)

Pituitary adenomas

Some rare neuroglial tumors

„Brain“ tumors curableby radiotherapy alone

Germinomas

Germinomas Primary CNS lymphomas

„Brain“ tumors curable bychemo(radio)therapy alone

PCNSLCurrent standards & recommendations

• PCNSL are curable tumors, but probably only in younger patients

• Surgery is no longer obsolete

• Modern HD-MTX-based pharmacotherapy approaches achievehigh remission rates (CR+PR) around 80%, but significantly lower„cure“ rates

• Whole brain radiotherapy (WBRT) induces dose-and time-dependent neurotoxicity, does not prolong survival and shouldbe avoided (in the first-line setting)

• PCNSL needs to be „cured“ up-front, not at recurrence, byintensified medical therapy potentially including stem celltransplantation

EANO Guideline on the Diagnosisand Treatment of Anaplastic Gliomas and Glioblastoma

Lancet Oncology 2014;15:e395–403

Weller Nat Rev Dis Prim 2015 in press

Weller Nat Rev Dis Prim 2015 in press

IDH-1/2 mutation

IDH1 R132H immunostaining Pyrosequencing

IDH-1/2 mutation

Can I use the IDH status fordiagnostic purposes?

Yes. IDH mutations are common inWHO grade II and III gliomas and canaid in the differential diagnosis, e.g.,from pilocytic astrocytomas andependymomas which lack IDHmutations.

Can I use the IDH status forprognostic purposes?

Yes. IDH mutations are prognosticallyfavourable across all glioma entities.

Can I use the IDH status as apredictive marker for clinicaldecision making?

Controversial – MGMT promotermethylation may be predictive forbenefit from alkylating chemotherapy.

MGMT+CH3

Cell death

O6-Methylguanin-methyltransferase (MGMT, AGAT),

a DNA repair protein, counteracts the effect of

alkylating agents:

unmethylated MGMT promotor

MGMT geneTranscription/translation

MGMT promotor active

Chemo-resistance

MGMT geneTranscription/translation

CH3

CH3

CH3

CH3

CH3

MGMT promotor

MGMT promotor methylation

inactive

Chemosen-sitivity

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MGMT promoter methylation

Can I use the MGMT status fordiagnostic purposes?

No.

Can I use the MGMT status forprognostic purposes?

Yes. MGMT promoter methylation ispositively prognostic in anaplasticglioma patients treated with RT orchemotherapy or both (NOA-04,EORTC 26951).

Can I use the MGMT status as apredictive marker for clinicaldecision making?

Yes. MGMT promoter methylationpredicts benefit from alkylating agentchemotherapy in glioblastoma (EORTC26981) (probably IDH wildtype gliomasin general) and is particularly useful inthe elderly (NOA-08).

1p/19q codeletion

Griffin et al.JNEN2006;65:988-94

A. von Deimling,Heidelberg

1p/19q codeletion

Can I use the 1p/19q status fordiagnostic purposes?

Sometimes. The presence of the 1p/19qcodeletion supports the diagnosis of anoligodendroglial tumor (and may berequired in the next WHO classification).

Can I use the 1p/19q status forprognostic purposes?

Yes. The 1p/19q codeletion is a strongprognosticator in anaplastic glioma patientstreated with RT or alkylating agentchemotherapy or both. Its role in WHOgrade II gliomas is less clear, but likely tobe similar.

Can I use the 1p/19q status as apredictive marker for clinicaldecision making?

Yes. RTOG 9402 and EORTC 26951suggest that the 1p/19q codeletion is apredictive marker for improved survival forpatients treated with PCV in addition to RTversus RT alone. Whether this holds truefor TMZ, too, is not known (but very likely).

Weller Nat Rev Dis Prim 2015 in press

New treatments for gliomason the horizon

Rindopepimut for EGFRvIII-positiveglioblastoma

ICT-107 for HLA2-positive glioblastoma

Checkpoint inhibitors

Tumor-treating fields (Optune)

Does Rindopepimut mediateEGFRvIII elimination at

recurrence?

EGFRvIII was selectively eliminated in recurrent tumors for 26/32(81%) patients across all three studies

− 15/15 control patients treated with RT/TMZ (+/- CPT-11,bevacizumab or erlotinib) were EGFRvIII(+) at recurrence

Robust anti-EGFRvIII titers in most patients; titers maintained for >6 months following cessation of treatment

Pre-Vaccine Primary Tumor Post Vaccine Recurrent Tumor

1. Mehta, et. al. JCO 2011

ACT IV Study Design

Adjuvant Temozolomide and VaccineTherapy (TMZ-V, 6-12 cycles)

VaccinePriming

RA

ND

OM

IZA

TI

ON

VaccineMaintenance

Therapy (VMT)

Follow Up

• Vaccine or control (KLH) is administeredDay 22 of each TMZ cycle

• Begin TMZ no sooner than 6 days afteradministration of the second vaccinepriming dose

• Begin TMZ no sooner than 28 days aftercompletion of CRT

• Begin TMZ when ANC ≥ 1000/µL andplatelets ≥ 100,000/µL

• TMZ dosed days 1-5 of each 28 day cycle

• Dose vaccine days1 and 15 of VaccinePriming cycle

• Start cycle within 4days afterrandomization andwithin 7-14 daysafter completion ofCRT

If no diseaseprogressionafter TMZ,continue dosingvaccine every28 days (Day 1±3 days of each28 day cycle)until intoleranceor diseaseprogression

Follow-up foroverall survivalevery 12 weeksafter diseaseprogression

Temozolomide Dosing

Vaccine or Control (KLH) Dosing

CRT Chemoradiation Therapy

Treatment will be discontinued upondisease progression, unacceptabletreatment-related toxicity, or patientrefusal to continue study treatment

D1 D15 C1D1 C1D22 C2D22 C3D22 etc…. C1D1 C2D1 etc…

ICT-107 is an Autologous Six-antigen DCVaccine

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Matured, activated,peptide-loaded DC

MHCclass I

Six 9-10 amino acid antigen epitopes• MAGE-1 (HLA - A1)• AIM-2 (A1)• gp100 (HLA - A2)• IL-13Rα2 (A2)• HER2/neu (A2)• TRP-2 (A2)

Rationale for antigen choice• Targeting multiple antigens minimizes tumor escape• High expression levels for all antigens on glioblastoma samples• Bias toward TAA associated with cancer stem cells

Control used in Phase III• PBMC without peptide loading

EORTC 1510 Trial Design

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SurgeryScreen

MRI

MGMTand

enroll

TMZ/RTEligibility

ConfirmationMRI

Va

cc

ine

Ind

uc

tio

nP

ha

se

Patient-SpecificVaccination• ICT-107 or Control• 1/wk for 4 wks

Ma

inte

nan

ce

Ph

as

e

ConsentHLA-A2 typing

Apheresis Randomize

Week – 2Rest Week

•DC therapy Maintenance Phase:

Maintenance with monthly CT-107 (patient-specific DC therapy) for 11 months, andonce every 6 months thereafter until depletion or confirmation of progressive disease.

CT-107 and TMZ will be administered two weeks apart during cycle 1 to cycle 6maintenance TMZ. TMZ will be given Days 1-5 ± 2 days on a 28-day cycle. Study DCtherapy will be given on Day 21 ± 2 days.

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• No vs residual < 1 cm

Stratifications• MGMT• Age• No vs residual < 1 cm3 tumor

Quadrennial Meeting of theWorld Federation of Neuro-Oncology WFNO 2017

in conjunction with the Meeting of theEuropean Association of Neuro-Oncology (EANO)

ZURICH, SWITZERLAND

Kongresshaus Zürich May 3-7, 2017

INVITATION www.eano.eu