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 .

ABSTRACT Background In glioblastoma, first‐line treatment can influence subsequent treatment lines. Therefore, progression‐free survival 2 (PFS2), the time from initial randomization to progression on subsequent treatment or death, may better predict overall survival (OS) compared to PFS. However, this association needs validation in glioblastoma, particularly with novel targeted agents in early clinical trials. Methods Medical records of glioblastoma patients from a multicentric Spanish cohort with genomic profiling treated between 2018 to 2023 were analyzed. Correlations between OS and PFS or PFS2 were calculated using an iterative multiple imputation approach and time‐to‐event endpoints with Kaplan–Meier methods. Results We analyzed 405 patients. Median OS, PFS, and PFS2 were 25.4, 8.7 and 16.4 months, respectively. Correlation between OS‐PFS was 0.69 (95% CI, 0.62–0.75), whilst for OS‐PFS2 it was 0.83 (95% CI, 0.78–0.87). In patients who received targeted therapy, OS‐PFS correlation was 0.51 (95% CI, 0.02–0.81), whilst for OS‐PFS2, it was 0.72 (95% CI, 0.30–0.91). For patients with ESCAT tier I‐II molecular targets, OS‐PFS correlation was 0.69 (95% CI, 0.26–0.89), weaker than OS‐PFS2 (0.83 [95% CI, 0.29–0.97]). PFS2 also performed better than PFS in ESCAT III‐IV patients (0.80 [95% CI, 0.75–0.85] vs. 0.69 [95% CI, 0.61–0.75]) and in those without targetable alterations (0.86 [95% CI, 0.74–0.92] vs. 0.68 [95% CI, 0.51–0.80]). Conclusions Progression‐free survival 2 (PFS2) is a more robust surrogate for OS than PFS in glioblastoma, including patients receiving targeted therapies or without actionable targets. These findings support adoption of PFS2 as a candidate surrogate endpoint in glioblastoma, offering a balance between trial feasibility and meaningful survival outcomes.

2041 Background: Patients (pts) with primary high-grade CNS tumors, especially those with glioblastoma (GBM), face poor clinical outcomes (GBM 5yr OS 5–10%). Seizure-related 6 homolog (SEZ6) is overexpressed in many tumor types, including primary CNS tumors. ABBV-706 is a SEZ6-targeting antibody-drug conjugate with topoisomerase 1-inhibitor payload that has shown a manageable safety profile in pts with small cell lung cancer. We present safety and efficacy data from a phase 1, FIH study evaluating ABBV-706 in pts with CNS tumors. Methods: This phase 1, FIH study (NCT05599984) enrolled pts ≥18 years with histologically/cytologically confirmed advanced relapsed/refractory GBM (IDH-wildtype, Grade [G] 4) or astrocytoma (IDH-mutant, G 3/4). Pts had ECOG performance score ≤1, and ≥1 measurable lesion per Response Assessment in Neuro-Oncology (RANO). Pts had prior surgical resection and progressed after receiving standard of care treatment. During dose escalation and expansion, pts received 1.3–3.5 mg/kg and 2.5 mg/kg ABBV-706, respectively. Treatment was every 3 weeks until disease progression or intolerable toxicity. Endpoints included safety and efficacy determined by RANO criteria. Results: As of Sep 27, 2025, 48 pts with primary CNS tumors (GBM, n=41; astrocytoma, n=6; missing indication, n=1) received ABBV-706 (1.3 mg/kg, n=1; 2.5 mg/kg, n=44; 3.0 mg/kg, n=1; 3.5 mg/kg, n=2). Among all pts, median age was 50 years (range 18–78), 58% were male, and the median number of prior lines of therapy was 2 (range 1–5). Median follow-up was 13.7 and 13.2 months for pts with GBM and astrocytoma, respectively. Treatment-related adverse events (TRAEs) were observed in 90% of pts. Most common toxicities were hematological (65%) and gastrointestinal (52%) events. G ≥3 TRAEs were observed in 60% of pts; most commonly anemia (40%). TRAEs led to treatment discontinuation, dose interruption, and dose reduction in 4%, 38%, and 27% of pts, respectively. No G 5 TRAEs were reported. One pt had pneumonitis (2.5 mg/kg, G 2). Among all pts, ORR was 8%, and 2 pts (4%) had a confirmed complete response. Efficacy data for GBM are shown in the Table. SEZ6 IHC expression was similar between GBM pts with (n=4) and without (n=31) an objective response. Conclusions: In pts with previously treated primary CNS tumors, ABBV-706 had a comparable safety profile to that observed in other tumors and showed encouraging antitumor activity. Clinical trial information: NCT05599984 . Efficacy of ABBV-706. a Pts with GBM2.5 mg/kg ABBV-706(n=41) BOR, n (%)CR b PR b SDPD b NE/not assessed 2 (5)4 (10)21 (51)9 (22)5 (12) ORR c , n (%), 95% CI 4 (10), 3–23 CBR, n (%), 95% CI>5 weeks>6 months 26 (63), 47–785 (12), 4–26 Median PFS, months (95% CI)Probability at 9 months, % (95% CI) 2.7 (2.3-5.4)10 (3-24) Median OS, months (95% CI)Probability at 12 months, % (95% CI) 6.4 (5.4–8.3)17 (6–33) a By investigator per RANO. b Including confirmed + preliminary. c Confirmed.

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.

Background: Glioblastoma IDH wild type (GBM IDH wt) has a poor prognosis and a strongly associated with inflammatory processes. Inflammatory molecules generate positive feedback with tumor cells fueling tumor growth as well as recruitment of immune cells that promote aggressiveness. Although the role of many inflammatory molecules is well known, there are many macromolecules, such as the S100A proteins, whose role is only now beginning to be established. Methods: Using RNA-seq, bioinformatics tools and a cohort of glioma patients to validate the results, we have analysed the inflammatory processes involved in glioma. Transcriptional profiles were also used to define biological processes of relevance to specific S100A proteins. Finally, we characterized the relevant immune populations with an IHC analysis and transcriptional profiling . Results: We have noted an increased expression of S100A in GBM IDH wt compared to gliomas IDH mutants. This allowed us to analyse the involvement of different members of the family, such as S100A9, A11 and A13 as possible regulators of inflammatory processes in the GBM-IDH wt microenvironment. Thus, we observed that S100A9 is located in hypoxic areas linked to the function of neutrophils, S100A11 is found in vascular areas associated with the function of perivascular pericytes and macrophages, and finally, S100A13 which is related to the dysfunction of microglia. Conclusion: Our findings define different functions for S100A9, A11 and A13 proteins that are associated with the architecture of the glioblastoma microenvironment and define its progression. Moreover, these alterations can be reversed by the RAGE inhibitor, Azeliragon which is in a phase I/II clinical trial NCT05635734.

Abstract INTRODUCTION The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral,brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Herein, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023). METHODS Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (aged ≥12 years; Karnofsky Performance Status, ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles. RESULTS Overall, 331 patients were randomized (median age, 40.0 years; oligodendroglioma, 172; astrocytoma, 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49) and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged. CONCLUSIONS Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.

The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60

Abstract INTRODUCTION The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Here, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023). METHODS Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (≥12 years; Karnofsky Performance Status ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles. RESULTS Overall, 331 patients were randomized (median age: 40.0 years; oligodendroglioma: 172; astrocytoma: 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49), and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged. CONCLUSIONS Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.

Background Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment.Methods We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response.Results We observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2Chigh-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association.Conclusions This study explored the role of neoplastic NKG2C/KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials.

To evaluate the impact of vorasidenib on health-related quality of life (HRQoL), neurocognition and seizure activity.

Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos ( P =0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos ( P =0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. Of the combined 205 patients, 57 (28

BACKGROUND:Glioblastoma (GBM) is a highly malignant brain tumor that affects men more often than women. In addition, the former shows a poorer survival prognosis. To date, the reason for this sex-specific aggressiveness remains unclear. Therefore, the aim of this study is to investigate tumor processes that explain these sex differences. METHODS:This was a retrospective study of GBM patients which was stratified according to sex. A cohort with 73 tumors was analyzed with immunohistochemistry, RNA-seq and RT-qPCR to characterize differences in vascular and immunological profiles. Transcriptomic profiling, gene set enrichment analysis, and pathway enrichment analysis were used for discovering molecular pathways predominant in each group. We further investigated the therapeutic effect of bevacizumab (vascular endothelial growth factor A (VEGFA) blocking antibody) in a retrospective GBM cohort (36 tumors) based on sex differences. RESULTS:We found that under hypoxic tumor conditions, 2 distinct tumor immuno-angiogenic ecosystems develop linked to sex differences and ESR1 expression is generated. One of these subgroups, which includes male patients with low ESR1 expression, is characterized by vascular fragility associated with the appearance of regions of necrosis and high inflammation (called necroinflamed tumors). This male-specific tumor subtype shows high inflammation related to myeloid-derived suppressor cells infiltration. Using this stratification, we identified a possible group of patients who could respond to bevacizumab (BVZ) and revealed a genetic signature that may find clinical applications as a predictor of those who may benefit most from this treatment. CONCLUSIONS:This study provides a stratification based on the sexual differences in GBM, which associates the poor prognosis with the presence of immunosuppressive myeloid cells in the necrotic areas. This new stratification could change the current prognosis of GBM and identifies those who respond to BVZ treatment.

Purpose After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. Methods Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. Results Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant ( p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different ( p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. Conclusion Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.