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Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized MRI examinations, which, in the absence of new symptoms or signs, are usually scheduled every 2–3 months. Here, we hypothesized that changes in daily activity are associated with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of 6 patients with GBM wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with 1-minute resolution. After tumor resection and radiation, daily activity declined in 2 patients 19 and 55 days before detection of progression by MRI but did not change for the 4 patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.

Abstract BACKGROUND Poly(ADP-ribose) polymerase inhibitors (PARPi), initially developed for BRCA-mutant tumors, are now being explored in gliomas to target DNA repair defects. In this retrospective analysis, we report our institutional experience using PARPi with temozolomide for glioma treatment. METHODS The medical record was retrospectively reviewed at our institution for neuro-oncology patients treated with off-label PARPi combined with temozolomide for > 1 month between 1/1/2010 and 5/1/2025. RESULTS Nineteen patients (median age 45, 47% female) were included. PARPi included olaparib (n = 18) and niraparib (n = 1). Tumor types were glioblastoma (GBM, n = 7), Grade 4 IDH-mutant astrocytoma (G4A, n = 4), Grade 3 astrocytoma (G3A, n = 2), Grade 3 oligodendroglioma (G3O, n = 3), Grade 2 oligodendroglioma (G2O, n = 2), and IDH1-mutant brainstem glioma (BG, n = 1; IDH status determined per CSF 2-hydroxyglutarate without surgically confirmed histologic subtyping). Patients were heavily pre-treated. One patient lost to follow-up was censored at last contact. Patients had KPS ≥ 70 in all but one case (KPS 60) and multiple prior progressions (treatment was initiated at 4th recurrence or higher in 16/19 patients). Median time from drug initiation to progression, drug initiation to death, and overall survival were as follows (months): GBM (3.0, 6.5, 34.9), G4A (1.4, 3.9, 80.3), G3A (3.4, 4.2, 83.3), G3O (3.8, 17.2, 121.2), G2O (3.0, 3.5, 159.9), BG (4, 5.5, 164.8). CONCLUSIONS This retrospective analysis supports the tolerability of combining PARPi with temozolomide in a real-world, heavily pretreated glioma population. Despite limited evidence of durable tumor control, the regimen provided transient disease stability in patients with few remaining options. These findings may inform treatment in compassionate or salvage settings particularly when alkylator treatment is considered, and highlight the need for prospective trials to identify response biomarkers and assess clinical utility.

Abstract BACKGROUND The IDH inhibitor vorasidenib was FDA-approved for treatment of IDH-mutant grade 2 gliomas in August 2024. We evaluated vorasidenib in patients with grade 3 and 4 IDH-mutant gliomas who would not have been eligible for the INDIGO trial. METHODS Retrospective review of patients with grade 3 or 4 IDH-mutant gliomas treated with vorasidenib between 9/1/24 and 5/31/25. Prior treatments, radiographic response, adverse events and seizure control were collected for each patient. RESULTS Thirty-two patients (median age 39.5, 46.9% female) met inclusion criteria. Tumor types included grade 3 oligodendroglioma (11, 34.4%), grade 3 astrocytoma (13, 40.6%) and grade 4 astrocytoma (8, 25%). Thirty patients had contrast-enhancement; 2 patients had non-enhancing tumor. Prior treatments included surgical resection (30, 93.8%), radiation (27, 84.4%), cytotoxic chemotherapy (25, 78.1%), bevacizumab (5, 15.6%), pembrolizumab (3, 9.4%), and ivosidenib (8, 25%). Four patients (12.5%) were naïve to systemic treatment at the time of vorasidenib initiation. Median duration of vorasidenib was 101.5 days (range 18-255) with 19 patients still on vorasidenib at the time of last follow-up. Seventeen patients (53.1%) had stable disease, 11 (34.4%) had progressive disease, 2 (6.3%) did not yet have response assessment, and 2 (6.3%) died. Grade 1 transaminitis occurred in 12 patients with no high grade transaminitis. Two patients developed lymphopenia; both were heavily pre-treated with multiple alkylating agents; no other hematologic toxicity was noted. One patient developed myalgias leading to vorasidenib discontinuation. Nine patients had fatigue, 4 headaches, 2 nausea, 2 decreased appetite. In patients with a history of epilepsy, there were no reported seizures. CONCLUSIONS Vorasidenib was well-tolerated in this heavily pre-treated cohort of grade 3–4 IDH-mutant gliomas, with low-grade transaminitis and fatigue being the most common toxicities. Preliminary results show disease stability in 53.1% of patients after a median of 3.5 months. Conclusions are limited by short-interval follow-up.

Abstract BACKGROUND High grade astrocytoma with piloid features (HGAP) is a newly recognized tumor with a distinct DNA methylation profile. Its clinical course, treatment response, and outcomes remain poorly understood. METHODS We conducted a retrospective cohort study across three Mayo Clinic sites including adults with a HGAP diagnosis confirmed by DNA methylation profiling. RESULTS 17 patients were included (median age 38 years, Q1, Q3: 29–59; 9 male). DNA methylation-based tumor classification using the NCI/Bethesda classifier (v2) indicated a match to HGAP with high confidence (calibrated score >0.9) in 14 cases and was suggestive in 3 cases. All had MAPK pathway alterations (NF-1 mutation in 11, FGFR1 mutation in 2, KIAA1549::BRAF fusion in 2, FGFR1 transcript variant suggestive of internal tandem duplication in 1, KANK2::NTRK2 fusion in 1). All tumors also had CDKN2A/B homozygous deletion and 9 lost ATRX expression. Tumors were infratentorial (n=8), supratentorial (n=7), and spinal (n=2) at initial presentation. First line treatment included surgery followed by chemoradiation with temozolomide (n=12), surgery followed by radiation (n=4), radiation alone (n=1), and surgery alone (n=1). Gross total resection was achieved in 3/17, 8/17 had subtotal resection and 5/17 had biopsy. 14/17 received a median RT dose of 5700 cGy (range, 4005–6000) in 30 fractions. The median follow-up duration was 34.9 months. 8 patients experienced disease progression. The median progression-free survival (mPFS) was 30.3 months (95% CI: 15.4–NR). 6/8 underwent surgery; 3/8 underwent RT. Systemic therapies were administered in 5/8 (lomustine, bevacizumab, pembrolizumab, temozolomide, trametinib, tovorafenib). 3/17 patients died due to progressive disease with an OS of 54.2, 94.6 and 17.4 months, respectively. The mOS for the whole cohort was 54.2 months (95% CI: 54.2-NR). CONCLUSION While the optimal management of this newly recognized entity has yet to be established, our cohort demonstrates a clinical behavior consistent with CNS WHO grade 3, aligning with current WHO interpretations.

Abstract BACKGROUND The Response Assessment in Neuro-Oncology (RANO) was recently updated to RANO 2.0, which no longer requires follow-up imaging to confirm progression in recurrent glioma patients recieving immunotherapy, as previously recommended by iRANO. This study evaluates the utility of RANO 2.0 to determine whether radiographic progression on initial post-treatment MRI is sufficient to guide timely discontinuation of ineffective therapy. METHODS This retrospective study, conducted at Mayo Clinic, included patients ≥18 years receiving ≥2 cycles of off-label pembrolizumab for recurrent glioma between 1/1/2014 – 5/1/2025. Radiographic response was assessed using the first MRI performed ≥30 days after pembrolizumab initiation. Progression was defined as a ≥25% increase in the product of perpendicular diameters of the lesion, clear progression of non-measurable disease, new lesion appearance, clinical deterioration, or death. For suspected pseudo-progression, sequential MRIs were reviewed; if progression was confirmed, the original date was used. RESULTS Sixty-two patients were included (mean age: 46.1 years; 64.5% male), receiving pembrolizumab for a median duration of 2.8 (1.4 – 19.4) months. Median time to initial radiographic response assessment was 1.6 (1.1 – 3.5) months, and progression-free survival was 2.3 (0.7 – 15.2) months. Thirty-seven (59.7%) patients were identified with progression at initial evaluation. Among them, 11 were initially suspected of pseudo-progression, and continued pembrolizumab: 3 received additional radiation, 2 initiated bevacizumab, while 6 remained on their prior regimens [pembrolizumab only (3); pembrolizumab with bevacizumab (3)]. However, all were subsequently confirmed to have true progression, with a median delay of 1.4 (0.7 – 7.1) months until pembrolizumab discontinuation. No true pseudo-progression cases were observed. CONCLUSIONS Our findings support the clinical applicability of RANO 2.0 in recurrent glioma patients receiving pembrolizumab. Initial radiographic progression reliably predicted true progression, suggesting limited value in confirmatory follow-up imaging. Early recognition of treatment failure may reduce delays in initiating salvage therapies, along with associated toxicity and cost.

Abstract Despite intensive research over the past two decades, all glioblastoma (GBM) Phase 3 drug trials have been negative. The utility of the preclinical studies used to inform development for 10 Phase 3 trials was evaluated by four criteria: 1) drug distribution to the brain, 2) tumor location (flank vs. intracranial), 3) GBM xenograft source (patient-derived (PD) vs. cell line-derived (CD)), and 4) magnitude of survival extension. For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%. B/P for imatinib was 1-3% and the other four drugs ranged from 25% to 51%. Except for enzastaurin, all drugs were studied in orthotopic tumor survival studies. The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide. However, only veliparib and sunitinib were studied in orthotopic PD models, and a single CD model (U87 or D54) was used exclusively for four drugs (enzastaurin, nimotuzumab, sunitinib, marizomib). In summary, 6 of 10 drugs had unknown or very poor brain distribution, 8 of 10 drugs were tested exclusively in CD models, which have questionable translational value, and 3 of 10 drugs had nominal activity (<50% survival prolongation) in preclinical survival studies. The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into advanced clinical testing.

Abstract BACKGROUND Cognitive symptoms are common among cancer patients treated with intracranial radiation but inadequately assessed and suboptimally treated, owing in part to the time-consuming and resource-intensive nature of formal neuropsychological testing. Through remote administration of brief cognitive assessments and symptom-directed interventions, decentralization uniquely addresses this problem. METHODS In this single-site phase 2 fully decentralized clinical trial (NCT06377696), patients treated with radiation therapy (RT) for primary or metastatic brain tumors undergo cognitive evaluations with the application, Mayo Test Drive, and the Short Test of Mental Status (STMS; via telehealth or in person), at baseline and every three months for one year. Participants are provided wearable devices for health promotion. Half the participants are randomized to metformin to evaluate this agent’s efficacy in treating RT-related cognitive symptoms. Target enrollment is 100 participants. RESULTS Seventy-three patients (median age 45.5, 46% female) with brain tumors who received RT were enrolled May 2024 to May 2025. In this unplanned interim analysis, we evaluated the impact of decentralization on study participation. Thirty-six participants (49%) reported a primary residence greater than 150 miles from our institution. Seven patients were consented remotely, the remainder in person. Of 380 study-related visits (201 STMS, 179 treatment toxicity checks) 216 (57%) were completed by telehealth. Thirty-two of 336 (9.5%) study-related lab draws were completed at locations outside our institution. Wearable device data was continuously collected, with median 3022 steps tracked per patient per day on study. 190/250 (76%) quality-of-life surveys sent digitally were completed to date. CONCLUSION Decentralization implemented as part of this clinical trial enabled participation despite significant distance from our institution and facilitated study-related assessments through digital solutions, eliminating the need for travel. Our findings demonstrate the feasibility of conducting a fully decentralized supportive care trial in neuro-oncology, which can increase participation and accelerate evaluation of novel therapeutics.

Abstract BACKGROUND Access to in-person evaluations is challenging for patients with glioma due to disease-related disability and distance from specialized neuro-oncology centers. Telehealth is an alternative to in-person evaluations, but acceptability of and therapy compliance with this model has not been prospectively evaluated. METHODS In this single-arm non-randomized pragmatic clinical trial, we compared patient satisfaction with telehealth and in-person assessments among patients with glioma undergoing chemotherapy with temozolomide. Participants acted as their own controls, alternating between telehealth and in-person visits. Patient satisfaction with care delivered was evaluated by Press-Ganey surveys with Likert response scales (1-5, 1=very poor, 5=very good). A digital pill diary (DPD) was implemented to track chemotherapy compliance. RESULTS We accrued 30 patients (median age 59, 38% female) between October 2024 and May 2025. Half of the patients (n=15) reported a primary residence greater than 150 miles from our institution. Surveys from 25 participants were reviewed, with 17/25 completing one or more surveys following an in-person visit, and 21/25 completing one or more surveys following a telehealth visit. Overall average Press-Ganey scores were similar between the two visit modalities with high scores (telehealth=4.8; in-person=4.7). Median scores for specific modalities were similarly highly rated: likelihood of recommending practice to others (telehealth=5.0; in-person=5.0), concern the care provider showed (telehealth=5.0, in-person=4.7), provider’s discussion of treatment options (telehealth=5.0, in-person=5.0), provider effort to include patients in decision-making (telehealth=5.0, in-person=5.0). DPDs used to monitor treatment compliance indicated adherence to all prescribed doses of temozolomide in 75/79 cycles; the other 4 (of 79) treatment cycles were halted per provider instructions. CONCLUSION This interim assessment demonstrates feasibility of treating patients with similar patient satisfaction of care delivered between telehealth and in-person visits. The DPD was effective in tracking chemotherapy administration. Additional results including visit type preference and acute care utilization data are maturing.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and glioblastoma (GBM). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent GBM and NSCLC. After determining the maximum tolerated dose, adults with recurrent GBM were treated in two expansion cohorts: (a) non-surgical cohort (6/12 patients thus far): EGFRvIII mutation, first recurrence; food-effect study included (b) surgical cohort (6/6 patients), any EGFR mutation, any recurrence; window-of-opportunity study (WOO) included. Among these 12 patients, median age = 60 years; 50% female; 58% ECOG 0). All patients received prior radiation and temozolomide. After the WOO or food-effect study, patients were dosed at 120 mg BID (5 days on, 2 days off), and escalated to 160 mg BID (5 days on, 2 days off) based on tolerability. Common adverse events (>40%) are comparable to other EGFR inhibitors (acneiform rash, diarrhea, fatigue, xerosis, pruritis). Treatment-related grade 3+ adverse events were limited to lymphopenia (n = 1). WSD0922-Fu exposure in the fed state exceeded the fasted state (median plasma Cmax and AUC0-24h are 1.6x and 1.3x, respectively) with a delayed Tmax (6.0 vs 1.8 hours). For the WOO, time between last dose administered to tumor collection ranged between 4 - 13.5 hours. Median tumor WSD0922-Fu concentration was 0.76 µg/g; estimated median unbound tumor concentration was 24.9 ng/g and within expectations for pharmacodynamic effect. Median brain/plasma ratio = 0.59; median unbound brain/unbound plasma = 0.88. Enrollment to the non-surgical cohort is ongoing, so formal efficacy data remain immature. However, examples of clinical efficacy will be shown along with data on recurrence patterns. Phase 2 clinical trial development is in progress.