Joachim M. Baehring, MD, DSc Associate Professor of Neurology, Medicine and Neurosurgery Director, Yale Brain Tumor Center Yale University School of

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1 Joachim M. Baehring, MD, DSc Associate Professor of Neurology, Medicine and Neurosurgery Director, Yale Brain Tumor Center Yale University School of Medicine New Haven, Connecticut 1

2 Disclosure of Conflicts of Interest Joachim M. Baehring, MD, DSc Joachim M. Baehring, MD, DSc, has affiliations with Sigma Tau Pharmaceuticals, Inc. (Speakers Bureau) Learning Objectives Summarize the strengths and limitations of current treatments for newly diagnosed and recurrent glioblastoma Describe prognostic factors in the survival of adults with glioblastoma Identify molecular and genetic biomarkers associated with response to treatment Identify emerging targeted treatment alternatives that have demonstrated favorable results in glioblastoma 2

3 Milestones in Neuro-Oncology Approvals Radiotherapy Lomustine Carmustine Carmustineimpegnated wafers TMZ for relapsed AA accelerated approval TMZ up front for GBM Bevacizumab for recurrent GBM First US commercial CT Levin criteria CT scans First US commercial MRI Macdonald criteria WHO Pathology criteria Brain Tumor Clinical Trial Endpoints Workshop RANO criteria Technology Advances AA=anaplastic astrocytoma; CT=computed tomography; GBM=glioblastoma multiforme; MRI=magnetic resonance imaging; RANO=Response Assessment in Neuro-Oncology. Epidemiology ~66,290 new patients are estimated to be diagnosed with primary brain tumors in the United States in ~33% tumors of neuroepithelial tissue (NET) ~50% of all NET are glioblastoma multiforme (GBM) Among patients with GBM 1,2 Median overall survival: 8 to 15 months 2-year survival rates: 13% to 27% Central Brain Tumor Registry of the United States (CBTRUS) Report. 2. Stupp R, et al. Lancet Oncol. 2009;10:

4 Incidence Distribution of All Primary Brain and CNS Tumors by Histology Lymphoma 2.3% All Other 12.2% Glioblastoma 20.3% Nerve Sheath 8.5% Craniopharyngioma 0.7% Pituitary 13.5% Astrocytomas 6.8% Ependymomas 1.8% Oligodendrogliomas 1.9% Embryonal, including medulloblastoma 1.1% 2012 CBTRUS Report. Meningioma 34.7% Incidence Distribution of All Gliomas by Histology Subtypes Ependymomas 5.8% All Other Gliomas 11.4% Oligodendrogliomas 6.4% Pilocytic Astrocytoma 5.2% Glioblastoma 53.9% Diffuse Astrocytoma 1.8% Anaplastic Astrocytoma 6.7% 2012 CBTRUS Report. All Other Astrocytomas 8.8% 4

5 Classification and Grading World Health Organization (WHO) Classification System Released in 1993; updated in 2007 Tumors classified by cell origin and level of aggression (Grades I IV) 1 Grade Histology Proportion of All Gliomas 2 Median Survival (y) 2 I Pilocytic astrocytoma 5.2% >10 II Well-differentiated astrocytoma 1.8% >4 III Anaplastic astrocytoma 13.8% , 3 IV Glioblastoma multiforme 53.9% <1 1. Kleihues, et al. Brain Pathol. 1993;3(3): CBTRUS Report. 3. Wick, et al. J Clin Oncol. 2009;27: Risk Factors for Malignant Glioma Family history of cancer in 19% of patients 1 Genetically inherited syndromes in 5% of patients with primary brain tumors 1 Neurofibromatosis types 1 and 2 Li-Fraumeni syndrome von Hippel-Lindau syndrome Turcot syndrome Tuberous sclerosis Brain irradiation in childhood 2 1. Grossman SA, et al. Cancer Invest. 1999;17: Neglia JP, et al. J Natl Cancer Inst. 2006;98:

6 Gliomagenesis DCC=deleted in colon cancer; LOH=loss of heterozygosity; RB=retinoblastoma. Courtesy of Marc C. Chamberlain; with permission. Frequent Genetic Alterations in Three Critical Signaling Pathways The Cancer Genome Atlas Research Network. Nature. 2008;455: ; with permission. 6

7 Symptoms Incidence of Symptoms in Patients With Glioma Patients with Symptoms (Median %) Low-grade glioma Malignant glioma Data modified from DeAngelis LM. N Engl J Med. 2001;344: Wen PY, Kesari S. N Engl J Med. 2008;359: Symptom Etiology Direct infiltration and destruction of neuronal networks Local pressure from Edema Hemorrhage Tumor mass Cyst formation Intracranial hypertension Mass effect CSF flow obstruction 7

8 Diagnostic Assessment Gold standard Magnetic resonance imaging (MRI) with contrast Computed tomography (CT) scan when MRI is contraindicated Adjunctive techniques Magnetic resonance spectroscopy (MRS) Perfusion MRI Positron emission tomography (PET) Tissue sample Confirm diagnosis Determine tumor type and grade Molecular genetic analysis Current Treatment: Surgery Rationale for extensive resection Provides adequate tissue for diagnosis Palliates mass effect Allows for improvements in tumor-related signs and symptoms May increase survival Helps halt disease progression by eliminating resistance clones National Comprehensive Cancer Network. Practice Guidelines in Oncology: Central Nervous System Cancers;

9 Surgery Challenges Biopsy vs. resection Tumor location Patient factors Co-administration of local therapy Treatment toxicity Clinical trial exclusion Surgery Maximal Safe Resection Wilson A. Available at: 2. Courtesy of Michael A. Vogelbaum, MD; with permission. 3. Brigham and Women s Hospital. Available at: 9

10 Benefit of Complete Surgical Resection Study EORTC Extent of Resection Complete Subtotal Biopsy Median OS with RT alone 14.2 months 11.7 months 7.8 months 2-year survival with RT alone Median OS with RT + temozolomide 2-year survival with RT + temozolomide 5-ALA % 9.4% 4.6% 18.8 months 13.5 months 9.4 months 38.4% 23.7% 10.4% Median OS 16.9 months 11.8 months 2-year survival 26% 7% OS=overall survival; RT=radiotherapy; 5-ALA=5-aminolevulinic acid induced tumor fluorescence. 1. Stupp R, et al. Lancet Oncol. 2009;10: Stummer W, et al. Neurosurgery. 2008;62: Surgery Plus Local Therapy Carmustine (BCNU) wafers Polyanhydride wafers, 7.7 mg carmustine (BCNU) 1 Carmustine released over 2 to 3 weeks >70% degradation by Week 3 Approval 1996 for recurrent GBM as adjunct to surgery expanded for all high-grade gliomas, including newly diagnosed 3 Local delivery obviates the blood brain barrier Lower toxicity than systemic chemotherapy 1. Gliadel wafer prescribing information. Accessed March 30, Brem H, et al. Lancet. 1995;345: Westphal M, et al. Neuro Oncol. 2003;5:

11 Surgery Plus Local Therapy BCNU Wafer Improves Survival vs. Placebo 1.00 Salvage 1.00 Adjuvant Probability of survival Placebo Hazard Ratio: 0.67 P=0.02 BCNU wafer Probability of survival Placebo Hazard Ratio: % CI: Risk Reduction: 29% P=0.018 BCNU wafer Time (weeks) Months from implant surgery Brem H, et al. Lancet. 1995;345: Westphal M, et al. Acta Neurochir (Wien). 2006;148: Westphal M, et al. Neuro Oncol. 2003;5: Current Treatment: Radiation Therapy (RT) Challenges Recurrence is the major source of therapeutic failure Surgery and radiation therapy often fail to prevent recurrence Most recurrent gliomas occur at close proximity to initial tumor Distance from Edge of Initial Tumor (cm) Incidence (% of All Recurrent Gliomas) < >3 3 Hochberg FH, Pruitt A. Neurology. 1980;30: Wallner KE, et al. Int J Radiat Oncol Biol Phys. 1989;16:

12 Radiation Therapy RTOG trial analyses Improved outcomes with involved-field vs. whole-brain RT Dose-response relationship: best response with 60 to 65 Gy conventional external beam RT (cebrt) No apparent survival benefit with: >65 Gy cebrt Conformal RT Accelerated or hyperfractionated schedules Boost gamma knife RT Brachytherapy boost Cardinale R, et al. Int J Radiat Oncol Biol Phys. 2006;65: Tsao MN, et al. Int J Radiat Oncol Biol Phys. 2005;63: Chang JE, et al. Clin Adv Hematol Oncol. 2007;5: , Radiation Therapy RT +/- SRS RT +/- SRS Survival rate (%) RT SRS+RT Median n Survival Time mo mo P=0.64 Survival probability RT SRS+RT Median n Survival Time mo mo P= Months Months to death since surgery SRS=stereotactic radiosurgery. Souhami L, et al. Int J Radiat Oncol Biol Phys. 2004;60: ; with permission. Laperriere NJ, et al. Int J Radiat Oncol Biol Phys. 1998;41: ; with permission. 12

13 Chemotherapy Challenges Issues of efficacy Intrinsic resistance Pharmacologic (tumor delivery) Concurrent medications Anticonvulsants Steroids Systemic toxicity Response measurements Current Treatment: Chemotherapy Three Major Meta-Analyses Fine et al. 1 Stewart 2 Spiegel et al. 3 Date of meta-analysis Trials analyzed, n Patients analyzed, n >3,000 3,004 >3,000 Agent(s) used Various Various Various Absolute increase in survival, % 1 year * 2 year * * TMZ treatment group only. 1. Fine HA, et al. Cancer. 1993;71: Stewart LA. Lancet. 2002;359: Spiegel BM, et al. CNS Drugs. 2007;21:

14 Current Treatment: Temozolomide (TMZ) Methylating agent Cytotoxic product is O 6 -methylguanine DNA adducts Initiates mismatch repair pathway recycling, resulting in apoptotic cell death Efficacy Activity in newly diagnosed anaplastic glioma 1 Activity in recurrent anaplastic astrocytoma 2 Activity in recurrent GBM 3 Activity in adjuvant treatment of GBM 4,5 1. Wick W, et al. J Clin Oncol. 2009;27: Yung WK, et al. J Clin Oncol. 1999;17: Yung WK, et al. Br J Cancer. 2000;83: Stupp R, et al. N Engl J Med. 2005;352: Stupp R, et al. J Clin Oncol. 2002;20: Temozolomide European Organization for the Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) Treatment Platform PCP Prophylaxis RT 30 2 Gy PCP Prophylaxis TMZ daily 42d 4 wks RT 30 2 Gy Radiotherapy (RT): Focal, 60 Gy in 6 wk to tumor volume plus 2- to 3-cm margin TMZ: During RT: 75 mg/m 2 /d (including weekends) for up to 49 d; administered 1 2 h before RT in AM on days without RT Maintenance: mg/m 2 /d 5d, for up to 6 cycles; antiemetic prophylaxis PCP=Pneumocystis carinii pneumonia. Stupp R, et al. N Engl J Med. 2005;352: Control Arm 5d 4 5d 5d wks Experimental Arm 6 cycles 14

15 Temozolomide EORTC/NCIC trial 1 RT alone vs. RT plus TMZ Primary endpoint: overall survival Secondary endpoints: progression-free survival, quality of life (QOL), safety No negative impact on QOL 5-year follow-up data 2 A benefit of combined therapy was recorded in all subgroups EORTC/NCIC Trial Survival RT RT + TMZ 2-year 10.4% 26.5% 5-Year Follow-Up Survival RT RT + TMZ 2-year 10.9% 27.3% 3-year 4.4% 16.0% 4-year 3.0% 12.1% 5-year 1.9% 9.8% 1. Stupp R, et al. N Engl J Med. 2005;352: Stupp R, et al. Lancet Oncol. 2009;10: Temozolomide DNA repair O 6 -methylguanine-dna-methyltransferase (MGMT) 1 Also known as hepatic O 6 -alkylguanine-dna alkyltransferase (AGT, AGAT) Reverses alkylation at O 6 position of guanine, prevents cell death High tumor levels cause resistance to alkylating agents Low tumor levels cause susceptibility to alkylating drugs MGMT and TMZ 2 Retrospective analysis of MGMT tumor content and TMZ sensitivity in EORTC/NCIC trial data Low levels of MGMT in glioblastoma tumors correspond with improved response to TMZ 1. Esteller M, et al. N Engl J Med. 2000;343: Hegi ME, et al. N Engl J Med. 2005;352:

16 MGMT Promoter Methylation and GBM: Outcomes MGMT unmethylated TMZ EORTC/NCIC Trial 1 Median 2-yr 3-yr 4-yr 5-yr 12.6 months 14.8% 11/1% 11.1% 8.3% RT only 11.8 months 1.8% 0% 0% 0% MGMT methylated TMZ 23.4 months 48.9% 23.1% 23.1% 13.8% RT only 15.3 months 23.9% 7.8% 7.8% 5.2% Methylation of MGMT promoter is a strong predictor for outcome and benefit from temozolomide chemotherapy 1,2 1. Stupp R, et al. Lancet Oncol. 2009;10: Hegi ME, et al. N Engl J Med. 2005;352: Current Treatment Remaining Questions Which aspect of the EORTC regimen has influenced survival? Which new treatments can be added to the EORTC regimen? How much TMZ should be given following radiation therapy (dose and duration)? Pseudoprogression? May appear as progression either clinically or by imaging May result in erroneous treatment modification Consider continuation of treatment despite early progressive changes 16

17 Pseudoprogression Pre-op Post-XRT/TMZ Post-op After 2 cycles TMZ After 4 cycles TMZ d Avella D, et al. Acta Neurochir Suppl. 1998;71: Pseudoprogression Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as pseudoprogression (pspd) in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P=.0002) patients. MGMT status (P=.001) and pspd detection (P=.045) significantly influenced survival. Improvement in the early recognition of pspd patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment. Brandes AA, et al. J Clin Oncol. 2008;26:

18 Best Initial Treatment Strategies: Summary Maximum safe resection Conventional fractionated EBRT (as defined by RTOG and EORTC studies) RT and concomitant TMZ (EORTC/NCIC study) Post-RT TMZ chemotherapy for 6 months (EORTC/NCIC study) National Comprehensive Cancer Network. Practice Guidelines in Oncology: Central Nervous System Cancers; Considerations for Challenging Patient Groups Elderly (age 70 and up): 20% or more of all GBM No standard of therapy; no consensus Usually excluded from trials 1 Compromised patients: 10% or more of all GBM Defined as moderate to severe impairment in performance (Karnofsky Performance Status <70) and inability to perform activities of daily living No standard of therapy; no consensus Usually excluded from trials 2 MGMT-expressing: >50% of all GBM Prospective evaluation is ongoing 1,3 1. Roa W, et al. J Clin Oncol. 2004;22: Keime-Guibert F, et al. N Engl J Med. 2007;356: Hegi ME, et al. N Engl J Med. 2005;352:

19 Genotype-Guided Therapy in High-Grade Gliomas MGMT methylation 1p19q co-deletion Isocitrate dehydrogenase 1/2 mutation (2q33) PTEN mutation EGFR overexpression/amplification/variant (EGFRvIII) VEGF expression Prognostic Classification RTOG Recursive Partitioning Classification System Patients with high-grade gliomas identified in the Radiation Therapy Oncology Group (RTOG) database Stratification into groups (Class 1 6) based on Age Performance status Histology Neurological function Duration of symptoms Extent of resection Prognostic variables may be used to compare trial data Class *GBM. Median Survival (mo) 2-Year Survival (%) * * * 9 6 6* Curran WJ Jr, et al. J Natl Cancer Inst. 1993;85: ; with permission. 19

20 Current Treatment Challenges Biologically aggressive tumors Brain localization Pharmacologic delivery Blood brain barrier Limited therapeutic response Intrinsic resistance to conventional therapies Microenvironment (hypoxia, interstitial pressure, angiogenesis) Neurotoxicity of glioma-directed treatments Susceptibility of normal brain to therapy-related injury Spread of malignant cells into brain parenchyma Chamberlain MC. Neurosurg Focus. 2006;20(4):E2. Options for Salvage Therapy Re-operation (if possible and clinically appropriate) Re-irradiation (if no other options or small-volume recurrence) Local therapy (in conjunction with re-operation or investigational therapy) Chemotherapy Bevacizumab Investigational therapy 20

21 Treatment of GBM at First Recurrence National Analysts Worldwide Survey, January 2009 (Question1b): Of your firstline GBM patients who progressed in the last 6 months, what percent fall into the following category? 10% 15% 9% 13% 1% Died before 2L diagnosis Not appropriate for/cannot tolerate further treatment Refused further treatment Progressed and will receive or have/is receiving a subsequent surgery or radiation but no systemic therapy Other Progressed and will receive subsequent systemic therapy 52% 1L Patients who progress, Q Prospective Trials of Bevacizumab for Recurrent GBM 21

22 Prospective Trials of Bevacizumab for Recurrent GBM Forty-eight heavily pretreated patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. 17 patients (35%) achieved radiographic response based on Macdonald criteria (one CR, 16 PR). Median PFS was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month OS was 57% (95% CI, 44% to 75%). Median OS was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Kreisl, et al. J Clin Oncol. 2009;27(5): Prospective Trials of Bevacizumab for Recurrent GBM Phase II, multicenter, open-label, noncomparative trial 167 patients; bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m 2 or 125 mg/m 2 (with or without concomitant enzymeinducing antiepileptic drugs, respectively) once every 2 weeks Primary end points: 6-month progression-free survival (42.6% (bev), 50.3% (bev + iri)) and objective response rate (28.2% (bev), 37.8% (bev+iri)) Secondary end points: safety and overall survival (median 9.2 months (bev), 8.7 months (bev+iri)) Grade 3 adverse events: 46.4% (bev; hypertension, convulsion), 65.8% (bev+iri; convulsion, neutropenia, and fatigue). Intracranial hemorrhage was noted in two patients (2.4%; bev) and three patients (3.8%; bev+iri) Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma. The BRAIN Study. Friedman HS, et al. J Clin Oncol. 2009;27:

23 Response Rate and 6-Month PFS in Pooled Analyses of Trials for Relapsed Glioblastoma Publication Sample Size Response Rate 6-Month PFS Overall Survival 1-Year Survival 8 MD Anderson trials % 15% 5.7 months 21% 16 NCCTG trials NA 9% 5.1 months 14% 12 NABTC trials % 16% 6.9 months 25% Lomustine control arm, phase III study of % 19% 7.1 months 24% enzastaurin 4 PFS=progression-free survival. 1. Wong ET, et al. J Clin Oncol. 1999;17: Ballman KV, et al. Neuro Oncol. 2007;9: Lamborn KR, et al. Neuro Oncol. 2008;10: Wick W, et al. J Clin Oncol. 2010;28: Radiation Sensitizers Radiosensitizers Motexafin gadolinium (MGd) 1 Putative radiation enhancer Phase I trial (safety, tolerability) 2- to 6-week course of MGd 1 case-matched analysis: MGd patients: median OS 16.1 months matched RTOG database patients: median OS 11.8 months Phase II trial completed accrual (RTOG 0513) Temozolomide (TMZ) 2,3 Pre-clinical activity 1. Ford JM, et al. Int J Radiat Oncol Biol Phys. 2007;69: Kil WJ, et al. Clin Cancer Res. 2008;14: Chakravarti A, et al. Clin Cancer Res. 2006;12:

24 Temozolomide RTOG 0525 Completed Phase III trial comparing conventional adjuvant TMZ with dose-intensive TMZ in newly diagnosed GBM Radiation (60 Gy in 2-Gy fractions) + Concurrent daily TMZ ( 49d max) n=1154 Standard Arm TMZ days 1 5 of 28-day cycle for 6 cycles* Experimental Arm TMZ days 1 21 of 28-day cycle for 6 cycles* * Up to 12 cycles may be given if continued improvement shown by MRI scan, decreasing corticosteroid requirement, improvement in performance status, or improvement in neurologic function. Radiation Therapy Oncology Group (RTOG) Summaries. Brain. Available at: Accessed March 30, No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p= 0.63), or median PFS (5.5, 6.7 mo, p= 0.06), or by methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p<0.0001), PFS (8.7, 5.7 mo, p<0.0001) and response (p = 0.012). Cox modeling showed that MGMT status and RPA class were significant predictors of OS while the treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade 3 toxicity in Arm 2 (19%, 27%, p= 0.008); mostly lymphopenia and fatigue. Gilbert,et al. J Clin Oncol. 229:2011 (suppl; abstr 2006). Up-Front Clinical Trials for GBM (completed or near completion) Bevacizumab - UCLA study (phase II) overall survival 19.6 months, progression-free survival 13.6 months - RTOG 0825 (phase III): completed accrual - AVAGLIO (phase III): ongoing 2 Cilengitide - CENTRIC (phase III) - CORE (phase II) Cediranib - RTOG 0837 (phase II) 3 : Randomized, Phase II, Double-Blind, Placebo- Controlled Trial of Conventional Chemoradiation and Adjuvant Temozolomide Plus Cediranib versus Conventional Chemoradiation and Adjuvant Temozolomide Plus Placebo in Patients with Newly Diagnosed Glioblastoma 1. Lai, et al. J Clin Oncol. 2011;29: J Clin Oncol. 29:2011 (suppl; abstr TPS136)

25 Major Signaling Pathways in Glioma Wen PY, Kesari S. N Engl J Med. 2008;359: ; with permission. Treatment Strategies Targeted Biological Therapy Target Epidermal growth factor receptor (EGFR) 1 Platelet-derived growth factor receptor (PDGFR) 2 Vascular endothelial growth factor receptor (VEGF-R) 3 Integrin 4 Akt Pathway 5 Mammalian target of rapamycin 6 (mtor) Farnesyl transferase 7 Agent(s) Erlotinib Imatinib Cediranib, sunitinib, CEP-5214, CEP-7055 Cilengitide Perifosin (PI3K) Temsirolimus Tipifarnib 1. Rich JN, et al. J Clin Oncol. 2004;22: Akhavan, et al. Neuro Oncol. 2010;12(8): Reardon, et al. Br J Cancer. 2009;101(12): Galanis, et al. J Clin Oncol. 2005;23(23): Batchelor, et al. Cancer Cell. 2007;11: Cloughesy TF, et al. J Clin Oncol. 2006;24: Nabors, et al. Cancer. 2012; Epub ahead of print. 25

26 Treatment Strategies Targeted Biological Therapy Target Histone deacetylase (HDAC) inhibitors 1 Ras-Raf-MAPK inhibitors 2 Multiple kinase inhibitors 3 Protein Kinase C 4 Proteasome 1 STAT3 5 C-Met/Hepatic growth factor 6 Agent(s) Suberoylanilide hydroxamic acid (SAHA), valproic acid Sorafenib Vandetanib (EGFR, VEGFR), vatalanib (VEGFR2, PDGFR, c-kit), AEE788 (EGFR, VEGFR2), XL184 (Met, VEGFR2) Enzastaurin Bortezomib WP1066 AMG Friday, et al. Neuro Oncol. 2012;14(2): Hainsworth JD, et al. Cancer. 2010;116(15): Drappatz, et al. Int J Radiat Oncol Biol Phys. 2010;78(1): Wick W, et al. J Clin Oncol. 2010;28(7): Heimberger AB, et al. Recent Pat CNS Drug Discov. 2008;3(3): Wen PY, et al. Neuro Oncol. 2011;13(4): Other Emerging Treatment Concepts Vaccines Dendritic cell-based vaccines 1 Rindopepimut 2 Immunomodulatory therapy (ipilimumab; anti PD1/PD1 ligand directed therapies) 3 Cancer stem cell targeted therapy Inhibition of base excision repair strategies PARP inhibitors 4 Methoxamine 5 Novel delivery strategies Nanoparticles 6 Convection-enhanced delivery 7 PRECISE: IL-13 (Cintredekin besudotox) linked to Pseudomonas exotoxin Efficacy comparable to BCNU wafer 8 1. Knutson KL. Curr Opin Mol Ther. 2002;4: Liu L, et al. Clin Cancer Res. 2006;12: Heimberger AB, et al. Expert Opin Biol Ther. 2009;9: Patel T, et al. Adv Drug Deliv Rev. 2012;64(7): Chen, et al. Nat Rev Immunol May;4(5): Ratliff JK, Oldfield EH. J Neurosurg. 2001;95: Tentori L, et al. Pharmacol Res. 2002;45: Kunwar S, et al. Presented at SNO 2007, Abstract MA

27 Thank You 27