Precision medicine for gliomas

Precision medicine for YAZMIN ODIA, MD MS LEAD PHYSICIAN OF MEDICAL NEURO-ONCOLOGY DISCLOSURES Novocure: Advisory Board for Optune in No other financial conflicts of interest Glioma OVERVIEW INFILTRATIVE, MALIGNANT, PRIMARY BRAIN TUMOR WHO 2016 GLIOMA CLASSIFICATION Not resectable Not curable CNS-born ATRX loss, p53 mutation Astrocytoma Rarely metastasize IDH-WT Astrocytoma Pre- IDH-WT, Secondary http://www.medicallibraryonline.com Primary 1

11/29/2017 Glioma imaging Glioma imaging MRI FINDINGS WHO Grade II-III Gliomas MRI FINDINGS WHO Grade IV s Glioma PROGNOSIS Glioma prognosis PROGNOSIS by Age and Grade Prognosis better for Oligodendro Explained by 1p/19q co-deletion Reifenberger J, AJP 1994 II III IV RTOG Boots-Sprenger SHE, Modern Pathology, 2013 2

Mutations in Isocitrate Dehydrogenases linked to Gliomagenesis Prognosis predicted by mutations in IDH1 (and IDH2) WHO 2016 GLIOMA CLASSIFICATION ATRX loss, p53 mutation Astrocytoma IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary Boots-Sprenger SHE, Modern Pathology, 2013 WHO 2016 GLIOMA CLASSIFICATION WHO 2016 GLIOMA CLASSIFICATION Molecular Profile ATRX loss, p53 mutation Astrocytoma ATRX loss, p53 mutation Astrocytoma IDH-WT Astrocytoma Pre- IDH-WT, Secondary IDH-WT Astrocytoma Pre- IDH-WT, Secondary BRAF mutation/fusion PA and PXA Histone 3 (K27M) mutant diffuse midline Primary WHO Grade BRAF mutation/fusion PA and PXA Histone 3 (K27M) mutant diffuse midline Primary Worse Prognosis 3

TREATMENT: IDH-WT WHO Grade III-IV Astrocytomas + radiation + concurrent/adjuvant temozolomide TREATMENT: s + radiation + concurrent/adjuvant temozolomide IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary Stupp R, NEJM 2005 TREATMENT: s MGMT promoter methylation status predicts response TREATMENT: s MGMT promoter methylation status predicts response O6-methylguanine methyltransferase (MGMT) DNA repair gene MGMT promoter hypermethylation leads to gene silencing Predicts response to alkylating chemotherapy, like temozolomide and nitrosoureas Predicts response to oxidizing radiation Hegi ME, NEJM 2005 4

TREATMENT: s (TTF) at recurrence (2010) and upfront (2016) TREATMENT: s + radiation + concurrent/adjuvant temozolomide + TTF Median OS increased by 3-5 months 2-Year Survival rates increased by ~15% Low Compliance Stupp R, JAMA 2016 TREATMENT: s + radiation + concurrent/adjuvant temozolomide + TTF Survival Benefit extends to 4 and 5-year TREATMENT: s + radiation + concurrent/adjuvant temozolomide + TTF MEDIAN OVERALL SURVIVAL 2-YEAR SURVIVAL 6 mos <5% 12 mos 10-12% + Temozolomide 15-16 mos 21-29% Stupp R, JAMA 2016 + TMZ + TTF 19-20 mos 43% Stupp R, NEJM 2005 and JAMA 2016 5

TREATMENT: Extrapolated to WHO II-III, IDH-WT Astrocytomas + radiation + concurrent/adjuvant temozolomide + TTF(?) IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary TREATMENT: Extrapolated to WHO II-III, IDH-WT Astrocytomas TTF trials pending for WHO III Patient compliance and physician acceptance remain low Unclear benefit in WHO II Unclear benefit in elderly and/or poor functional status Hypofractionated (shortened) radiation course Temozolomide alone for MGMT hypermethylated tumors TREATMENT: Implications of Molecular Profile TREATMENT: IDH-mutant Gliomas ATRX loss, p53 mutation Astrocytoma ATRX loss, p53 mutation Astrocytoma IDH-WT Astrocytoma Pre- Primary 6

TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro ATRX loss, p53 mutation Astrocytoma Pre- Primary TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro + + Procarbazine, CCNU, Vincristine (PCV) TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro 1p/19q Intact Astrocytomas 1p/19q Intact Astrocytomas 1p/19q Co-deleted Oligodendro van den Bent MJ, JCO 2013 EORTC 26951 1p/19q Co-deleted Oligodendro Cairncross G, JCO 2013 RTOG 9402 7

TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro Procarbazine, CCNU, Vincristine (PCV) WHO grade III + PCV + radiation WHO grade II Observe: LOW RISK (<40 years, unilateral, & gross total resection) PCV + radiation: HIGH RISK (>40 years, bilateral, or subtotal resection) TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro PCV superior to temozolomide, but more toxic TOXICITY vs. CONTROL PCV TEMOZOLOMIDE Toxicity 10-40% <10% Noncompliance/Refusal 5-10% <5% Response Rate 90-100% 35-80% Median Time to Progression 7.2 years 3.2 years Median Overall Survival 10.5 years 7.6 years Lassman AB, CNS Onc 2015 TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro Balancing Treatment Toxicity vs. Disease Control PCV vs. TMZ? upfront or deferred to recurrence? -induced cognitive deficits TREATMENT: IDH-mutant Astrocytomas ATRX loss, p53 mutation Astrocytoma Pre- 8

TREATMENT: IDH-mutant Astrocytomas + radiation + concurrent/adjuvant temozolomide? + PCV + radiation? TREATMENT: IDH-mutant Astrocytomas + radiation + concurrent/adjuvant temozolomide? + PCV + radiation? Additive benefit of molecular profiles PCV + RT RT only 1p/19q co-deletion > IDH1 mutations > MGMT hypermethylation Toxicity vs. Control Timing Cairncross JCO 2014 RTOG9402 alone for WHO grade II? TREATMENT: Multimodal Approach TREATMENT: Multimodal Approach 9

TREATMENT: Multimodal Approach TREATMENT: Bevacizumab (VGEF) inhibits angiogenesis Genomics & Molecular Profiling Initial promising results: Progression-free but not overall survival benefit Dramatic MRI response due to steroid-like effect Increasing concern for more invasive phenotype after exposure Palliative benefit only TREATMENT: EGFR amplification and/or EGFRvIII mutation TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance 10

TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Rindopepimut vaccine targeted EGFRvIII TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Rindopepimut vaccine targeted EGFRvIII negative! TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Rindopepimut vaccine targeted EGFRvIII negative! ABT414 antibody drug conjugate (ADC) Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF 11

TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF Promising early response, now in Phase III trial TREATMENT: for rare glioma subtypes BRAF-V600E and possibly BRAF fusion alterations in PXA or PA Rindopepimut vaccine targeted EGFRvIII negative! ABT414 antibody drug conjugate (ADC) Regimen based on BRAF-V600E mutant melanoma BRAF inhibitor with/without concurrent MEK inhibitors Initial promising results, ongoing trials H3-K27M Diffuse Midline Glioma Limited options, prognosis remains poor Ongoing trials targeting mutation and downstream effects TREATMENT: TREATMENT 12

TREATMENT: Vaccines CTLA-4 and OX40 Inhibitors Checkpoint Inhibitors TREATMENT: Vaccines Negative or In Development Rindopepimut; Polio, Heat Shock (HSPPC-96), Toca TREATMENT: Vaccines Negative or In Development TREATMENT: Vaccines Negative or In Development 511/FC CTLA-4 Inhibitors Checkpoint Inhibitors CTLA-4 Inhibitors in development Ipilimumab combination therapy, reduced dose Checkpoint Inhibitors CTLA-4 Inhibitors Checkpoint Inhibitors Nivolumab and Pembrolizumab in trials for 13

TREATMENT: Vaccines Negative or In Development TREATMENT: Multimodal CTLA-4 Inhibitors Checkpoint Inhibitors Multimodal Response linked to high mutational load TREATMENT: Evolving Gliomas - SUMMARY GLIOMAS - SUMMARY TREATMENT: Personalized Guided by Genomic and Molecular Profiles Advanced by Clinical Trials Highly Variable and Unpredictable Course Genomics & Molecular Targets Quality of Life & Patient Preferences 14

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