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Center for Neuro-Oncology Dana Farber/Brigham and Women’S Cancer Center Advances in the Treatment of Gliomas: Challenges and Opportunities Patrick Y. Wen, M.D. Center For Neuro-Oncology Dana Farber/Brigham and Women’s Cancer Center Division of Neuro-Oncology, Department of Neurology Brigham and Women’s Hospital Harvard Medical School DISCLOSURES • Research Support Advisory Board – Acerta – Cavion – Agios – Cortice Biosciences – Angiochem – Foundation Medicine – Astra Zeneca – Genentech/Roche – Genentech/Roche – Monteris – GlaxoSmithKline – Novartis – Karyopharm – Novocure – Merck – Regeneron – Novartis – Vascular Biogenic – Oncoceutics Speaker – Sanofi-Aventis – Merck – Vascular Biogenics Milestones in Neuro-Oncology Novo TTF Approvals TMZ up front for GBM Radiotherapy TMZ for Lomustine relapsed AA Avastin for accelerated recurrent Carmustine Gliadel wafer approval GBM 1970 1980 1990 2000 2010 First US First US Macdonald commercial CT RANO commercial criteria: Brain Tumor Clinical Trial Criteria Levin criteria: MRI MRI + steroids; Endpoints CT scans WHO Pathology Criteria Workshop Technology Advances AA=anaplastic astrocytoma; CT=computed tomography; GBM=glioblastoma multiforme; MRI=magnetic resonance imaging; RANO=Response Assessment in Neuro-Oncology. Treatment of Gliomas Outline • Standard therapy for GBM • Molecular pathogenesis of gliomas and WHO classification • Targeted therapies • Immunotherapies • Lower grade gliomas Lancet Oncol. 2009 May;10(5):459-66. Lancet Oncology 2009 Methylated MGMT Benefit mainly in patients with methylated MGMT promoter Unmethylated MGMT Patients with unmethylated MGMT promoter have minimal benefit Should consider withholding TMZ in unmethylated patients, especially in context of clinical trials - Avoids need for phase I with TMZ - Allows full dose of novel agent to be used Chinot et al: (AVAglio) NEJM Gilbert et al: (RTOG 0825). NEJM 2014;370:8:709-722 2014;370:8:699-708 Median PFS was longer in BEV group than in the PFS longer in the BEV group (10.7 months vs. 7.3 placebo (10.6 months vs. 6.2 months; HR 0.64; months; HR for progression or death, 0.79). 95%; [CI], 0.55 to 0.74; P<0.001) No significant difference in OS between BEV and PFS benefit was observed across subgroups placebo group (median, 15.7 and 16.1 months, OS not differ significantly between groups (HR respectively; HR for death in the bevacizumab group, 0.88; 95% CI, 0.76 to 1.02; P = 0.10). 1.13). Bevacizumab in Newly-Diagnosed GBM 3-4 to 4.4 month improvement in PFS No improvement in OS Tumor Treating Fields Are Delivered by the NovoTTF-100A System • Tumor Treating Fields (NovoTTF Therapy) uses electricity to disrupt mitosis1,2 – Specifically targets dividing cancer cells, not quiescent normal cells1 • Single-use transducer arrays deliver NovoTTF Therapy through the scalp – Arrays deliver NovoTTF Therapy at a low intensity (1-3 V/cm) and intermediate frequency (200 kHZ) 1. Kirson ED, et al. Proc Natl Acad Sci. 2007;104(24):10152-10157. 2. Gutin PH, Wong ET. ASCO Educ Book. 2012;32:126-131. EF-14: A Prospective, Multi-Center Study of NovoTTF-100A System with TMZ vs. TMZ Alone in Patients with Newly Diagnosed GBM Stupp et al. JAMA 2015;314(23):2535-2543 • Novo-TTF improves PFS and OS by @ 3 months • Controversial • FDA approved in US Recurrent GBM Surgery Reirradiation Gliadel wafers Dose-dense TMZ Nitrosoureas (lomustine, carmustine) Bevacizumab +/- CCNU Negative trials PFS6 = 9-15% Clinical Trials EORTC 26101 Phase III study of Bevacizumab + Lomustine versus Lomustine in patients with Recurrent Glioblastoma Stratification: age, PFS R Bevacizumab 10mg/kg A every 2 weeks + N Lomustine 90mg/m2 f D every 6 weeks o O l M l 1st recurrence I o Glioblastoma Z w A T u I p O Lomustine N 110mg/m2 every 6 weeks EORTC: 26101: Progression-Free Survival (PFS) Observe Patients without 100 d Median PFS, progression at 90 Patients, events, months 1 year 80 Treatment N N (95% CI) (95% CI) 1.54 months 1.9% Response70 [%] LOM 149LOM 143 LOM+BEV (1.48–2.53) (0.4–6.0) Objective60 response 14 41.5 p<0.0001 BEV+LO 4.17 months 8.8% CR 50 2880.7 260 1.9 M (3.65–4.27) (5.5–13.0) 40 Steroids [%] 30 HR 0.49 (95% CI 0.39–0.61) At baseline 49 50 p<0.0001 Steroid20 (re) -start 39 39 Probability of PFS (%) Probability 10 1.54* 4.17* months months 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months O N Patients at risk, N LOM 143 149 64 37 25 17 5 2 0 0 0 0 0 0 Bv+LOM 260 288 249 154 82 54 27 15 7 5 2 2 2 1 *Stratified analysis Bv, bevacizumab; CI, confidence interval; HR, hazard ratio; LOM, lomustine; O, observed events Wick et al, SNO 2015 EORTC 26101: Overall Survival (OS) Patients Patients surviving surviving 100 Patients Observed Median OS at 9 mo at 1 year Treatm. N events, N (95% CI) (95% CI) (95% CI) 90 8.64 80 months 47.5% 34.1% LOM 149 113 (7.62– (39.0–55.5) (25.8 –42.6) 70 F/U 15.3 mo 10.41) OS (%) 60 9.10 months 51.2% 31.5% 50 BEV+LOM 288 216 (8.08– (45.2–57.0) (25.7 –37.6) 40 F/U 13.6 mo 10.05) 30 20 HR 0.95 (95% CI 0.74–1.21) Probability of Probability 8.64 9.10 10 p=0.650 months months 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months O N Patients at risk, N LOM 113 149 132 102 55 32 17 11 7 6 3 2 0 0 Bv+LOM 216 288 273 207 122 58 25 10 9 6 4 1 1 1 Bv, bevacizumab; CI, confidence interval; HR, hazard ratio; LOM, lomustine; O, observed events Wick et al, SNO 2015 Effect of bevacizumab on peritumoral edema Pre- bev Post- bev Molecular Pathogenesis of Gliomas and the WHO Classification Brennan et al TCGA Cell 2013 Progress in Diagnosis and Classification of Lower Grade Gliomas N Engl J Med. 2015;372:2481-98 N Engl J Med. 2015;372:2499-508 Nat Genetics 2015; 47:458-468 Classification of Lower Grade (II and III) Gliomas Clinical Outcomes TCGA NEJM 2015 Wen and Reardon. Nat Rev Neurol (2016) • Diffuse gliomas can be divided based on molecular alterations into 6 subgroups • IDH muted tumors can be divided in 3 groups. 2 have good prognosis; 1 (G- CIMP) low does not • IDH wildtype tumors can also be divided into 3 subgroups. 2 have poor prognosis (GBM) but the pilocytic astrocytic–like group has good prognosis Cell 2016 WHO Classification (2016) • Glioblastoma, IDH-wildtype – Giant cell glioblastoma – Gliosarcoma – Epitheliod glioblastoma • Glioblastoma, IDH-mutated • Glioblastoma, NOS In this era of improved underderstanding of the molecular pathogenesis of gliomas and the new WHO Classification, who should be eligible for a GBM trial? Cecarrelli Cell 2016 TCGA NEJM 2015 Who should be eligible for a GBM trial? • Traditionally any tumor diagnosed as GBM histologically Now: • For phase II trials may want to exclude patients with good prognosis such as IDH mutated patients that may affect outcome in studies with small number of patients – IDH WT GBM (at least by IHC for IDH1 R132H mutation, but ideally also by sequencing) – ? IDH wildtype lower grade gliomas? – Exclude pilocytic astrocytoma-like LGG – ?? Include IDH mutated, G-CIMP low patients • For phase III: ? Less rstrictive Who should be eligible for a GBM trial? • Caveats: – More sophisticated testing available only at limited sites; need for central testing and standardization – Time for genotyping may delay treatment; especially problematic for recurrent GBM • Compromise – IDH WT tumors (by IHC) Who should be eligible for a lower grade glioma trial ? • Include both grade II and III tumors in same trial? Either • Oligodendrogliomas (IDH mutated, co-deletion of 1p/19q) • Astrocytomas (IDH mutated, no co-deletion of 1p/19q; often with ATRX and p53 mutations) • No Oligoastrocytomas Targeted Molecular Therapies Reasons for Lack of Progress in Targeted Therapies For High-Grade Gliomas • Poor models • Lack of “easy” targets • Co-activation of tyrosine kinases • Redundant signaling pathways • Spatial and temporal heterogeneity • Failure to genetically enrich patient population • Blood-brain barrier • Stem cell resistance • Limited resources and pharmaceutical industry interest Red: EGFR GBM have significant Amplification spatial heterogeneity Green: PDGFRA Amplification Science 2014 PNAS 2013;110:4013 There is also temporal heterogeneity: molecular alterations at recurrence different from those at diagnosis Neuro-Oncologist Heterogeneity • Drivers versus passengers? • Are tumor stem cells the main/only target? • Interaction and interdependency between tumor cells with each other and stroma/environment? • But heterogeneity is not unique to GBM • Progress with targeted agents seen with other cancers with heterogeneity Parker et al. Frontiers in Oncology 2015 Targeting Critical Downstream Signaling Nodes Selinexor (exportin inhibitor) Debio 0932 (HSP 90 inhibitor) Marizomib (proteosome inhibitor) ONC-201 (stress response pathway) ? NFkB Bredel et al, 2009. ? MYC, other transcription regulators Epigenetics Mack et al. Nat Neuroscience 2016 Targeting Tumor Metabolism The Warburg Effect Otto Heinrich Warburg, 1883–1970 Vander Heiden et al, 2009. Wen and Kesari NEJM 2008 Need to develop effective combination therapies and understand resistance mechanisms better! • But combinations can be toxic! • Need potent specific drugs that cross the BBB 2013 Phase I Study of LDE225 and BKM120 • Recommended phase II dose of LDE225 = 800mg/d • Recommended phase II dose of BKM120 = 100mg/d • Combination not very well tolerated • MTD only 400mg/d LDE225 + 80mg/d BKM120 • Some activity seen but development of combination discontinued Schmidt et al Nat Rev Clin Oncol 2015 Change in therapy based on mutations in circulating DNA or molecular imaging Blood Brain Barrier Major issue that prevents most drugs from getting to GBM (especially non-enhancing areas) Drug efflux pumps also a problem Benarroch Neurology 2012;78:1268 EGFR Inhibitors Unclear if we have ever adequately inhibited EGFR • Few achieve adequate levels in CNS • Poor CNS penetration – Gefitinib – Erlotinib – Lapatinib – Afatinib (Neuro-Oncology 2015;17:430) – Neratinib • Possible BBB penetration – Dacomitinib – Tesevatinib Need To Assess Drug Penetration In Non-Enhancing Tumor Also Need to know ability of drug to cross BBB before embarking on extensive development Molecular Imaging • Image drugs in brain tumors • Image pathway inhibition, apoptosis, proliferation Strategies to overcome BBB • Convection Enhanced Delivery • Improve Drugs Penetration Across BBB – Ideally all small molecules would have good BBB penetration e.g.
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