BACKGROUND AND OBJECTIVES:Molecularly defined oligodendrogliomas are rare tumors whose prognosis has improved over time because of more effective treatments. However, several aspects of management are still controversial, and studies with long-term follow-up are needed. The main aim of this study was to analyze and compare the natural history and management of patients with OG2 and OG3 and define which factors have the strongest effect on outcome. METHODS:We reviewed an institutional retrospective cohort (1996-2024) of patients with molecularly defined OG2 and OG3 according to World Health Organization 2021. We retrieved information on baseline clinical features, MRI characteristics (i.e., presence and pattern of contrast enhancement), extent of resection, initial treatment modalities after surgery, and management at progression. The relationships of these factors with progression-free survival (PFS) and overall survival (OS) were studied with univariate and multivariate analyses. RESULTS:Among 240 patients with IDH-mutant 1p/19q-codeleted oligodendrogliomas, grade 2 tumors were 149 (62.1%) and grade 3 were 91 (37.9%) with a median age of 42 and 44 years, respectively. Male/female ratio was 73/76 (49%/51%). Among patients with OG3, 70/91 (77%) exhibited a diffuse grade 3 histology (OG3d), whereas 21/91 (23%) had focal grade 3 areas only (OG3f). Overall, patients with OG2 and OG3 had similar median PFS (57.6 months, CI 53.2-61.9, vs 59.8 months, CI 41.9-77.6, p = 0.25), and prolonged median OS (274 months vs not reached). However, patients with OG3 exhibited a shorter time to radiotherapy at progression and their survival probability declined more rapidly within the first decade after surgery. The extent of resection was the only factor that significantly affected both PFS and OS in a multivariate analysis (for PFS, hazard ratio [HR] 0.90, 0.62-0.99, p = 0.026; for OS, HR 0.29, 0.13-0.79, p = 0.016), whereas tumor grade did not. Temozolomide alone as initial treatment of high-risk OG2 and OG3 with large residual tumor after surgery was not detrimental for survival. The same was true for observation in a small group of young patients with nonenhancing OG3 who have undergone complete resection and with only focal areas of malignancy (OG3f). DISCUSSION:This large retrospective cohort of IDH-mutant 1p/19q-codeleted oligodendrogliomas receiving standard treatments could serve as a benchmark for comparison with new IDH inhibitors in future clinical studies.

Background and ObjectivesMolecularly defined oligodendrogliomas are rare tumors whose prognosis has improved over time because of more effective treatments. However, several aspects of management are still controversial, and studies with long-term follow-up are needed. The main aim of this study was to analyze and compare the natural history and management of patients with OG2 and OG3 and define which factors have the strongest effect on outcome.MethodsWe reviewed an institutional retrospective cohort (1996-2024) of patients with molecularly defined OG2 and OG3 according to World Health Organization 2021. We retrieved information on baseline clinical features, MRI characteristics (i.e., presence and pattern of contrast enhancement), extent of resection, initial treatment modalities after surgery, and management at progression. The relationships of these factors with progression-free survival (PFS) and overall survival (OS) were studied with univariate and multivariate analyses.ResultsAmong 240 patients with IDH-mutant 1p/19q-codeleted oligodendrogliomas, grade 2 tumors were 149 (62.1%) and grade 3 were 91 (37.9%) with a median age of 42 and 44 years, respectively. Male/female ratio was 73/76 (49%/51%). Among patients with OG3, 70/91 (77%) exhibited a diffuse grade 3 histology (OG3d), whereas 21/91 (23%) had focal grade 3 areas only (OG3f). Overall, patients with OG2 and OG3 had similar median PFS (57.6 months, CI 53.2-61.9, vs 59.8 months, CI 41.9-77.6, p = 0.25), and prolonged median OS (274 months vs not reached). However, patients with OG3 exhibited a shorter time to radiotherapy at progression and their survival probability declined more rapidly within the first decade after surgery. The extent of resection was the only factor that significantly affected both PFS and OS in a multivariate analysis (for PFS, hazard ratio [HR] 0.90, 0.62-0.99, p = 0.026; for OS, HR 0.29, 0.13-0.79, p = 0.016), whereas tumor grade did not. Temozolomide alone as initial treatment of high-risk OG2 and OG3 with large residual tumor after surgery was not detrimental for survival. The same was true for observation in a small group of young patients with nonenhancing OG3 who have undergone complete resection and with only focal areas of malignancy (OG3f).DiscussionThis large retrospective cohort of IDH-mutant 1p/19q-codeleted oligodendrogliomas receiving standard treatments could serve as a benchmark for comparison with new IDH inhibitors in future clinical studies.

Gliomas are rare, aggressive CNS tumors with poor prognosis, and clinical trials are essential for access to novel therapies. We assessed cross-country disparities in glioma trial activity within the WHO European Region and compared patterns with lung cancer trials. We performed a cross-sectional search of ClinicalTrials.gov for glioma trials involving WHO European Region countries. Eight countries representing contrasting trial patterns were analyzed (France, Germany, Italy, Denmark, Poland, Hungary, Greece, Turkey). Trial access was standardized by estimated annual incident cases using country-specific incidence rates and population. Lung cancer trials were analyzed in parallel. Temporal trends and associations with gross national income (GNI) per capita and human development index (HDI) were also evaluated. Of 3,292 glioma trials registered globally, 1,058 involved at least one WHO European Region country; 640 included at least one selected country. France, Germany, and Italy had the highest trial volume and growth since 2004, whereas Turkey, Hungary, and Greece remained consistently low. After adjustment for estimated annual glioma cases, Denmark, France, and Germany showed the highest trial access. Glioma trial access correlated with GNI per capita (ρ = 0.76, p = 0.028) but not with HDI (ρ = 0.69, p = 0.058). Lung cancer trials were more numerous and showed no association with GNI per capita or HDI. Several countries demonstrated marked discordance, with minimal glioma trial activity despite considerable lung cancer trial volumes. Glioma clinical trial access across Europe is highly uneven in contrast to lung cancer trials. Targeted capacity-building strategies to promote equitable access to glioma research is needed.

BACKGROUND:No standardized method exists for seizure assessment in glioma clinical trials. We describe the development and evaluation of RANO-TREAT (Tumor Related Epilepsy Assessment Tool) for seizure assessment and its association with changes on brain MRI. METHODS:Patients with glioma/glioneuronal tumors and ≥ 1 prior seizure along with clinicians completed RANO-TREAT in conjunction with brain MRIs, yielding multiple RANO-TREAT scores at clinic visits over time. Unweighted (primary) and weighted (post-hoc) scores were correlated with disease progression via MRI in all patients and patients with IDHmt tumors, separately. Cohorts were randomly split by patient into cohort-specific training and validation sets. Weights for RANO-TREAT items were defined by multivariable generalized estimating equation models in cohort-specific training sets and validated in cohort-specific validation sets. A nomogram was developed using overall cohort training and validation sets. RESULTS:Four hundred and ninety patients (310 IDHmt tumors) had ≥ 1 visits and 285 patients (168 IDHmt tumors) had ≥ 2 visits. Unweighted RANO-TREAT scores (OR:1.01; 95%CI:0.998-1.02; P = .13) and score changes (OR:1.00; 95%CI:0.99-1.02; P = .63) were not associated with progressive disease on MRI. Post-hoc analysis using training and validation sets demonstrated weighted RANO-TREAT scores were correlated with progressive disease in both overall cohort validation set (OR:2.51; 95%CI:1.80-3.52; P < .0001) and IDHmt cohort validation set (OR:4.53; 95%CI:2.11-9.75; P = .0001). Weighted analyses for patients with ≥ 2 visits showed similar associations in validation sets. CONCLUSIONS:This prospective study suggests an association of seizure control evaluated by a new standardized tool with disease progression in glioma. This tool requires further systematic evaluation in glioma clinical trials alongside more traditional endpoints.

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 .

2043 Background: Grade 2 diffuse gliomas with isocitrate dehydrogenase 1/2 mutations (mIDH1/2) are incurable brain tumors with poor long-term prognosis and tumor-related symptoms, eg seizures, that negatively impact patients’ (pts) quality of life (QoL). Vorasidenib (VOR) is an oral, brain-penetrant, dual inhibitor of mIDH1/2 approved in >40 countries for treating grade 2 mIDH1/2 gliomas following the positive clinical outcomes, including tumor volume reduction, shown in the Phase 3 INDIGO study (NCT04164901). We investigated the effect of long-term VOR treatment on seizure activity and QoL in pts with mIDH1/2 glioma in INDIGO. Methods: Pts aged ≥12 years with grade 2 mIDH1/2 glioma, no prior glioma treatment other than surgery and with controlled seizures were randomized 1:1 to receive VOR 40 mg or placebo (PBO) daily. Data from the pre- and post-unblinding periods were used; PBO pts after crossover were excluded from the analyses. Exploratory analyses for the number of on-treatment seizures were conducted in pts with ≥1 seizure in the baseline or on-treatment periods using a negative binomial regression model. Seizure severity was self-reported (1 [not bad] to 10 [as bad as imaginable]). QoL was measured using the Functional Assessment of Cancer Therapy – Brain (FACT-Br) scale and FACT-Br brain cancer subscale (BrCS), and changes were estimated with time-to-event analysis. Results: During the study, 110/331 pts (33.2%) reported ≥1 seizure (VOR n=55; PBO n=55). VOR treatment showed a constant and sustained effect on seizure control, reflected by significantly lower seizure rates per person per year than in the PBO group (Table), and lower number and severity of seizures over time. In addition, in pts with a seizure burden (≥1 seizure), VOR significantly delayed time to first worsening of FACT-Br and FACT-Br BrCS scores (hazard ratio [95% confidence interval]: FACT-Br, 0.38 [0.15, 1.00], P =0.0435; FACT-Br BrCS, 0.32 [0.11, 0.91], P =0.0263). Conclusions: In pts with mIDH glioma and ≥1 on-study seizure, long-term VOR treatment generally led to a sustained decrease in seizure activity and severity and delayed worsening of QoL. These results suggest that VOR may have an additional benefit on QoL in pts who experience seizures. Clinical trial information: NCT04164901 . Exploratory analyses of VOR treatment and seizure rate in pts who reported ≥1 seizure in the baseline or on-treatment periods in INDIGO. VOR(n = 56) PBO(n = 56) Patients with ≥1 on-treatment seizure, n (%) 55 (98.2) 55 (98.2) Rate of on-treatment seizures per person-year* (95% CI) 13.2 (5.8, 29.8) 64.9 (26.5, 159.1) Ratio of rates: VOR vs PBO (95% CI) 0.20 (0.08, 0.52) Two-sided P value † 0.0008 *Estimated using negative binomial regression model adjusted by number of seizures and tumor size at baseline. † Not prespecified and not adjusted for multiplicity; should be interpreted with caution. Data cut-off: January 17, 2025. CI, confidence interval; PBO, placebo; VOR, vorasidenib.

Intracranial metastases (ICM), specifically parenchymal brain metastases, remain a major clinical challenge in solid tumor oncology, despite recent advances in cancer therapies which have led to improvements in survival for these patients. Improving outcomes even further in this patient population will require a multi-disciplinary approach, including pre-clinical and translational studies, clinical trials, and studies of patient reported outcomes and quality of life. At the 2023 and 2024 joint Society for Neuro-Oncology (SNO) and American Society of Clinical Oncology (ASCO) CNS Metastases Conferences, two ICM collaborative group think tanks convened, composed of diverse, multi-disciplinary stakeholders, including basic and translational researchers, clinical trialists, and clinicians from academia and the community setting. Here we summarize the key knowledge gaps and consensus recommendations put forth by these two think tanks. Advances in ICM research and improvements in patient outcomes will require close inter-specialty and inter-institutional collaboration between stakeholders, including pre-clinical and translational researchers, clinical investigators, industry, and regulatory bodies.

TIMP1 mediates brain metastasis in a CD8+ T cell-dependent manner. Supplementary Figure 5 shows additional data corresponding to Figure 4.

Overall survival according to TIMP1 in the CSF. Overall survival of brain metastasis patients with different primary tumors according to their levels of TIMP1 in the cerebrospinal fluid (CSF). The table contains information corresponding to Supplementary Figure 9B.

TIMP1 is a downstream target of STAT3 in brain metastasis-associated astrocytes. Supplementary Figure 3 shows additional data corresponding to Figure 3.

TIMP1 levels from ELISA applied to CSF from patient samples. Levels of TIMP1 in the blood or in the cerebrospinal fluid (CSF) of non-cancer patients and brain metastasis patients from different primary tumors. Immune Cluster is shown for patients in Figure 7N. The table contains information corresponding to Figure 7L, 7N and Supplementary Figure 9A,C-D.

TIMP1 through CD63 alters relevant properties of CD8+ T cells. Supplementary Figure 6 shows additional data corresponding to Figure 6.

DEG cluster 3 brain metastasis-associated astrocytes. Differentially expressed genes (DEGs) found in cluster number 3 of brain metastasis associated-astrocytes. Significantly deregulated genes are highlighted. Red indicates upregulation and green indicates downregulation respect to tumor free condition. The table contains information corresponding to Figure 1D.

Phosphoproteomic analysis of CD8+ T cells incubated with astrospheres conditioned medium. Results from phosphopeptides quantification of the LC-MS/MS analysis of CD8+ lymphocytes incubated with pSTAT3- (D1) and wt (D2) or cKOGFAP-Timp1 (D2KO) pSTAT3+ astrospheres conditioned medium. The table contains information corresponding to Figure 6K and Supplementary Figure 7A.

Statistics of multiple experimental arms from in vivo immunotherapy experiments. Unpaired two-tailed Student’s t-test of different comparisons between the following experimental conditions: IgG2, silibinin and immune checkpoint blockade (ICB) (Anti-PD1 plus Anti-CTLA4) alone or in combination with silibinin in mice intracardially injected with B16/F10-BrM cells. Unpaired two-tailed Student’s t-test of different comparisons between the following experimental conditions: IgG2, cKOGFAP-Timp1 and immune checkpoint blockade (ICB) (Anti-PD1 plus Anti-CTLA4) alone or in combination in mice intracardially injected with E0771-BrM cells. The table contains information corresponding to Figure 7C and Supplementary Figure 8L.

Human brain metastases evaluated for pERK1/2 regarding their immune cluster. Information regarding multiplex of immune cells in human brain metastasis samples used for assessing pERK1/2 status in CD8+ T cells. The table contains information corresponding to Figure 6M.

BACKGROUND:A high pSTAT3 expression in reactive astrocytes surrounding brain metastases (BrM) promotes tumor growth in preclinical models. The impact of STAT3 expression on outcome of patients with BrM from breast cancer is unknown. METHODS:The expression of pSTAT3 in reactive astrocytes of 100 resected BrM from breast cancer was investigated by immunohistochemistry and correlated with molecular subtypes, risk of intracranial recurrence and progression-free survival. To explore whether clinical findings could be replicated in preclinical models, we used two human BrM cell lines (triple-negative MDA231 and HER2-positive HCC1954-), and evaluated pSTAT3 expression on established BrM. RESULTS:High pSTAT3 expression in reactive astrocytes was detected in 57% of BrM, and prevailed in triple-negative (80.9%) over HER2-positive (43.2%) and luminal (33.3%) metastases (P = .002). A different pSTAT3 expression was confirmed in animal models: as it was detected in 50% of reactive astrocytes in triple-negative MDA231 BrM lesions compared with 13% in HER2-positive HCC1954-BrM lesions (P = .0001). Patients with high pSTAT3 expression in BrM displayed higher intracranial recurrence rate (66.7 vs 33.3%) (P = .0353), and shorter intracranial PFS (9 months vs 28 months) (P = .0002), and this finding was significant for triple-negative patients only (P = .0008). CONCLUSIONS:This study indicates that STAT3 expression prevails in reactive astrocytes surrounding triple-negative BrM in comparison to HER2-positive and luminal BrM, and these findings mirror those observed in animal models. A high STAT3 expression correlates with higher risk of intracranial recurrence and shorter progression-free survival, particularly in patients with triple-negative BrM.

TIMP1 binding to CD63 modulates kinase signaling in CD8+ T cells. Supplementary Figure 7 shows additional data corresponding to Figure 6.