The determinants of immune checkpoint blockade (ICB) response in glioblastoma (GBM) with wild-type isocitrate dehydrogenase remain poorly understood. Here we profiled 181 ICB-treated GBM cases using bulk DNA sequencing, bulk RNA sequencing and single-nucleus RNA sequencing to investigate the genomic features associated with ICB outcomes. Baseline tumor transcriptional subtype was predictive of overall survival following ICB, with mesenchymal (MES) GBM associated with improved outcomes to ICB but not standard chemoradiation. Non-MES-associated genetic lesions, including those in PDGFRA and CDKN2A, were associated with worse survival following ICB but not standard therapy. Tumor mutational burden was not predictive of outcomes. Survival was associated with pre-ICB enrichment for MES-like malignant cells, marked by high human leukocyte antigen class I expression and greater T cell infiltration. Paired tumor analyses linked ICB exposure to outgrowth of subclones harboring lesions associated with non-MES subtypes, supporting MES-to-non-MES transition as a common trajectory of acquired resistance to ICB, distinct from standard chemoradiation.

BACKGROUND AND PURPOSE:Mutations in isocitrate dehydrogenase (IDH) lead to production of the oncometabolite 2-hydroxygluterate (2-HG), which suppresses homologous recombination and induces poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Preclinical studies demonstrate that IDH-mutant gliomas are sensitive to PARP inhibition. Tumor growth rate (TGR) assessment offers a novel approach to evaluate treatment effects beyond traditional response criteria. Here, we report the change in TGR in a multicenter phase Ib/II study of the PARP inhibitor pamiparib with low-dose temozolomide in recurrent IDH-mutant gliomas, and evaluate TGR as an independent prognostic biomarker for overall survival. MATERIALS AND METHODS:In this Adult Brain Tumor Consortium multicenter phase Ib/II clinical trial (ABTC-1801; NCT03914742), patients with recurrent IDH-mutant gliomas were enrolled in three cohorts: Arm A (grade 2-3, failed ≥2 alkylators), Arm B (grade 2-3, failed single alkylator ≥12 months prior), and an exploratory cohort of grade 4 IDH-mutant patients. All patients received pamiparib 60mg twice daily with temozolomide 20mg daily. Tumor growth rates were assessed using serial MRI FLAIR measurements before and during treatment. Growth rate inhibition was defined as a decrease in TGR after treatment compared to pre-treatment growth rate. RESULTS:Among evaluable patients in the dose expansion cohorts enrolled between 2020-2022, 45.5% (5/11) in Arm A, 30% (6/20) in Arm B, and 30% (3/10) in the grade 4 arm demonstrated a decrease in TGR during treatment relative to pre-treatment TGRs. Cox regression analysis showed that higher post-treatment TGR (HR=1.0065 [95%CI:1.0031-1.01], P=0.0002; Arms A-B, HR=1.0068 [95%CI:1.0027-1.011], P=0.0012) and an increase in TGR after treatment were significantly associated with shorter survival for all patients as well as when only including grades 2-3 gliomas in Arms A-B (All patients, HR=1.007 [95%CI:1.0032-1.0107], P=0.0003; Arms A-B, HR=1.008 [95%CI:1.0034-1.0126], P=0.0006). Patients with TGR change >+25 mL/6 months had significantly worse survival compared to those with TGR <+25 mL/6 months (HR=4.946, P=0.0044; Arms A-B, HR=3.210, P=0.0108). CONCLUSIONS:TGR changes were significantly associated with survival outcomes, suggesting that growth stabilization may be an important metric for assessing treatment benefit in IDH-mutant gliomas.

BACKGROUND:Classical leptomeningeal disease (cLMD) impacts the entire craniospinal axis, but isolated parenchymal metastases sometimes display focal leptomeningeal extension (fLME) without diffuse LMD elsewhere. We assessed whether patients with fLME can be managed with stereotactic radiation (SRS/SRT) as opposed to whole brain/craniospinal radiation without excess development of marginal recurrences or subsequent cLMD. METHODS:We identified 796 patients with 2,354 newly-diagnosed brain metastases (BrM) without cLMD at diagnosis managed at a tertiary center between 2007 and 2022. Each metastasis was assessed for fLME, defined as isolated leptomeningeal extension of an intact BrM without cytologic or radiographic evidence of cLMD. Multivariable Fine and Gray's models were constructed for the primary outcomes of local recurrence and cLMD development. RESULTS:Among 796 patients, 138 (17.3%) displayed evidence of fLME, corresponding to 185 of 2,354 (7.9%) BrM. Patients with versus without fLME did not display excess local recurrences (1-year rate: 4.5% vs. 8.2%, respectively, P = .14; multivariable HR 0.56 [95% CI 0.30-1.07], P = .08), including in lesions managed with SRS/SRT (1-year rate: 4.4% vs. 4.9%, respectively; P = .63; multivariable HR 1.21 [95% CI 0.58-2.50], P = .61). The presence of fLME was not a significant predictor of subsequent cLMD (1-year rate: 5.2% vs. 5.2%, P = .99; multivariable HR 0.87 [95% CI 0.44-1.71], P = .68), including following treatment with SRS/SRT (1-year rate: 6.2% vs. 4.1%, P = .83; multivariable HR 0.92 [95% CI 0.36-2.39], P = .87). CONCLUSIONS:We describe a novel entity, fLME, which displays patterns of intracranial failure similar to parenchymal BrM. Stereotactic approaches may be viable in this population.

Oncogenic BRAF alterations occur in a subset of diffuse gliomas across WHO grades and are increasingly identified through modern molecular diagnostics. In addition to standard glioma therapies, targeted treatments are available for patients with BRAF-altered glioma supported by variable evidence spanning randomized trials, single-arm studies, and real-world evidence. This joint consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO) synthesizes current knowledge on the diagnosis and management of BRAF-altered gliomas across age groups, tumor grades, and lines of therapy. Particular emphasis is placed on expert consensus in clinical scenarios where high-quality trial evidence remains limited. The review addresses rationale testing for BRAF alterations, selection, and monitoring of targeted therapies, management of treatment-related toxicities, approaches to resistance, and priorities for future research. It aims to provide practical, evidence-based guidance for clinicians while highlighting gaps to inform prospective studies.

TPS2103 Background: Treatment for newly diagnosed IDH-mutant astrocytoma, WHO grade 3, is based on the results of the CATNON study, demonstrating benefit of radiotherapy followed by 12 months of adjuvant temozolomide. While temozolomide and radiotherapy significantly improved survival, the prognosis for these patients remains limited and more effective therapies are required. This trial will evaluate the benefit of the addition of the IDH1 and IDH-2 inhibitor vorasidenib to adjuvant temozolomide versus placebo following standard radiotherapy to evaluate possible improvement in outcomes. Methods: Alliance A072301 (NCT07215910) is a multicenter, double-blinded phase 3 randomized study to determine if the addition of vorasidenib to adjuvant temozolomide significantly improves progression-free survival (PFS), based on blinded central review in patients with newly diagnosed, IDH-mutant astrocytoma, WHO grade 3. Key inclusion criteria include age ≥ 12 years old, histological confirmation of astrocytoma (absence of 1p/19q codeletion), WHO grade 3, presence of any IDH mutation, plan for radiation and chemotherapy and surgery within 6 months. The presence of CDKN2A/B homozygous deletion, spinal or leptomeningeal disease, as well as prior chemotherapy, cranial irradiation or IDH inhibitor therapy, is exclusionary. 408 patients will be randomized 1:1 to receive vorasidenib 40 mg or placebo daily with 12 cycles of temozolomide following radiotherapy and then continued as monotherapy until disease progression or unacceptable toxicity. Stratification factors include age (< 40 years old vs ≥ 40 years old) and residual disease (< 2 cm vs ≥ 2 cm). Tumor assessments with MRI will be every three months for the first two years, every four months for the next two years and then every six months thereafter as per blinded independent central review using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria. Key secondary endpoints include PFS by local review, time to next treatment, safety and tolerability, quality of life measures. Exploratory measures will include seizure frequency. The trial will have 85% power to detect a hazard ratio of 0.625 with one-sided type I error rate of 0.025. Enrollment for the trial commenced February 2026. Support: U10CA180821, U10CA180882, U24CA196171. https://acknowledgments.alliancefound.org.

2058 Background: The management of isocitrate dehydrogenase (IDH) mutant glioma is rapidly evolving following the recent FDA approval of the mutant IDH inhibitor, vorasidenib. Optimal treatment decisions for many specific clinical scenarios remain undefined leading different neuro-oncology providers to recommend different treatment approaches. The aim of this study was to characterize how clinicians collectively approach different clinical scenarios and evaluate how demographic and professional backgrounds influence decision-making in IDH-mutant glioma. Methods: An online survey was developed by a team of neuro-oncologists and radiation oncologists and distributed via email and X to clinicians treating patients IDH-mutant glioma. The survey included demographic questions and multiple case-based clinical scenarios with standardized response options. We compared the responses of neuro/medical oncologists, radiation oncologists, and neurosurgeons, and performed univariable regression to identify predictors of treatment preference, as well as to understand familiarity and enthusiasm with the use of IDH inhibitors. Results: A total of 153 clinicians (58% neuro/medical-oncologists, 34% radiation oncologists, 8% neurosurgeons) completed the online survey. Five of ten scenarios reached consensus (>75% agreement on a treatment option), while the remainder demonstrated heterogeneity of treatment approaches. Compared to neuro/medical oncologists, radiation oncologists were less likely than neuro/medical oncologists to recommend IDH inhibitor therapy (IRR 0.57, p<0.001) and more likely to recommend radiotherapy (IRR 1.54, p<0.001) or chemo-radiotherapy (IRR 1.47, p<0.001). Neuro-oncologists and neurosurgeons reported the most and least familiarity, respectively, with the use of IDH inhibitors whereas medical oncologists and radiation oncologists reported the most and least enthusiasm for IDH inhibitor use, respectively. Conclusions: Our survey results evidence substantial variation in real-world management of IDH-mutant glioma across specialties and institutions. While several clinical scenarios demonstrated strong therapeutic consensus, others revealed diverse approaches, underscoring the need for ongoing multidisciplinary collaboration and further advancement of evidence-based consensus to guide clinical decisions.

PURPOSE:Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS:The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS:After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION:The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Epilepsy is commonly associated with gliomas, with glioma-neuron hyperexcitable interactions promoting tumor growth. Glioma vaccines are a promising form of immunotherapy, however immune-mediated effects on hyperexcitability are poorly understood. Seizures induce a proinflammatory state, whereas gliomas manipulate the microenvironment to evade adaptive immunity. This meta-analysis aimed to evaluate the incidence of seizures after glioma vaccine therapy as a clinical marker of peritumoral hyperexcitability. Studies were identified by query of the MEDLINE, Embase, and Web of Science databases with filtering for clinical trials and review of references. Inclusion criteria were prospective trials of cancer vaccines in patients with histologically confirmed diffuse glioma. Studies were excluded if seizure incidence was not reported or if data for all adverse events (AEs) regardless of treatment attribution was unavailable. Serious AEs were defined as grade 3 or higher by the Common Terminology Criteria for Adverse Events when available. Seizure incidence was calculated by pooled proportions with random effects using a generalized linear mixed model. Binary outcome meta-analysis of controlled trials was performed using the Mantel-Haenszel method with random effects. After applying pre-screening exclusion criteria, there were 125 studies screened for seizure-related AEs, and 53 studies with 2002 vaccine-treated patients were included in the final analysis. Treatment-emergent seizures of any grade occurred in 19.3

Background Preclinical studies demonstrate activity of poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors in isocitrate dehydrogenase (IDH) mutant gliomas. We investigated safety, tolerability, pharmacokinetics, and efficacy of the PARP inhibitor pamiparib in conjunction with metronomic low-dose temozolomide in patients with recurrent IDH mutant (IDHmt) gliomas in a multicenter Phase I/II/window of opportunity study.Methods Patients received pamiparib in conjunction with daily temozolomide. Following Phase I determination of maximum tolerated dose (MTD), we enrolled 2 patient cohorts (Arm A, multiple prior chemotherapy regimens; Arm B, single prior regimen) in a 2-stage design. Exploratory cohorts examined grade 4 IDHmt patients and intratumoral pharmacokinetics of pamiparib. The primary endpoint was objective radiographic response (ORR) by RANO criteria.Results Sixty-six subjects were enrolled. We established pamiparib 60 mg twice daily with temozolomide 20 mg daily as the phase II dose. In non-enhancing and enhancing tumor, pamiparib exhibited an unbound tumor/plasma ratio of 0.92 and 0.98, respectively. 0/15 Arm A and 1/24 Arm B patients achieved a centrally confirmed partial response. Median progression-free survival for Arm A was 5.9 months (95% CI, 1.2-14.8 months), and for Arm B was 9.7 months (95% CI, 5.7-21.7 months). Grade 3+ anemia and neutropenia affected 24% and 33% of patients, respectively. Twenty-two of 66 patients (33.3%) discontinued study treatment for reasons other than tumor progression.Conclusions Pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors. While some patients achieved prolonged progression-free survival, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial and impacted long-term tolerability.

Focused ultrasound (FUS) is an emerging therapeutic and diagnostic technology in neuro-oncology, offering new strategies for molecular diagnosis, drug delivery and tumor ablation across a range of brain tumors, including glioblastoma (GBM), brain metastases, and diffuse intrinsic pontine glioma (DIPG). The prognosis for aggressive brain tumors remains poor, despite advances in surgery, radiation, and chemotherapy. A considerable challenge is the limited ability to deliver therapeutics across the blood-brain barrier (BBB), particularly to infiltrative or non-enhancing tumor regions. FUS introduces an incisionless approach to the molecular subtyping of brain tumors, enhancing therapeutic delivery, and offers novel therapeutic approaches such as sonodynamic therapy (SDT). This review summarizes the FUS mechanisms and highlights the critical role of imaging modalities confirming target engagement, assessing bioeffects and outcomes, and ensuring safety. We also explore future directions, including the integration of liquid biopsy, artificial intelligence, and outpatient-ready FUS platforms, which will position FUS as a promising adjunct to standard neuro-oncologic care.

BACKGROUND:Generalizable, large-scale data describing outcomes and treatment approaches for older adults with brain metastases remain limited. In this investigation, we evaluated prognosis and patterns of care in this population over time, with particular attention to the potential impact of social determinants of health. METHODS:We used the SEER-Medicare database to delineate survival, treatment patterns, and disparities among patients aged ≥65 years with brain metastases diagnosed between 2010 to 2020. Survival was assessed with Kaplan-Meier methods and multivariable Cox regression. RESULTS:This study included 67,832 patients (51% female). The median survival from diagnosis of brain metastases was 3.42 months, improving modestly from 2.99 months in 2010 to 3.88 months in 2019. Higher zip-code-level annual income (HR 0.98 per $10,000 increase, 95% CI: 0.97 to 0.98, p < 0.001) and higher rates of high school graduation (HR 0.98 per 10% increase, 95% CI: 0.97 to 0.99, p = 0.001) were associated with lower mortality. Among patients managed with brain-directed radiation, 62% and 38% received non-stereotactic (inclusive of whole brain radiation) and stereotactic approaches, respectively. Use of stereotactic radiation increased from 22% in 2010 to 54% in 2019. Compared to White patients, Black patients (HR 0.79, 95% CI: 0.73 to 0.86, p < 0.001) and Hispanic patients (HR 0.87, 95% CI: 0.79 to 0.95, p = 0.002) were less likely to receive stereotactic radiation. CONCLUSIONS:The prognosis among older patients with brain metastases remains poor. Many patients continue to receive non-stereotactic approaches. Further work to improve the prognosis of older patients with brain metastases and optimize patterns of care is needed.

ABSTRACT:BackgroundThe oncological role of resection in elderly patients with glioblastoma remains controversial. We evaluated the value of resection in patients ≥65 years with (1) newly diagnosed and (2) recurrent glioblastoma by comparing the prognostic relevance of extent of resection to patients <65 years. METHODS:The international RANO resect group retrospectively collected patients with newly diagnosed and recurrent IDH-wildtype glioblastoma from ten neuro-oncological centers. Associations of residual tumor with molecular and clinical markers and survival were analyzed. RESULTS:A total of 1260 patients with newly diagnosed glioblastoma were identified, including 512 patients ≥65 years. Lower postoperative contrast-enhancing tumor volumes were favorably associated with survival on uni- and multivariate analyses; however, the associations with outcome were more pronounced in younger patients. Only in patients <65 years, supramaximal resection was associated with more favorable survival (40 vs 20 months, P = .001). In 310 patients with first recurrence (≥65 years: 92), maximal resection of contrast-enhancing tumor was associated with favorable outcomes, particularly in younger patients. Neither older nor younger patients had favorable outcome associations of supramaximal resection in the recurrent setting. All findings were confirmed in propensity-score-matched analyses to minimize confounding effects of inherent differences in demographic and clinical markers (including second-line treatments) between older and younger patients. CONCLUSIONS:While complete contrast-enhancing tumor resection is prognostic for favorable outcomes in older patients, associations of supramaximal resection with improved outcomes were only retained in younger patients with newly diagnosed disease. Those findings support stratified surgical approaches.

IDH-mutant glioma management has been rapidly evolving following the 2024 FDA approval of the mutant IDH inhibitor (IDHi), vorasidenib. However, optimal treatment decisions for many specific scenarios remain unclear. The aim of this study was to provide insight into how clinicians collectively approach different clinical scenarios and evaluate how demographic and professional backgrounds influence decision-making for IDH-mutant glioma. A survey was developed by a team of neuro-oncologists and radiation oncologists and distributed via email and X (formerly Twitter) to clinicians who treat patients with IDH-mutant glioma (neuro/medical oncologists, radiation oncologists, and neurosurgeons). The survey included demographic questions and 10–13 case-based clinical scenarios with standardized response options. We compared responses between neuro/medical oncologists and radiation oncologists and performed univariable regression to identify predictors of treatment preference and IDHi familiarity/enthusiasm. A total of 153 clinicians (58

BACKGROUND AND OBJECTIVES:Seizures are common in patients with brain metastases (BMs), causing significant morbidity and reduced quality of life. The relationship between BM location and seizure risk remains unclear. Nononcologic literature suggests that primary motor cortex disruption may predispose to seizures. This study evaluated whether BM in primary motor cortex display increased seizure risk relative to BM in other locations. METHODS:In this retrospective cohort study, patients with radiographic evidence of BM managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2003 and 2022, and maintained in a database, were included. Abstracted covariables spanned demographic (age, sex, and race), clinical (comorbidities and performance status), oncologic (cancer type, extracranial/intracranial disease extent, and prior systemic therapy), radiotherapeutic/neurosurgical (employment and type of radiation, presence of preceding brain-directed surgery), and outcome/seizure-related (presence, timing, and nature of seizures) domains. The exposure variable was BM in the primary motor cortex, and the outcome measure was seizures on a per-patient level. The effect of primary motor cortex involvement on seizure risk, at diagnosis and thereafter, was evaluated using univariable/multivariable logistic, and Fine and Gray competing risks regression, respectively. To limit confounding by lesion number, analyses were repeated in patients with a single BM at diagnosis (n = 1,174). RESULTS:Among 3,043 patients with (n = 570, 18.7%) vs without (n = 2,473, 81.3%) BM in primary motor cortex, the mean age was 60 vs 61 years, and 61% vs 62% of patients were female, respectively. Primary motor cortex involvement was associated with increased seizure risk at diagnosis (24.4% vs 10.3%, odds ratio 2.87, 95% CI 2.23-3.98, p < 0.001) and after initial diagnosis (hazard ratio [HR] 1.95, 95% CI 1.56-2.43, p < 0.001). Of 1,446 patients who developed additional BM after initial intracranial oncologic involvement, those with disease involving primary motor cortex were more likely to develop seizures thereafter (HR 2.11, 95% CI 1.56-2.86, p < 0.001). DISCUSSION:Patients with BM in the primary motor cortex may display increased seizure risk. As this study was retrospective, routine use of antiseizure medications in patients with BM in primary motor cortex in the off-trial setting is not recommended. However, dedicated trials evaluating prophylactic antiseizure medications in this population may be warranted.

Importance:Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective:To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants:Phase 3, open-label, randomized clinical trial conducted at 4 United States-based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention:Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures:Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory-Brain Tumor instrument (scale, 0-10; score change range, -10 to 10; -10 = best). A clinically meaningful Δ was defined as 0.98. Results:Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory-Brain Tumor score from 2.69 to 2.37 (mean change, -0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, -1.06 [95% CI, -1.54 to -0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance:In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration:ClinicalTrials.gov Identifier: NCT03075072.

BACKGROUND:Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. METHODS:We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). RESULTS:The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. CONCLUSION:Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Isocitrate dehydrogenase (IDH)-mutant gliomas constitute a distinct molecular subtype of diffuse gliomas, characterized by unique biology and relatively favorable clinical outcomes. However, despite their more indolent initial course, these tumors ultimately develop treatment resistance and remain incurable. Standard treatment approaches have relied on surgery followed by radiation and alkylating chemotherapy, which provide meaningful disease control but are associated with cumulative neurocognitive toxicities. The oral mutant IDH inhibitor vorasidenib recently became the first targeted therapy available for IDH-mutant glioma. Based on results of the randomized phase 3 INDIGO trial, vorasidenib was approved by the US Food and Drug Administration in 2024 as a first-line treatment option for grade 2 IDH-mutant glioma following surgery. In this review, we summarize the current therapeutic paradigm for IDH-mutant glioma, including the use of radiation and chemotherapy as well as the evolving role of mutant IDH-targeted therapy. We also highlight emerging therapeutic strategies, including approaches targeting key biologically informed vulnerabilities such as DNA damage repair pathways, cell-cycle and metabolic dependencies, tumor-associated hypermethylation, and anti-tumor immune activation. Collectively, these advances reflect a rapidly evolving treatment landscape driven by improved understanding of IDH biology, and hold promise to overcome therapeutic resistance and improve patient outcomes.

2010 Background: Grade 2 gliomas with isocitrate dehydrogenase 1/2 mutations (mIDH1/2) are diffuse, slowly progressive, malignant brain tumors with a poor long-term prognosis. In the Phase 3 INDIGO trial (NCT04164901) of patients (pts) with grade 2 mIDH1/2 glioma, vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mIDH1/2, demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint, progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint, time to next intervention (TTNI), vs placebo (PBO) at the preplanned interim analysis (data cut-off [DCO]: September 6, 2022). An additional 6 months of data up to study unblinding, March 7, 2023, showed that median PFS was not reached (95% confidence interval [CI]: 22.1 mos, not estimable [NE]) with VOR vs 11.4 mos (95% CI: 11.1, 13.9) with PBO, and median TTNI was NE (95% CI: NE, NE) with VOR vs 20.1 mos (95% CI: 17.5, 27.1) with PBO. Here, we present updated efficacy and safety results as of January 17, 2025, from pts randomized to VOR. Methods: Key eligibility criteria included residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma after surgery only; aged ≥12 years; Karnofsky performance score ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy (CT/RT). Pts were randomized 1:1 to VOR 40 mg daily in 28-day cycles or PBO. After study unblinding, pts receiving PBO were permitted to cross over to VOR. Primary endpoint: radiographic PFS per BIRC. Key secondary endpoint: TTNI. Results: 331 pts were randomized: 168 to VOR and 163 to PBO (median age: 40.0 years [range: 16–71]; oligodendroglioma: 172; astrocytoma: 159). As of January 17, 2025, 98/168 (58.3%) pts remained on VOR, and median follow-up was 41.6 mos (95% CI: 40.5, 42.7). Median PFS per investigator (INV) in pts randomized to VOR was 49.9 mos (95% CI: 39.6, NE), and median TTNI was NE (95% CI: 52.0 mos, NE). At 42 mos, 59.2% (95% CI: 49.9, 67.4) of pts were progression-free and 75.1% (95% CI: 67.4, 81.2) were not in need of CT/RT or surgery. Objective response rate per INV was 31.5% (95% CI: 24.6, 39.2). Median overall survival was not reached. PFS and overall response per BIRC will be presented. The safety profile of VOR was consistent with previous reports. No new safety signals were observed. Conclusions: In the randomized, Phase 3 trial of a targeted therapy in grade 2 mIDH1/2 glioma, over 3 years of follow-up in pts randomized to VOR support the robustness of PFS and TTNI results and confirm a durable and sustained treatment benefit with VOR. VOR is now approved in over 40 countries as a monotherapy for pts with grade 2 mIDH1/2 glioma following surgery. Clinical trial information: NCT04164901 .