Recap of the 2017 Annual Meeting of the
Society for Neuro-Oncology
Roy E. Strowd, Albert H. Kim, and Patrick Y. Wen
This article originally appeared in SNO’s official journal, Neuro-Oncology, Volume 20, Issue 2.
To see photos from the event, click here.
2017 SNO Annual Meeting Summary
The 22nd Annual Scientific Meeting of the Society for Neuro-Oncology (SNO) took place November 16–19, 2017, in San Francisco, California. This year’s meeting enjoyed record attendance, with 2484 attendees at the main meeting representing 50 countries. Over 1046 attendees participated in the SNO Education Day. Abstract submissions for this year’s meeting reached a new record, with 1275 total submissions representing a significant increase from the 1024 submissions in 2016.
The Cancer Moonshot Project was featured broadly across the meeting, including keynote presentations from Dr W. K. Alfred Yung, who highlighted areas where neuro-oncology plays a pivotal role within the 10 Blue Ribbon Panel priority areas for accelerating progress in cancer. Dr Walter Koroshetz provided an update on neuro-oncology initiatives at the National Institute of Neurological Disorders and Stroke (NINDS), including translational funding opportunities in the NINDS Brain Initiative. Other keynote speakers discussed seminal findings that microRNAs can drive cancer (Dr Carlo Croce) and new computational technologies can decode mutational signatures across cancers (Dr Ludmil Alexandrov), and Dr Jennifer Doudna discussed the discovery of the CRISPR/Cas9 system.
The meeting featured impactful addresses from Dr Susan Chang, the Victor Levin Award Recipient, and Dr Webster Cavenee, the Lifetime Achievement Award Recipient, and a memorial tribute was held to honor Jan Esenwein with the dedication of the new Jan Esenwein Public Service Award. The following summarizes just a few of the many important updates and advances presented at this year’s meeting.
Update on SNO Education Day
Thematically, the SNO Education Day focused on 3 Cancer Moonshot recommendations: overcome therapeutic resistance, minimize side effects of cancer treatments, and develop new cancer technologies. Dr Trever Bivona opened the discussion with a keynote address on the direct and indirect mechanisms through which epidermal growth factor receptor (EGFR) mutant non–small cell lung cancers evade targeted therapies. The morning sessions focused on phosphatidylinositol-3 kinase inhibitor evasion pathways, the role of intratumoral heterogeneity in generating resistant tumoral subclones, extrachromosomal DNA as a mechanism for oncogene amplification, the challenges of harnessing the immune response to brain tumors, and the role of macrophages and microglia in low-grade gliomas.
The afternoon focused on mechanisms of resistance to specific therapies, including temozolomide (TMZ), bevacizumab, radiation, checkpoint blockade, and translational approaches to overcome these mechanisms of resistance, including poly(ADP-ribose) polymerase inhibitors and other novel approaches. A complementary track was opened with a keynote address by Dr Donald Abrams examining the importance of integrative approaches to current cancer treatments, taking into account the potential impact of diet and alternative therapies. This track of educational sessions focused on brain tumor survivorship and care plans, the importance of patient-reported outcomes, quality of life measures in meningioma patients, nutrition and the ketogenic diet, chemotherapy-induced ototoxicity, and patient sleep-wake disturbances. Dr Gregory Armstrong and Nino Chiocca concluded the sessions with a highlight of the role of patient reported outcomes in long-term survivors of pediatric cancers, and Dr Chiocca reflected on the need for mechanistic understandings of drug resistance to overcome therapeutic failures.
Late-Breaking Abstracts: Initial Results of the Phase II Study of Depatux-m
Two late-breaking abstracts failed to meet their primary endpoints but did offer subgroup analyses that will be the subject of future phase III studies. Initial results were presented of the phase II EORTC-1410-BTG study of depatux-m, a tumor-specific antibody–drug conjugate consisting of the antibody ABT-806 bound to monomethyl auristatin F toxin. This open-label study randomized 260 patients with confirmed EGFR-amplified glioblastoma at first recurrence to depatux-m, depatux-m with TMZ, or either lomustine or TMZ monotherapy. No survival difference was observed between the placebo and depatux-m monotherapy groups. Median survival of 9.6 months (1-y overall survival [OS] 39.7%) was longer in the depatux-m/TMZ arm compared with 8.2 months (1-y OS 28.2%) in the placebo arm, with a hazard ratio (HR) for death of 0.71 (95% CI: 0.50–1.02). Although the primary endpoint was not met, a trend toward survival advantage with the depatux-m/TMZ combination was observed in patients with EGFR-amplified first recurrent glioblastoma. This will be further investigated in the phase III setting.
Phase IIb results were presented of the multicenter randomized placebo-controlled trial of an autologous formalin- fixed tumor vaccine (AFTV) for patients with newly diagnosed glioblastoma. Prior studies have demonstrated clinical activity and in vivo immunoactivation of AFTV vaccines derived from paraffin-embedded tissue. In this phase IIb study, adults with newly diagnosed extensively resected glioblastoma were randomized to AFTV versus placebo. Median OS was not different between the AFTV-treated (25.6 mo) and placebo-treated patients (31.5 mo, HR 1.19, 95% CI: 0.57 2.47, P = 0.64). However, in a subgroup analysis, 3-year OS did trend toward favoring AFTV treatment for tumors with negative p53 immunostaining (79% vs 43%, P = 0.072) and patients receiving total resection (81% vs 46%, P = 0.067). These subgroups will be further evaluated in the planned phase III study.
Results of the CeTeG/NOA-04 Phase III Trial
Dr Ulrich Herrlinger, one of 2 recipients of the Adult Clinical Research Award, presented initial efficacy results of this phase III trial of lomustine (CCNU) and TMZ in O6- methylguanine-DNA methyltransferase (MGMT) promoter methylated newly diagnosed glioblastoma. This study investigated the combination of CCNU/TMZ in 129 newly diagnosed MGMT methylated glioblastomas following resection or biopsy. The primary outcome was 2-year landmark survival. Patients were randomly assigned 1:1 to experimental treatment with CCNU (100 mg/m2/d, D1) and TMZ (100 mg/m2/d, D2–6) administered every 6 weeks without concurrent TMZ during radiotherapy or control treatment with standard concurrent chemoradiotherapy followed by 6 cycles of adjuvant TMZ. CCNU/TMZ was more toxic, with 36% unable to escalate adjuvant TMZ to 200 mg/m2/d and only 39% completing all 6 planned cycles of therapy compared with only 3.2% of TMZ-only-treated patients not escalating adjuvantly and 60% completing all 6 cycles. Median OS was prolonged from 31.4 months with TMZ alone to 37.9 months with CCNU/TMZ (HR 0.60, 95% CI: 0.35–1.0, P = 0.064). Two-year landmark survival was improved from 65% (95% CI: 57–82%) to 71% (95% CI: 61–83%). Despite meeting its primary endpoint of improvement in OS, progression-free survival (PFS) was not different between the 2 groups (P = 0.41). Potential explanations for this discrepancy between PFS and OS were presented, including higher frequency of pseudoprogression in the experimental arm. Salvage therapies did not clearly contribute to this discrepancy, and further discussion is anticipated to clarify how these data should inform clinical practice.
Update on Targeted Therapy in Isocitrate Dehydrogenase Mutated Gliomas
Results from the phase I study of AG-120, a first-inclass mutant isocitrate dehydrogenase 1 (IDH1) inhibitor for patients with recurrent or progressive IDH1 mutant glioma, were presented by Dr Ingo Mellinghoff, recipient of an Adult Clinical Research Award. Updates were provided for the cohort of non-enhancing gliomas, including results of an exploratory imaging analysis investigating treatment- induced changes in tumor growth rate by volumetric analysis. In this cohort of 35 patients with non-enhancing disease (n = 11 from dose escalation; n = 24 from dose expansion), the majority of tumors were World Health Organization grade II (n = 24), though grade III (n = 8) and grade IV tumors (n = 1) were included. The agent continues to show a favorable safety and toxicity profile. The overall response rate was 6% (n = 2), though 83% of patients had stable disease (n = 29). Median duration on AG-120 was 14.7 months (range 1.4–25 mo) and 63% remained on AG-120 for ≥1 year. Exploratory imaging analysis using volumetric quantification of T2/fluid attenuated inversion recovery (FLAIR) disease to assess tumor growth rate prior to and following treatment with AG-120 suggested a plateauing or reduction in tumor growth rate with treatment. Further refinement of the methodology used for growth rate imaging analysis continues and could potentially be an important contribution of this study.
The Role of IDH Mutation in Alternative Telomere Lengthening
Dr Joydeep Mukherjee, one of 2 recipients of the Adult Basic Research Award as well as recipient of the Andrew Parsa Young Investigator Award, presented mechanistic data on the role of mutant IDH in cooperating with loss of alpha thalassemia/mental retardation syndrome X-linked protein (ATRX) to drive alternative lengthening of telomeres and rescue gliomas from telomere-induced cell death. Telomere maintenance is critical for cell survival. In the absence of telomerase reverse transcriptase (TERT) activation, human tumors like gliomas utilize the recombination- based alternative lengthening of telomeres (ALT) pathway to maintain telomere integrity. Prior studies have shown that ATRX loss and p53 mutation alone are insufficient to drive an ALT cellular phenotype. Dr Mukherjee and colleagues showed that mutant IDH1 or ATRX loss alone are insufficient to drive the ALT phenotype. However, the combination of mutant IDH1 expression and loss of ATRX resulted in tumorigenic cells with an ALT phenotype, which was mediated by downregulation of RAP1 (repressor/ activator protein 1) and XRCC1 (X-ray repair cross complementing protein 4), genes important in the telomere capping shelterin complex and fusion of dysfunctional telomeres through alternative nonhomologous end joining. These IDH1-mutant, ATRX-deficient cells were driven to use ALT to resolve telomeric dysfunction and escape cell death. These data suggest that agents which alter the linkage between mutant IDH and DNA repair pathway preference may have therapeutic potential in IDH mutant gliomas.
Molecular Characterization of Aggressive Meningiomas Identifies Forkhead Box M1 as a Prognostic Marker
Data on the comprehensive genomic characterization of aggressive meningiomas was presented by Dr David Raleigh, recipient of the other Adult Basic Research Award. This timely work builds on recent data suggesting that meningioma location and histologic variants are associated with specific mutational profiles in these tumors. In this report of data from the University of California San Francisco Meningioma Database, whole-exome sequencing, DNA methylation arrays, RNA-sequencing, Nanostring, and immunohistochemistry were performed on a discovery and validation set of aggressive grades I– III meningiomas to elucidate new drivers of meningioma aggressiveness. Similar to prior studies, whole-exome sequencing demonstrated poorer survival in tumors with increased somatic mutation burden. Interestingly, the proto-oncogene FOXM1 (Forkhead box protein M1) appeared to be an important driver of aggressiveness. RNA-seq identified FOXM1 expression to be associated with higher proliferation rates and poorer OS. High FOXM1 mRNA expression was also associated with decreased local recurrence-free survival (P = 0.004). FOXM1 promoted cell proliferation gene expression in part by potentiating betacatenin activity. Through this integrated genomic analysis, FOXM1 was identified as a novel biomarker of aggressiveness, with implications for drug development.
Molecular Profiling Is Critical in Pediatric Embryonal Trials
The Children’s Oncology Group trial ACNS0332 was a phase III trial randomizing children with high-risk medulloblastoma or primitive neuroectodermal tumors to carboplatin during radiation therapy and/or isotretinoin during maintenance. The trial closed prematurely; data were provided on DNA methylation analysis for 60 patients and showed frequent molecular discrepancies with histologic diagnosis, including high-grade gliomas (n = 18), atypical teratoid rhabdoid tumors, and ependymomas that were not intended for the study. Outcomes were significantly poorer for these molecularly classified high-grade gliomas, underscoring the importance of molecular classification in future studies of supratentorial embryonal tumors.
Post-hoc Analysis of IDH1/2 Mutation and 1p/19q Codeletion Status in RTOG 9802
Molecular analysis was presented of tissue from the phase III randomized study of radiation with or without procarbazine/ lomustine/vincristine (PCV) chemotherapy for highrisk low-grade gliomas. Of the initial study population, 39% had available samples for testing (n = 97). Progression-free survival was significantly longer with the addition of PCV for IDH mutant/codeleted and IDH mutant/non-codeleted but not IDH non-mutated/non-codeleted gliomas. Similar results were observed for OS, though the benefit in IDH mutant/codeleted tumors did not result in statistical significance due to the generally favorable survival profile in this group.
Bevacizumab for Progressive Neurofibromatosis 2–Associated Vestibular Schwannomas
Results were presented from the RARE-19 study, a phase II multicenter study of dose-intensified bevacizumab induction followed by maintenance. Of the 22 patients with progressive vestibular schwannomas who were enrolled, hearing response (primary endpoint) was observed in 42% and radiographic response in 21%, which was similar to previous studies using lower doses. Premature ovarian insufficiency was observed and requires further exploration as these data are integrated into clinical practice.
Intracavitary Toca 511 for Recurrent High-Grade Glioma
Updated results from 2 of 3 ongoing open-label, phase I trials investigating ascending doses of the retroviral replicating vector Toca 511 were presented. The intracavitary study (NCT01470794) enrolled recurrent high-grade glioma patients who underwent intracavitary injection followed by oral Toca 5-fluorocytosine (FC) with or without bevacizumab or lomustine. Responses have been favorable, with 3 complete responses and 2 partial responses in the Tocaonly arm, 1 complete response in the Toca/bevacizumab arm, and a median duration of response in all patients of 25.2 months.
Intravenous Toca 511 for Recurrent High-Grade Glioma
Data from the intravenous study (NCT01985256) were also presented. This study enrolled recurrent high-grade glioma patients who received pre-resection intravenous Toca 511 followed by intracavitary injection at resection and subsequent oral Toca FC. Following intravenous administration, the investigators demonstrated that cytosine deaminase protein was detectable and quantifiable in resected gliomas and that Toca 511 can infect and spread independently of T-cell infiltration in the tumor microenvironment.
Novel Small-Molecule Inhibitor of OLIG2
Data were presented on a small-molecule inhibitor, CT-179, which was shown to modulate the transcription of oligodendrocyte transcription factor (OLIG2) target genes and result in inhibition of cell growth, induction of apoptosis, and G2/M arrest of glioma stemlike cells in vitro.
Volumetric Analysis of Postsurgical Residual Tumor in Patients on the RTOG 0825 Study
Volumetric analysis was presented of residual enhancing and non-enhancing tumor for patients in this randomized phase III study of bevacizumab for newly diagnosed glioblastoma. Discordance was noted between post-hoc volumetric assessment of complete resection and physician determination in the study. Smaller residual tumor volume following resection was associated with improved outcomes. Patients with greater residual T2/FLAIR volumes had poorer OS when treated with bevacizumab (HR 1.42, P = 0.02).
The 23rd Annual Scientific Meeting of the Society for Neuro-Oncology will be held in New Orleans, Louisiana, November 15-18, 2018.