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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 • • 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 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 (%) PFS of 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 (%) 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 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 • 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 – – – – (Neuro-Oncology 2015;17:430) – • Possible BBB penetration – – 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, , proliferation Strategies to overcome BBB • Convection Enhanced Delivery

• Improve Drugs Penetration Across BBB – Ideally all small molecules would have good BBB penetration e.g. buparlisib, GDC0084 – ANG1005 (transported through LRP1 receptors) – Nanoparticles – Antibodies that cross BBB (Atwal et al; Yu et al Sci. Trans. Med. 2011). – Inhibitors of drug efflux pumps – Microbubbles and focused ultrasound

Some Potential Molecular Targets in GBM

• PI3K/mTOR • FGFR/TACC • BRAF V600 • MET • MDM2 • CDK4/6

• IDH (GBM and grade II/III gliomas)

Brennan TCGA 2013 Fusions in GBM (? 4.4%) Yoshihara et al. Oncogene 2015 FGFR/TACC (3-4%) EGFR-SEPT 14 (? 4%) EGFR-PSPH (? 2%) NTRK (?1%) EML4-ALK Fusion

NAB2-STAT6 (Diamandes Diag Path 2016)

Science 2012

Phase II Trials of AZD 4547 and BGJ398 (FGFR inhibitors) Brennan et al TCGA Cell 2013 • MDM2-amplified PDCLs 44 x more sensitive than TP53 mutated lines • TP53 wild-type PDCLs with normal MDM2/4 levels had heterogenous response

Oct 19, 2015 (Epub) Antiangiogenic Therapies

• Multiple mechanisms of resistance • There will much less emphasis on targeting in the next few yrs 2015 Polio Virus

People Magazine Viral Gene Therapy

• Toca 511: Retroviral replicating vector with CD gene that converts orally delivered Toca FC (extended-release 5-FC) into 5-FU

• DNX2401 (Delta 24 RGD)

• Measles Virus • Ad-RTS-hIL-12 • HSV

• Dendritic cell vaccines – DCVax, ICT107 • Peptide vaccines – Rindopepimut (CDX110) – 1CT-102 – SL-701 – CMV – IDH1 Chen/Mellman Immunity 39:1-10, 2013 • Other vaccines (eg, HSPPC-96) • Checkpoint inhibitors – CTLA4 () – PD1(, , pidilizumab) – PDL1 antibodies (MPDL3280A, MEDI4736) • Adoptive T Cell Therapy: Chimeric Antigen Receptor (CAR) T Lymphocytes • TGFb inhibitor (LY2157299); STAT3, etc

Immune system is suppressed in GBM

Table 1. Mechanisms of tumor immunosuppression. Defects in antigen Tumor cell HLA antigen loss32 processing Defective MHC-II induction in tumor-associated microglia and macrophages127 T cell dysfunction Weakened proliferative responses3, 31

Insufficient synthesis of TH1 cytokine IL-23, 31 Increased proportion of Tregs (CD4+CD25+ cells)32,35,39,56,127 Glioma secretion of immune- Il-1052, 95 inhibiting molecules 24, 27, 37, 126 Prostaglandin E2 TGF-beta210, 24, 34, 36, 79 Active induction of apoptosis Fas ligand (CD95L)57, 134 in T-cells 44, 114 Galectin-1

• Glioblastomas make immunosuppressive substances and Tregs are increased

• RT and TMZ also produce lymphopenia • Corticosteroids

Bower et al. 2007 Grossman CCR 2011 ICT-107 is an Autologous Six-antigen DC Vaccine

Matured, Activated, Peptide-loaded DC Six 9-10 amino acid antigen epitopes MHC • MAGE-1 (HLA - A1) Class I • AIM-2 (A1) • gp100 (HLA - A2) • IL-13Rα2 (A2) CSC • HER2/neu (A2) Antigen expressio • TRP-2 (A2) (HLA) n gp100 * (A2) Rationale for antigen choice MAGE-1 * • Targeting multiple antigens minimizes tumor escape (A1) • High expression levels for all antigens on GBM samples • Bias toward TAA associated with cancer stem cells IL-13Rα2 + (A2)

Control used in Ph II Her-2/neu + • Matured, activated DC without peptide loading (A2) AIM-2 ++ (A1) TRP-2 ++ 60 (A2) Wen et al ASCO 2014 ICT-107 Phase III Trial in HLA-A2 positive Newly- Diagnosed GBM (EORTC and Alliance Foundation)

Week 1 Clinical Assessments SOC Maintenance TMZ§ DC Therapy Induction Phase. Apheresis Subject specific DC therapy

1/week for 4 weeks Week 2

*

ICT-107 Rest Week

OR Week 3

Eligibility Eligibility Maintenance DC Therapyβ

Informed Confirmation Consent + Tumor Assessments Screen & Enroll* & Screen

Control Phase Maintenance (ICT-107 or Control) SOC SOC Chemoradiation

Visit 3 (Week -1) Randomization (1:1) Week 4

Complete Surgical Resection of the tumor and MRI and tumor the of Resection Surgical Complete Rest Week

*Chemoradiation for 6 weeks; induction TMZ (75mg/m2/day for 42 days) and focal radiotherapy (60 Gy in 30 fractions, 5 days/week for 6 weeks). First administration of TMZ to be within 8 weeks of resection surgery.

§ Administered 5 days per week for 6 months (Day 1 to Day 5 of Cycle 1 – Cycle 6). Dose Cycle 1: 150 mg/m2/day. Dose Cycles 2 – 6: 200 mg/m2/day. Doses may be reduced or discontinued based on toxicities.

β Maintenance administration on Day 21 of Cycles 1 to 11, coupled with Maintenance TMZ cycles 1-6. If TMZ is delayed, study DC therapy will also be delayed to ensure TMZ and study therapy cycles remain synchronized. Extended Maintenance administration after one year of DC therapy (15 injections) will continue every 6 months until depletion or confirmation of PD. Ridopepimut (CDX110) Peptide Vaccine against EGFRvIII Mutation

Sampson JCO 2010; 1;28(31):4722-9) REACT TRIAL: Bev +/- Rindopepimut in Recurrent GBM (Overall survival improved)

Median, months OS 12 OS 18 OS 24 (95% CI) Rindopepimut + BV 11.3 (9.9, 16.2) 44% 32% 25% Control + BV 9.3 (7.1, 11.4) 32% 13% 0%

1 0 0

) HR = 0.53 (0.32, 0.88)

%

(

l 7 5 p = 0.0137* Per-protocol population analyses: a

v HR = 0.53 (0.31, 0.90) i

v p = 0.0177* r

u 5 0

S

l

l

a r

e 2 5

v O

0 0 6 1 2 1 8 2 4 3 0 3 6 4 2

M o n t h s Five patients in the rindopepimut + BV arm, and 1 patient in the control + BV arm, continue survival follow-up without progression per expert review. * Log-rank test (2-sided) 64

NeoVax (DFCI-Reardon, Wu, Fritz)

• Personalized vaccine • Newly-diagnosed GBM undergo whole exome sequencing • 10-20 neoantigens identified and personalized vaccine made

DFCI 13-024 Hacohen Ca Immunol Res 2013 Immune Checkpoint Blockade

Cytotoxic T Lymphocyte Antigen – 4 (CTLA-4) Initial T cell activation

Programmed Death – 1 (PD-1/PD-L1) Later/after T cell activation

Postow et al. J Clin Oncol 33:1974, 2015 Neoantigens Predict Response to PD-1 Blockade in NSCLC

Rizvi NA et al. Science 2015 2016

Response to Nivolumab

Tumor Mutation and Neoantigen Analysis 64 yr old Caucasion female – sustained partial response Pembrolizumab 10 mg/kg q 2wks

Baseline (9/26/14; no decadron)

13 months, ongoing (10/29/15; no decadron) 4 weeks on MK3475 (PD1 inhibitor) Progression vs “pseudoprogression”?

Ongoing/Planned Strategies

• Improved vaccines • Combination of checkpoint inhibitors – Tetanus toxoid and viral therapies – Neovax, IMA950 (Immatics) – Multiple preclinical studies • Hypofractionated RT + checkpoint suggests antitumor effect of viral inhibitors therapies augmented by combination with PD1 antibodies, • Checkpoint inhibitors with etc hypermutated tumors • Combination of checkpoint inhibitors • Combination of vaccines and and antiangiogenic therapies checkpoint inhibitors – VEGF immunosuppressive – Neovax with pembrolizumab – Anti-VEGF therapy may affect • Combination of complementary balance of M1 and M2 immunotherapies macrophages – Ipilimumab (CTLA4 Ab) + • Combination of immunotherapies nivolumab (PD1 Ab) and targeted therapies – Anti-LAG and anti-CD137 with – BRAF inhibitors with checkpoint nivolumab inhibitors in melanoma – IDO inhibitors + checkpoint – Two therapies not mutually inhibitors? exclusive How To Develop Drugs More Efficiently? • Should we focus on newly-diagnosed GBM where tumors are molecularly less complexed and perhaps less resistant, rather than focusing on recurrent tumors?

Recurrent GBM Newly-Diagnosed GBM

TMZ

Optune

• How can we evaluate drugs in first line faster and more efficiently? Adaptive Randomization Strategies

• Multiple arm study • Allocation of patients based on Bayesian probability of treatment efficacy • Treatment arms with success are more likely to accrue patients • Treatment arms with poor results are dropped, alternative arms added, and accrual continues until clear evidence of superior treatment(s) emerge

Winner

Courtesy of Mark Gilbert, MD.

Potential Design For Unmethylated Newly-Diagnosed GBM INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) (Alexander, Trippa, Ligon, Wen)

Molecular/Imaging RT + TMZ Reoperation biomarker Adjuvant TMZ assessment R (Whole exome A RT/TMZ followed by

sequencing, array PFS N Abemaciclb CGH) D (CDK 4/6 inhibitor)

Newly diagnosed O OS

GBM ABC2 M RT + CC115 I (mTOR/DNA PK Z inhibitor) E

RT/TMZ followed by 4-5 Neratinib weeks (EGFR Inhibitor) Tissue Adaptive design

Preclinical models Co-clinical trials to Preclinical surrogate endpoint generate biomarker/tx development hypotheses (50-70 patients/arm) Cloughesy, Barker, Berry NCT Clinical Cancer Program - Brain Tumors NCT Neuro Master Match (N2M2) - Trial concept

Patient with newly diagnosed glioblastoma MGMT promoter unmethylated Standard: PFS6 expected: 40% HM450 k Array No Match Panel Seq SOC: RT/TMZ Transcriptome/Exome Radiotherapy (RT) + Endpoint: Match PFS6 targeted: 60% 40% APG101 according to CD95L promoter methylation Safety in each subtrial 20% according Alk fusion / relevant expression

5% MDM2 antagonist according to P53 wildtype and MDM2 amplification

25% according to PD-1L expression and MMR deficiency

3% according to SHH activation

25% according to mTor Ser2448 phosphorylation Courtesy of 20% according to CDK4/6 activation Wolfgang Wick Lower Grade Gliomas (Grade II and III Gliomas) WHO Classification of Lower Grade Gliomas Classification based on IDH and 1p/19q status, if available

Astrocytoma Anaplastic oligodendroglioma • Diffuse astrocytoma, IDH mutant • Anaplastic astrocytoma, IDH mutant • Gemistocytic astrocytoma, IDH- • Anaplastic astrocytoma, IDH- mutant wildtype • Diffuse astrocytoma, IDH-wildtype • Anaplastic astrocytoma, NOS • Diffuse astrocytoma, NOS

Oligodendroglioma Anaplastic oligodendroglioma • Oligodendroglioma, IDH-mutant & • Anaplastic oligodendroglioma, IDH 1p/19q codeleted mutant & 1p/19q-codeleted • Oligodendroglioma, NOS • Anaplastic oligodendroglioma, NOS

Oligoastrocytoma, NOS Anaplastic oligoastrocytoma (NOS)

Anaplastic Oligodendroglioma

IDH, TERT mutations 1p/19q loss Anaplastic Oligodendroglioma

PCV followed by RT RT followed by PCV Anaplastic Oligodendroglioma RTOG 9402

Addition of PCV to RT improves outcome significantly

Cairncross JCO 2012 Anaplastic Oligodendroglioma EORTC 2695

Codeletion (loss) of 1p/19q

Codeleted pts benefit from PCV

Intact (no loss) of 1p/19q

Van den Bent JCO 2012 Low-Grade Astrocytoma (WHO Grade II) IDH, TP53, ATRX mutations

Low-Grade Oligodendroglioma (WHO Grade II) IDH, TERT mutations, 1p/19q loss

RTOG 9802 SCHEMA LOW RISK Arm 1 = Observe Age <40 AND GROSS TOTAL RESECTION R A Arm 2 = Radiation Therapy Stratify by: N (54 Gy/30 fractions) Oligo-dominant D Vs. O HIGH RISK Astro-dominant; M KPS; I Age >40 OR Age; Z Arm 3 = Radiation Therapy SUBTOTAL Enhancement E PCV x 6 RESECTION/ cycles 2 BIOPSY CCNU 110 mg/m (day 1) PCBZ 60 mg/m2 (days 8-21) VCR 1.4 mg/m2 (days 8 & 29)

(2.0 mg cap) Buckner SNO 2014 2016;374:1344

RT Alone RT + PCV Overall Survival Estimate (%) Estimate (%) Median 7.8 years 13.3 years 5-year 63 % 72% 10-year 40% 60%

RT + PCV significantly prolongs survival in high-risk low grade gliomas compared to RT alone Buckner et al NEJM 2016 2016;374:1344

Benefit: Oligodendroglioma (HR 0.43; p=0.009) > Oligoastrocytoma (HR 0.56; p=0.05) > Astrocytoma (HR 0.73; p=31) 2016;374:1344

• Patients with high risk grade II gliomas (> age 40 yrs or subtotal resection) should probably be treated with radiotherapy and chemotherapy • Unanswered Questions • What subgroups benefit most from RT + chemotherapy – RTOG 9802 had limited molecular data – Which groups? (1p/19q, IDH mutated, MGMT methylated) • RT + chemotherapy for low risk grade II gliomas? • For very young patients with small amount of residual tumor is it OK to watch closely and delay treatment • PCV or TMZ

IDH Mutations Promote Oncogenesis in Gliomas

• IDH mutations are early and important transformational events that remain important throughout the tumor life cycle • Inhibition of αKG-dependent dioxygenases by excess 2-HG causes genetic and epigenetic dysregulation, leading to carcinogenesis

DIFFERENTIATION RESTORED DIFFERENTIATION BLOCKED Inhibitor Epigenetic Normal cell death / IDH Me Me “re-wiring” 2-HG HOMEOSTASIS Isocitrate mIDH Unchecked cell proliferation Me CANCER

αKG Differentiation

HSC Progenitor ProgenitorMature Cell Science 2013 Phase I Trial of AG120 in Solid Tumors With IDH-1 Mutations

Other IDH1 inhibitors: IDH305, AG881; IDH2 inhibitor AG221 Effects on Glioma Tumor Size in Subjects Evaluable for Volumetric Analysis: A Single Site Experience

Grade II Max Max Best oligoastrocytoma volume 2HG SPD change change change by MRS

−64% −100% −30% Grade II oligodendroglioma

−19% −53% +3%

Tumor volume Tumor Grade III anaplastic oligoastrocytoma

+73% +37% −2%

Pre-AG-120 treatment

Data from Dana Farber Cancer Institute (R Huang, A Lin) SPD, sum of the product of diameters PDGFRA FIP1L1

Nature. 2016 Jan 7;529(7584):110-4 5-Azacytidine (demethylating agent) PDGFR Inhibition 2015

• Mutant IDH1 decreases NAD+ levels by downregulating Naprt1 and inhibiting an alternate NAD+ salvage pathway

• NAD+ depletion triggers autophagy and results in cytotoxicity

• Nampt inhibitors may have therapeutic potential

IDH1R132H Immunotherapy (Schumacher et al Nature 2014)

spontaneous mutation- A humanized IDH1 Vaccination of established specific T cell response in a mutant mouse tumor IDH1 mutant tumors subset of patients with IDH1 model IDH1RH tumors therapeutic 120 mutant glioma 110

) vacc

2 100 90 sham R132H wt 80 70 60 50 40 30 tumor area tumor (mm 20 MOG vehicle 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 time post inoculation (days) Elimination of IDH1 mutant tumor cells Summary

• Limited progress to date but outlook much more promising • Improved understanding of molecular pathogenesis of gliomas and new WHO classification will hopefully accelerate progress • Need to leverage advances in genomics, have drugs that pass through BBB and adequately inhibit targeted pathways, and understand issues of heterogeneity and resistance • Immunotherapy and targeting tumor metabolism and epigenetics holds promise • Real progress in classification and treatment of of LGG Neuro-Oncology Radiation Oncology Neuro-Oncology Clinical Research Rameen Beroukhim Brian Alexander Karly Griffin Eudocia (Kalem) Quant Lee Ayal Aizer Bethany Murphy Lakshmi Nayak Karen Marcus Christine McCluskey Andrew Norden Daphne Haas-Kogen Sarah Gaffey David Reardon Tijy Tankachan Mikael Rinne Neuropathology Chimay Bhavsar Keith Ligon Majagamy Ramos Nurses Shak Ramkissoon Jennifer Barrs Debra Lafrankie (Program Nurse) Azra Ligon David Hastie Lisa Doherty (NP) Sandro Santagata Matthew Mendoza Sandra Ruland (Program Nurse) Victoria Caruso Jennifer Rifenburg (NP) Lais Cabrera Julee Pulverenti (Research PA) Rujuta Gadgil Thank You! Wafae Belatreche Neurosurgery Sarah Charbonneau Ennio Chiocca Laura Holtz Ian Dunn Alex Golby Laboratory Research Tom Roberts Mark Johnson Funding: NIH/NCI UM1 CA137443-06, P50 Ed Laws CA165962, R01CA129371, RO1FD004400, Ivy Jean Zhao Osama al-Mefty Consortium for Early Phase Trials for Glioblastomas, Chuck Stiles Elizabeth Claus NBTS, Brain Tumor Funders Collaborative