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Supplementary Table S1

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Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Outcome related to location

Radiological necrosis in a cerebral Grade III tumor

Supplementary Methods and Supplementary Table 1. The supplementary data file contains the supplemental methods section describing the source of the patient samples used in the initial validation of the five-gene signature assay and supplementary table 1 which lists the number of patients with MB with tumor samples assessed per the five-gene signature assay from each clinical study as a second validation set.

Purpose:The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data.Experimental Design:Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS).Results:One-hundred thirteen patients were randomized to the RT/TMZ arm (n = 54) or the RT/TMZ+BEV (BEV arm; n = 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Total/near-total resection occurred in 44 of 68 (65%) Cerebral cases but in only 5 of 45 (11%) Midline cases (P < 0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than in Cerebral tumors (10/68, P < 0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (P < 0.05). Pseudoprogression occurred in 8 of 111 (6.2%) cases.Conclusions:This study has shown that the poor outcome of midline tumors (compared with cerebral) may be related to (1) lesser surgical resection, (2) H3 K27M histone mutations, and (3) higher leptomeningeal dissemination.

Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway–activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway–activated medulloblastoma.Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded.Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment. Clin Cancer Res; 21(3); 585–93. ©2014 AACR.

Purpose:Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients.Patients and Methods:Patients ages 1 to BRAF V600–mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2.Results:Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%).Conclusions:Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.

Investigator-assessed percent change at maximum reduction from baseline in tumor measurement per RANO criteria

LBA2002 Background: LGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. Most patients (pts) with pLGG have disease progression and require post-surgical therapy. The standard of care is chemotherapy, such as carboplatin + vincristine (C+V), which may be less effective in BRAF V600–mutant disease; thus, alternative treatment options are needed. Dab + tram showed encouraging efficacy in a Phase I/II study (NCT02124772) in pts with previously treated BRAF V600–mutant pLGG. We describe the results of a randomized Phase II study (NCT02684058) of first-line dab + tram vs C+V in BRAF V600–mutant pLGG. Methods: Pts aged 1 to

10040 Background: A defining feature of malignant rhabdoid tumors (MRTs), epithelioid sarcoma (ES), and poorly differentiated chordomas (PDC) is loss of integrase interactor 1 (INI1) expression, which induces dependence on enhancer of zeste homolog 2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the US Food and Drug Administration for patients (pts) aged ≥16 y with metastatic or locally advanced ES ineligible for complete resection. Pediatric dose escalation and interim efficacy and safety data for the dose expansion were previously reported. Updated efficacy, safety, subgroup analyses, and translational results are reported here. Methods: NCT02601937 is a phase 1 multicenter study evaluating TAZ monotherapy ≤2400 mg/m2 daily in pediatric pts with relapsed or refractory INI1− tumors (MRT, atypical teratoid rhabdoid tumor [ATRT], select tumors with rhabdoid features, other INI1− tumors, and SS18-SSX synovial sarcoma). Primary endpoint for dose expansion was objective response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival. Selected exploratory flow data using 250,000 cells from peripheral blood were available for up to 25 pts. Results: Phase 1 enrolled 109 pts (escalation, n=46; expansion, n=63; Table) with mean ages of 5.4 y in the dose escalation and 7.4 y in the dose expansion. ORRs were 7% (3/46) in the dose escalation and 14% (9/63) in the dose expansion. Per tumor category in the dose expansion, ORRs were 24% (5/21) ATRT, 33% (2/6) PDC, 22% (2/9) ES, and 0% in non–CNS RTs (n=21) and other tumors (n=6). ORR for pts with prior radiotherapy was 14% (11/80) vs 3% (1/29) with prior radiotherapy ( P>0.05). In the dose expansion, median PFS was 8 wk (95% CI: 8–13), OS was 21 wk (95% CI: 13–38), and DOR was 35 wk (95% CI: 24–121). Grade 3–4 treatment-related treatment-emergent adverse event rates were 15% (7/46) in the dose escalation and 22% (14/63) in dose expansion. Differences between responders (R) and nonresponders (NR) at C1D1 for neutrophil counts were significant ( P50,000 total CD3 T cells vs 0% (0/19) of NR. Conclusions: TAZ showed promising antitumor activity in ATRT, ES, and PDC. Potential synergism between prior radiotherapy and TAZ requires further investigation. TAZ was generally well tolerated. The biological/clinical significance of differences in peripheral blood cell counts between R and NR at C1D1 needs further investigation. Clinical trial information: NCT02601937. [Table: see text]

2009 Background: HGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. Overall response rates (ORRs) with current standards of care are low, particularly in the second line, and 2-y overall survival (OS) rates are ≤35%. BRAF V600 mutation is infrequent (≈5% of pHGGs) but associated with improved survival from time of initial diagnosis. In previous trials, dab monotherapy and dab + tram yielded encouraging outcomes in BRAF V600–mutant HGG in pediatric and adult patients (pts), respectively. We describe the results of a Phase II study (NCT02684058) of dab + tram in r/r BRAF V600–mutant pHGG. Methods: Pts aged 1 to

Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients withPatients ages 1 to18 years who hadOverall, 32 patients with pLGG were enrolled (part 1,Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with

BACKGROUND Fotemustine is a nitrosourea with theoretic and preclinical advantages over the original analogs, carmustine and lomustine, in the treatment of brain tumors. This is the first pediatric Phase I study of fotemustine. METHODS Patients younger than 21 with recurrent/resistant brain tumors were enrolled in a conventional Phase I study. Fotemustine was administered intravenously every 3 weeks at increasing dose levels starting at 100 mg/m2. Toxicity and response data were monitored closely. RESULTS Fifteen evaluable patients entered the study and received a total of 45 courses of fotemustine (dose range, 100–175 mg/m2). Myelosuppression was observed, with the dose-limiting toxicity being Grade 4 neutropenia and thrombocytopenia. Toxicity was delayed and cumulative. The maximum tolerated dose was 150 mg/m2 every 3 weeks. There were three documented radiologic responses (20% of patients) comprising one partial response and two minor responses in patients with a sarcoma, medulloblastoma, and ependymoma, respectively. CONCLUSIONS Fotemustine administered at a dose of 150 mg/m2 every 3 weeks is well tolerated in children and has antitumor activity in several brain tumors. This is the first dedicated Phase I study of a single agent nitrosourea in a pediatric population. More comparative studies should be undertaken to define the optimum nitrosourea analog for use in children with brain tumors. Cancer 2002;95:1294–301. © 2002 American Cancer Society. DOI 10.1002/cncr.10814

Craniopharyngiomas are classified as histologically benign tumours that are usually treated by surgery alone or in combination with radiotherapy. However, the difficulty in managing recurrent tumours and the desire to try to avoid treatment-related morbidity from both surgery and irradiation has led to exploration of the role of chemotherapy in this tumour. In the majority of cases this has involved the application of intratumoral bleomycin in cystic craniopharyngiomas. This review reports the published experience of this type of local chemotherapy, including delivery, scheduling, outcomes and toxicity. In addition, the rarely reported use of systemic chemotherapy is discussed.