Citations

Abstract The WHO 2021 classification of central nervous system tumors incorporated molecular markers to better define diffuse glioma subgroups. We analyzed array-based copy number, targeted next-generation sequencing, germline genotyping, and Illumina EPIC array methylation data from 404 primary IDH-mutant astrocytomas to further understand the relationship between copy number and outcomes. Loss of chromosome arm 13q was associated with poor overall survival after adjusting for age, sex, tumor grade, and treatment status (hazard ratio [HR]=2.04 (95% confidence interval: 1.25-3.33), p=0.004). Chromosome 13q loss was also significantly associated with the total number of copy number alterations (p<0.001). Loss of arm 11p was associated with poor survival in the adjusted analysis (HR=2.29 (1.38-3.79), p=0.001). Unsupervised clustering of the raw copy number data identified 12 clusters, where each cluster was defined by distinct copy number alteration(s). Clusters that contained 13q loss exhibited worse overall survival compared to other clusters. The clusters were significantly associated with age at diagnosis (p=0.015), tumor grade (p<0.001) and copy number complexity (p<0.001). The clusters with a high proportion of grade 4 tumors and with the highest complexity had the poorest overall survival. These findings highlight the prognostic relevance of chromosome 13q and 11p losses in IDH-mutant astrocytomas and support the integration of additional copy number alterations into molecular classification frameworks of IDH-mutant astrocytomas to improve risk stratification and patient management.

Abstract BACKGROUND Craniopharyngiomas are a rare tumor along the pituitary-hypothalamic axis. Genetic analysis revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We previously reported that BRAF/MEK inhibition was associated with significant anti-tumor activity in newly-diagnosed PCP patients (Brastianos et al. NEJM 2023). We have now evaluated the efficacy of vemurafenib/cobimetinib in a separate cohort of patients with recurrent PCP whose tumors progressed after prior radiation. METHODS In this multicenter, NCI-sponsored cooperative group trial, patients with histologically confirmed BRAF-positive PCP who progressed after radiation were treated with vemurafenib/cobimetinib. The primary endpoint of response rate (RR) based on centrally determined imaging data was to be evaluated in 16 patients, where a partial response was defined as ≥20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR ≥ 30% (vs. null 5%; α=0.04). In this design, 3 or more observed responses in 16 evaluable patients would be considered evidence of promising activity. RESULTS Of the planned 16 patients, a total of 5 patients enrolled before the study was closed due to slow accrual. Median follow-up was 50 months (95% CI: 32 to not yet reached). Based on volumetric response criteria, all 5 patients had a response to treatment (100%; 95% CI: 47.8% to 100%). To date, 2 patients progressed, one of whom died 22 months after study entry. This cohort met the criteria for efficacy under the original design with >3 responders. No grade 4 or 5 toxicities were observed. CONCLUSIONS Vemurafenib/cobimetinib resulted in an objective response in all patients with previously treated PCP. The study met primary endpoint, similar to that reported for previously untreated PCP. Thus, BRAF/MEK inhibitors could be an effective tool for previously treated PCP and warrants further evaluation. SUPPORT U10CA180821; U10CA180882; Genentech, https://acknowledgments.alliancefound.org;ClinicalTrials.gov: NCT03224767

Abstract Aberrant vasculature is a hallmark of glioblastoma (GBM), contributing to both blood–brain barrier (BBB) dysfunction and frequent intracranial hemorrhage. Myeloid cells, including microglia and macrophages, are known to co-opt tumor vasculature during tumor progression, but the nature and consequences of their physical interactions with blood vessels require clearer definition. To address this, we characterize vessel-associated myeloid cells in murine gliomas with high spatial and temporal resolution, leveraging in vivo two-photon imaging, MRI, and transgenic mouse lines. To investigate the role of microglia in glioma vasculature, we pretreated glioma-bearing mice with CSF1R inhibitors (PLX3397 & PLX5622) to ablate microglia prior to tumor inoculation. Strikingly, over half of the microglia-depleted mice developed acute, lethal paralysis between days 11–15, whereas control tumor-bearing mice remained asymptomatic. MRI revealed extensive intracranial hemorrhage and edema, and two-photon imaging showed nodular, abnormal vasculature. This vascular dysfunction led to a dramatic reduction in median survival—from 30 days in control glioma-bearing mice to 15 days in PLX-treated mice with gliomas. To identify the protective microglial population involved, we examined vascular–myeloid interactions. We found that the peritumoral region harbored dense capillary networks supporting tumor expansion, along with a marked increase in myeloid cells with somas directly contacting blood vessels. Using TMEM119CreER/+:R26tdTomato/+ mice, we confirmed these vessel-associated cells as brain-resident microglia, not infiltrating macrophages. Quantitatively, ~60% of peritumoral microglia were vessel-associated, compared to ~30% in naïve or contralateral hemispheres. These microglia displayed elongated somata and processes aligned with vessels or wrapping around vessels, which is a phenotype also observed following single-vessel photothrombosis, suggesting a response to impaired blood flow and BBB leakage. Our findings uncover a critical neurovascular role for vessel-associated microglia in maintaining vascular integrity during glioma progression and highlight the importance of preserving, reprogramming, and further investigating this population in GBM therapies.

Abstract BACKGROUND Pembrolizumab is FDA approved for solid tumors with high tumor mutation burden (TMB) and may thus have efficacy in hypermutant glioma. This study aimed to identify factors influencing efficacy of pembrolizumab in recurrent glioma. METHODS This retrospective study at Mayo Clinic included patients with adult-type diffuse gliomas who received pembrolizumab (≥2 cycles) for recurrent disease (01/01/2014–05/01/2025). The Mayo Clinic Solid Tumor Panel (MCSTP), which uses the Illumina TruSight Oncology 500 High-Throughput next-generation sequencing (NGS) assay, was also used to assess the molecular characteristics of the recurrent tumors. Responders to pembrolizumab were defined as patients who did not meet RANO 2.0 criteria for progressive disease on first radiographic response assessment. Progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox-Regression analyses. RESULTS Sixty-two patients were identified (median age: 46 years; 65% male; 94% white). All patients received pembrolizumab and had prior alkylating chemotherapy. The median PFS from pembrolizumab initiation was 2.3 months. Twenty-five (40%) patients were responders. Patients with IDH-mutant, 1p/19q co-deleted gliomas (OLIGO, n=13) had a longer PFS (4.3 months) than IDH wildtype gliomas (IDH-WT, n=33, 2.2 months, p=0.012) and IDH-mutant, 1p/19q non-co-deleted (IDH-MUT, n=16, 1.7 months, p=0.0006). The proportion of responders was significantly greater in OLIGO patients (IDH-WT, 33%; IDH-MUT, 19%; OLIGO, 85%, p=0.0008). Overall PFS was not impacted by patient age, sex, or extent of initial resection. Twenty-nine percent of patient tumors tested thus far (6/21) had a high TMB (≥10 mut/Mb). Two-thirds (4/6) of high TMB patients were responders, while only one-third (5/15) of low TMB patients were responders. CONCLUSIONS Patients with recurrent OLIGO may have a longer PFS with pembrolizumab therapy than IDH-WT and IDH-MUT. Furthermore, high TMB may be associated with longer PFS with pembrolizumab therapy in glioma. Additional patients are being assessed using MCSTP (total expected n=43); complete data will be presented.

Abstract INTRODUCTION Leptomeningeal disease (LMD) represents a serious neurological complication of systemic malignancies. Once diagnosed, LMD has been associated with limited life-expectancy. Herein, we report a patient with non-small cell lung cancer (NSCLC) with LMD who achieved almost 7-year overall survival (OS) from her LMD diagnosis. CASE REPORT A 60-year-old female developed worsening dry cough at age of 52. A 3-cm FDG-avid right lower lobe lung mass was found. Biopsy revealed NSCLC with EGFR exon 19 deletion. Surveillance imaging was implemented given early-stage disease. Two years later, she was found to have focal LMD along with parenchymal brain metastases. She underwent surgical resection with concomitant placement of Ommaya Reservoir. She was initiated on Osimertinib. This resulted in improvement of her focal LMD, and control of extracranial disease for 33 months when neuroimaging revealed evidence of recurrent LMD over right lateral temporal lobe. Osimertinib dose was then increased from 80 mg to 160 mg daily. At 42 months, she developed LMD progression. Despite treatment with stereotactic radiosurgery, she had further LMD progression, and another surgical resection was performed at 55 months, yet LMD recurred at 62 months, and she was enrolled in phase-2 WSD0922 clinical trial utilizing an oral brain-penetrant non-competitive reversible EGFR inhibitor with complete radiological resolution of LMD. At 73 months, she had LMD relapse and was initiated on intrathecal pemetrexed and intravenous amivantamab, and has thus far received 11 doses of intrathecal pemetrexed and amivantamab every two weeks with complete radiological response. At last follow-up, the patient is alive 82 months from her LMD diagnosis with excellent functional status. DISCUSSION our case highlights that leveraging different mechanisms of action to target EGFR mutation in sequential fashion along with consideration of intrathecal chemotherapy in patients with LMD related to metastatic EGFR-mutated NSCLC can potentially help control LMD and prolong OS.

Abstract OBJECTIVE Despite advancements in therapy and improved survival rates for patients with primary central nervous system lymphoma (PCNSL), the optimal management strategy for recurrent or refractory PCNSL (r/r PCNSL) remains undefined. In such cases, repeat brain biopsy is often performed to confirm disease recurrence, though its diagnostic and therapeutic value is uncertain. This study evaluates whether repeat brain biopsy provides new, actionable diagnostic insights that influence treatment decisions. METHODS A retrospective analysis was conducted on patients with a confirmed diagnosis of PCNSL who underwent repeat brain biopsy for suspected recurrent or refractory disease between 2005 and 2023. Patients with a history of other CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. RESULTS Twenty patients met inclusion criteria (55% female), with a mean age at biopsy of 56 years in the PCNSL group and 61 years in the r/r PCNSL group. While the overall distribution of presenting symptoms did not significantly differ (p = 0.2), gait instability, weakness, and cognitive decline were more common in r/r PCNSL. PCNSL more often presented with single lesions, while r/r PCNSL had predominantly multiple lesions (p < 0.05). Periventricular enhancement was significantly more frequent in r/r PCNSL (p < 0.05), though other radiologic features were comparable. Repeat biopsy confirmed DLBCL in 90% of cases; no infections or alternate malignancies were identified. Diagnostic clarification was the primary indication for repeat biopsy. Chemotherapy regimens were altered in 50% of post-biopsy cases, without a corresponding difference in overall survival (p = 0.79). Procedure-related morbidity was observed in three patients (15%). CONCLUSIONS The second biopsy in most cases reaffirmed the original diagnosis of diffuse large B cell lymphoma. Although biopsy results led to treatment adjustments; these changes did not affect overall survival.

Abstract Berubicin is a unique anthracycline engineered to have the ability to cross the blood-brain barrier (BBB). Herein we present the primary results from a large global trial of Berubicin vs. Lomustine randomizing patients with progressive disease after only one prior therapy, all being IDH WT and stratified for MGMT methylation. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rates (ORR) of complete (CR) and partial (PR) responses. Eligibility was determined radiologically by central reads based on progression of disease, and in 2.5 years 252 patients were enrolled with 168 randomized to Berubicin and 84 to Lomustine. Safety assessment showed that Berubicin was well tolerated and myelosuppressive side effects were manageable with growth factors. Importantly, although anthracyclines are known to cause cardiotoxicity, evaluation with frequent troponin measurements, ECG and ECHO testing revealed no evidence of impact on cardiac function. The primary endpoint, OS, showed Berubicin and Lomustine had similar outcomes. Median overall survival for Berubicin was 8.7 months (6.7, 9.9) and for Lomustine was 9.3 months (6.7, 10.7) with a Hazard Ratio of 1.13 (p = 0.5351). PFS of Berubicin and Lomustine were also similar (1.5 vs, 1.6 months). There were no responses in the Lomustine arm and stable disease in 35.2% of patients while Berubicin had a response rate of 5.8% (PR) and stable disease of 33.6% with a combined disease control rate (DCR) of 39.4%. Additional data will be presented and discussed. Anthracyclines are characteristically used in combination for systemic therapy (e.g. leukemia, lymphoma, certain breast cancers), so there is promise that combination therapy will be the next pertinent approach to treatment of GBM. Evaluation of activity against a range of pediatric brain tumors is being pursued and preliminary results will be presented at the time of the conference.

Abstract BACKGROUND High-grade and recurrent meningiomas frequently demonstrate aggressive behavior and therapeutic resistance, with limited treatment options. Dysregulation of the MAPK and FAK pathways drive meningioma progression, but compensatory activation between these pathways could limit single agent efficacy. Recently, a clinical trial (Alliance A071401) showed encouraging efficacy of single-agent FAK inhibition in recurrent/progressive meningioma (Brastianos et al, JCO 2023). This preclinical study aimed to evaluate the therapeutic potential of dual RAF/MEK (avutometinib) and FAK (VS-4718) inhibition in suppressing tumor growth and improving survival in intracranial meningioma models. METHODS Orthotopic intracranial models were established by injecting IOMM-Lee (Fluc-mCherry) or CH157-MN (eGFP-LUC2) cells into nu/nu mice. Mice were randomized into four groups: vehicle, VS-4718 (murine formulation of defactinib, 50 mg/kg, BID), avutometinib (0.3 mg/kg, QD), or combination therapy. Treatments were administered for a 4-week period. Tumor growth was monitored via bioluminescent imaging (BLI) at baseline, midpoint, and study endpoint. Pharmacokinetic (PK) and pharmacodynamic (PD) effects were assessed by intratumoral drug concentrations and Western blotting for p-ERK and p-AKT, respectively. RESULTS In the NF2-mutant CH157-MN model, avutometinib increased median survival from 12.5 to 20.5 days (p=0.001), while combination therapy extended survival further to 22 days (p<0.0001 vs vehicle). Similarly, in the NF2-wildtype IOMM-Lee model, avutometinib raised survival from 27.5 to 33 days (p=0.0237), with combination therapy reaching 34.5 days (p=0.0057 vs vehicle). VS-4718 monotherapy did not extend survival in both models. BLI demonstrated significant inhibition of tumor growth in both avutometinib and combination groups in both tumor models. PK analysis revealed Kp values of 0.26–0.37 for avutometinib and 0.46–0.50 for VS-4718 in orthotopic tumor tissue. Furthermore, combination therapy lowered p-ERK in tumors (p=0.001) compared to vehicle. CONCLUSION Dual RAF/MEK and FAK inhibitor therapy blocks MAPK activation and enhances survival in orthotopic meningioma models, supporting further clinical evaluation for aggressive meningiomas.

Abstract BACKGROUND Bevacizumab is an anti-angiogenic monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) used in the treatment of various cancers including recurrent glioblastoma (rGBM) and is particularly useful in mitigating cerebral edema and radiation necrosis. Complications associated with bevacizumab that are of concern for patients requiring urgent surgical procedures include: impaired wound healing, increased bleeding risk and infection. Recent bevacizumab use (e.g. <28 days) is considered a contraindication to surgical procedures. Therapeutic plasma exchange (TPE) is a procedure that nonspecifically removes substances from plasma such as immunoglobulins. We reviewed our institutional experience with the use of TPE to remove bevacizumab for patients who required urgent neurosurgical intervention. METHODS Single center retrospective study from: 01/01/2022 to 12/31/2024 (first patient treated for this indication was in 2022). Inclusion criteria: patients who underwent perioperatively TPE to remove bevacizumab. Data collected from electronic medical record included age, gender, pertinent medical history, indication for bevacizumab and TPE for its removal, TPE procedure parameters, and clinical outcomes. RESULTS Four patients met study inclusion criteria, all were male. Three patients had a diagnosis of rGBM, one patient had a diagnosis of metastatic melanoma. All patients had received bevacizumab within 21 days of TPE (range 8-21). All subjects underwent 3 daily, 1 plasma volume TPE. Eleven of 12 procedures used the Fenwal Amicus® Separator. Neurosurgical outcomes were favorable. In one patient, bevacizumab levels measured by ELISA decreased from 1087.63 ng/mL to 145.35 ng/mL after the third procedure. No post-surgical wound complications (e.g., wound dehiscence, bleeding, infection) were observed in four patients requiring urgent neurosurgery despite recent administration of bevacizumab. CONCLUSIONS TPE was successful and well-tolerated by subjects in this study. Perioperative bevacizumab removal by TPE may be considered to reduce the risk of wound healing complications associated with bevacizumab.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2y) with symptomatic NF1-PN. In ReNeu, symptomatic improvement and PN volume reductions were observed at the earliest assessments (~91 and ~152 days, respectively) and were sustained. This analysis evaluated time to first onset and resolution of commonly reported TRAEs in the ReNeu trial. METHODS Data cutoff (DCO) was September 20, 2023. Median time to first onset and resolution (days) for common TRAEs (≥15%) were evaluated for prepubescents (≥2 to <12y, n=32), postpubescents (≥12 to <18y, n=24), younger adults (≥18 to ≤50y, n=48), and older adults (>50y, n=10). RESULTS Common TRAEs were mostly grades 1 to 2 (83%). In prepubescents, median day (range) of onset was 32 (14, 263) for vomiting, 71 (19, 386) for dermatitis acneiform, 123 (1, 663) for diarrhea, 124 (52, 775) for paronychia, and 127 (2, 663) for nausea. For postpubescents, median day (range) of onset was 8 (1, 438) for diarrhea, 8 (2, 574) for nausea, 12 (1, 252) for dermatitis acneiform, 28 (2, 354) for vomiting, and 110 (43, 245) for paronychia. In younger adults, median day (range) of onset was 5 (1, 352) for nausea, 8 (2, 15) for dermatitis acneiform, 9 (2, 73) for diarrhea, and 29 (1, 264) for vomiting. For older adults, median day (range) of onset was 4 (1, 286) for diarrhea, 9 (2, 15) for nausea, and 13 (2, 38) for dermatitis acneiform. Time to resolution was variable between TRAEs and among patients in all age groups; 90% resolved completely by DCO. Among all patients, 18 had a TRAE of asymptomatic ejection fraction decrease, with all but one resolving by DCO. CONCLUSIONS Overall, common TRAEs arose before treatment benefits and were generally resoluble by DCO. Proactively managing TRAEs may improve treatment experience and adherence.