SAMO Masterclass 2015 CNS Tumors Berne, 18 September, 2015 · SAMO Masterclass 2015 CNS Tumors...
Transcript of SAMO Masterclass 2015 CNS Tumors Berne, 18 September, 2015 · SAMO Masterclass 2015 CNS Tumors...
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
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
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).
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
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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