Pediatric Brain Tumors: The Need for “Pristine” Biologic and Clinical Data Roger J. Packer, MD Senior Vice-President Neuroscience and Behavioral Medicine Director, Brain Tumor Institute Children’s National Health System Washington, DC

Welcome to CBTTC CNHS honored to be a member Leaders of efforts at CNHS Brian Rood, MD Javad Nazarian, PhD Efforts like CBTTC of critical importance We are clearly in the molecular era Great opportunities Molecular/Genetic/Biologic advances leaped over clinical advance data past decade; clinical has not kept up Early biologic assumptions not as clear cut as regards therapeutic/prognostic implications (clinical data not as “clean”) Transition from retrospective to prospective studies, role of CBTTC critical

100% 90% 80% Percent Event-Free 70% 60% 50% 1 2 3 4 5 6 7 Time (years) A9961 Event-Free Survival from Study Entry RegA RegB 100% 90% 85 +/- 3% 80% Percent Event-Free 83 +/- 3% 70% 60% p=0.65 50% 1 2 3 4 5 6 7 Time (years)

Medulloblastoma: Trial Design Present cooperative group trials 10+ years to complete Not taken advantage of biologic insights Reduction or dosing fraction changes of RT not going to get where we need to go Accelerated Hyperfractionation Reduced dose CSRT Proton beam Need studies that can accrue in 18-36 months with outcome measure within 3-5 years of initiation (closer to 36 months, the better)

Medulloblastoma: Consensus and Controversies Taylor MD et al, Acta Neuropathol. 2012

Northcott. J Clin Oncol 28. 2010

SHH Subgroup Therapeutically 2 subgroups Mutation-driven For “upstream” (infants, adults) mutations How do we measure benefit of a SHH inhibitor (survival as good as “average-risk”) For downstream mutations Presently there are not effective molecularly-targeted agents

Clinical prognostication of patients with SHH medulloblastoma. Clinical prognostication of patients with SHH medulloblastoma. (A) Risk stratification of SHH medulloblastomas by molecular and clinical prognostic markers. Decision tree, with events plot depicting status of molecular and clinical markers across risk groups below. (B) Overall survival curves for SHH risk groups. (C) Average time-dependent areas under the curve (AUCs) for risk groups stratified using only clinical or molecular markers or both. Risk stratification regimens applied to SHH and non-SHH medulloblastomas. ***P < .001 by Friedman rank sum tests. (D) Survival curves for SHH risk groups in validation cohort. Survival differences evaluated by log-rank tests; hazard ratio estimates derived from Cox proportional hazards analyses. Shih D J et al. JCO 2014;32:886-896 ©2014 by American Society of Clinical Oncology

Current Medulloblastoma Subclassification Ramaswamy et al, Acta Neuropathologica2014

Proposed model to “move-up” novel agents for high-risk medulloblastoma: children > 3 or 4 DIAGNOSIS Risk Stratification Targeted Induction chemotherapy plus novel agent Evaluation of Response/MRD Radiation Therapy (consolidation) Evaluation of Response/MRD Maintenance plus novel agents ?Targeted ?non-targeted PFS/OS

DIPG and Non-BS HGG

Molecular Subgroups of Pediatric HGG

PNOC’s Pediatric HGG/DIPG Approach H3.3 K27 M positiveMidline Gliomas DIPG Not eligible for 007 HGG & DIPG No Biopsy required Biopsy required Genomic Based Precision Medicine Approach PNOC007: H3.3K27M peptide Vaccine trial CED of nanoliposomalCPT11 for DIPG PD1 + XRT Immunotherapy Targeted CNS delivery + liposomal technology Immunotherapy Genomic Based Precision Medicine Approach

PA – a single pathway disease Zhang et al. Nature Genetics 2013  Time for clinical prime-time! Jones et al. Nature Genetics 2013

Relevant Pathways for LGG

Selumetinib: Response

Largest Percentage Reduction in Tumor Volume from Baseline by BRAF Aberration (Min Tumor Vol/Baseline Vol)