Caron, Samantha

Abstract Purpose Bevacizumab is an effective treatment for radiation necrosis; dose dependent radiographic and edema response data are lacking. Methods Multicenter, retrospective cohort study of adult patients with primary central nervous system tumors or brain metastases who received bevacizumab for radiation necrosis between June 2021 and July 2024. Patients were grouped by bevacizumab dose (7.5 mg/kg vs 10 mg/kg administered every three weeks). Primary outcome was edema response, assessed by a blinded neuro-oncologist. Secondary outcomes included contrast enhancing disease response, clinical response, adverse events, treatment discontinuation, and re-dosing for recurrent radiation necrosis. Analyses were performed with and without adjustment for tumor type. Results 104 patients were included (7.5 mg/kg, n = 53; 10 mg/kg, n = 51). Edema response differed between dosing groups in unadjusted analyses (p = 0.032), favoring the 7.5 mg/kg cohort; however, this association was attenuated after adjustment for tumor type. Contrast enhancing disease response did not differ between groups in either unadjusted or adjusted analyses (p = 0.43). Clinical response was higher in the 7.5 mg/kg group (65.2% vs 37.8%, p = 0.013). Tumor type differed significantly between cohorts (p < 0.001), with more primary CNS tumors in the 10 mg/kg group. Rates of adverse events, treatment discontinuation, and re-dosing were similar. Conclusions While lower-dose bevacizumab was associated with greater edema reduction in unadjusted analyses, this effect was attenuated after accounting for tumor type. Importantly, 7.5 mg/kg dosing appeared sufficient for achieving edema control and contrast enhancing disease response. These findings support an individualized approach to bevacizumab dosing in radiation necrosis and highlight the need for prospective, tumor-stratified studies.

Abstract Background Peritumoral brain edema (PTBE) is a frequent complication of CNS tumors and radiation therapy (RT). PTBE is primarily treated with corticosteroids, but prolonged use is associated with severe toxicities including myopathy and immunosuppression. Bevacizumab, an alternative treatment, is not recommended in patients with thromboembolic events and intracerebral hemorrhage. Plasma kallikrein is a key driver of tumor-related edema. By targeting this pathogenic enzyme, the orally delivered inhibitor, RZ402, may provide therapeutic value by controlling edema and decreasing corticosteroid use. Methods In this single-patient investigational new drug protocol, we report results from use of RZ402 for treatment of cerebral edema related to metastatic melanoma and RT. Results A 74-year-old man with BRAF-wildtype melanoma had a right frontal and basal ganglia hemorrhagic metastasis not amenable to resection, treated with stereotactic RT (30 Gy, 5 fractions), followed by ipilimumab and nivolumab. MRI obtained 5 months after RT showed increased edema associated with midline shift. After 12 weeks of treatment with high-dose dexamethasone (16 mg daily), edema remained persistent and patient was unable to tolerate dose reduction below 4 mg daily. Course was complicated by a pulmonary embolus prompting initiation of anticoagulation, leading to deferral of bevacizumab. Patient was treated with RZ402, which was tolerated well with no reported toxicities. Dexamethasone was discontinued over 4 weeks. Follow up imaging 6 weeks after RZ402 initiation and off dexamethasone demonstrated stability without rebound edema. Patient did experience adrenal insufficiency characterized by severe fatigue, managed with low-dose prednisone. RZ402 was discontinued after 8 weeks of treatment with patient remaining clinically stable. Conclusion Despite persistent edema after prolonged use of corticosteroids, the selective plasma kallikrein inhibitor RZ402 was associated with radiographic stabilization and discontinuation of dexamethasone for this patient. These findings support prospective evaluation of RZ402 in treatment of symptomatic cerebral edema related to CNS tumors.

Abstract Background Isocitrate dehydrogenase-1 (IDH-1) inhibitor ivosidenib and dual-IDH1/2 inhibitor vorasidenib have demonstrated clinical activity in the treatment of IDH-mutant gliomas. We evaluated the efficacy of vorasidenib in patients with prior exposure to ivosidenib. Methods Retrospective review of patients with IDH-mutant glioma treated with vorasidenib who had prior treatment with ivosidenib. Previous treatments, radiographic response, and adverse events were collected and analyzed descriptively. Results Twenty-nine patients (median age 42, 34% female) were evaluated. Tumor types included IDH-mutant astrocytoma (grade 2 n = 9, 31%; grade 3 n = 3, 10%; grade 4 n = 3, 10%) and oligodendroglioma (grade 2 n = 10, 34%; grade 3 n = 4, 14%). Treatments received prior to ivosidenib included surgical resection (n = 23, 79%), radiation (n = 16, 55%), temozolomide (n = 15, 52%), procarbazine, lomustine, vincristine (PCV, n = 2, 7%), bevacizumab (n = 3, 10%), lomustine (n = 2, 7%), and pembrolizumab (n = 1, 3%). Four patients received additional treatment in between ivosidenib and vorasidenib treatment. Ten of 16 (63%) patients who experienced disease progression on ivosidenib achieved stable disease and remain on vorasidenib, while 6 (37%) had continued progression. Eleven patients with stable disease on ivosidenib transitioned to vorasidenib following FDA approval and remained without progression. Two patients who transitioned to vorasidenib due to ivosidenib-related adverse effects (diarrhea and fatigue) experienced symptom resolution and maintained disease stability. Conclusions Vorasidenib demonstrated clinical efficacy in patients with IDH-mutant gliomas previously treated with ivosidenib. Notably, stable patients who transitioned maintained disease stability, while some of those with progressive disease achieved stabilization with vorasidenib. These findings support vorasidenib as a viable therapeutic option following ivosidenib exposure.

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 &gt; 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 Tovorafenib is a type II rapidly accelerated fibrosarcoma (RAF) kinase inhibitor approved by the FDA in 2024 for relapsing or chemotherapy-refractory pediatric low-grade gliomas with mutations or alterations in the gene BRAF. There is potential for the use of this drug outside the pediatric population. We present a single institution case series of adults with CNS tumors with mutations or alterations in BRAF treated (off-label) with tovorafenib. METHODS Chart review. RESULTS 8 adult (age &gt;18) patients were treated with tovorafenib at our institution between March 2024 and June 2025. Age range was 21-66 years old (median age 42). The population included 5 males and 3 females. Indications for treatment were pilocytic astrocytoma (n = 2), high grade astrocytoma with piloid features (HGAP) (n = 2), Erdheim-Chester disease (n = 2), pleomorphic xanthoastrocytoma (n = 1), and otherwise unclassified low-grade glioma (n = 1). All patients had mutations or alterations in BRAF including KIAA1549 fusion (n = 4), V600E mutation (n = 3), or GAB2 fusion (n = 1). Radiographic response to therapy was seen in 5/8 patients with 3 cases of radiographic stability (though one patient later progressed) and 2 cases of decrease in tumor size (in a pilocytic astrocytoma and in an HGAP). Both cases of decreased tumor size after treatment were in tumors with KIAA1549 fusions. Adverse effects of tovorafenib included fatigue (n=2), headache, myalgias, diplopia, cytopenias, and transaminitis (n=1). 3/8 patients had to pause or stop treatment due to adverse effects (intolerable headache, cytopenias, and transaminitis respectively). CONCLUSION Tovorafenib is a promising new treatment for CNS tumors with BRAF mutations or alterations. Our single institution case series suggests the efficacy of this drug for multiple tumor types in adults. Certain tumor subtypes such as KIAA1549 fusions may be more likely to benefit from this treatment.

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 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 (&gt;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.

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by development of multiple neoplasms, including central nervous system (CNS) hemangioblastomas, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and retinal hemangioblastomas. Belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, has demonstrated efficacy in treating VHL-associated tumors. This study evaluates our institutional experience with belzutifan in patients with VHL-related tumors. MATERIAL AND METHODS We conducted a retrospective cohort study across three Mayo Clinic sites, including patients aged ≥18 years with genetically confirmed VHL disease who received belzutifan between October 2021 and March 2025. Clinical/radiological data, and adverse events (AEs) were extracted from electronic health records. Tumor responses were assessed using RECIST v1.1 criteria for RCC, pNET, CNS hemangioblastoma. Retinal hemangioblastoma responses were evaluated through ophthalmologic assessments. RESULTS Forty-five patients were included (median age 44 58% female). Sixty-seven percent had RCC, 91% had CNS hemangioblastomas, 53% had pNETs, and 62% had retinal hemangioblastomas. The median duration of belzutifan therapy was 22.6 months (range 1.0-41.4 months). Among patients with RCC (n=26), overall response rate (ORR) was 19% and median time to best response (MTBR) was 7.4 months. Five patients had partial response (PR), 15 had stable disease (SD), and 1 had progressive disease (PD). For CNS hemangioblastomas (n=41), ORR was 12%, MTBR was 6.2 months. 5 patients had PR, 30 had SD, and none had PD. For pNET (n=17), ORR was 41%, MTBR was 8.2 months. One patient had CR, 6 patients had PR, 6 had SD, none had PD. For retinal hemangioblastomas (n=28), 6 (21%) showed improvement, 9 (32%) remained stable, and 3 (11%) showed progression. MTBR was 6.7 months. Treatment-related AEs occurred in 98% of patients. Common AEs included anemia (89%), fatigue (80%), hypoxia (18%), and headache (13%). Grade 3 AEs were observed in 20% of patients, including anemia (7%), hypoxia (9%), fatigue (4%), pneumonitis (2%), loss of consciousness (2%). One patient experienced a grade 4 event (status epilepticus). Anemia management involved iron supplementation (n=11), RBC transfusion (n=3), dose reduction (n=2), treatment holiday (n=8), permanent discontinuation (n=1). Hypoxia management included dose reduction (n=1), treatment holiday (n=3), discontinuation (n=1). CONCLUSION Belzutifan shows clinical activity across various VHL-associated neoplasms in real-world practice, with a manageable safety profile. The lower ORR compared to the phase III trial may reflect differences in baseline disease, including lower tumor burden in our cohort. These findings support its continued use in VHL disease, with attention to monitoring and managing treatment-related AEs.

e13893 Background: For individuals with CNS tumors who have experience difficulties with in-person (IP) evaluations due to disease-related neurologic disability or the costs associated with travel, telehealth (TH) offers a convenient and timely alternative for accessing specialized neuro-oncology care. We report our institution’s experience with telehealth utilization in neuro-oncology. Methods: We conducted a retrospective review of patients who had at least one neuro-oncology telehealth visit between August 2021 and May 2024 at Mayo Clinic in Rochester, Minnesota. Reasons for visits, outcomes of appointments, acute care utilization following visits was reviewed. Results: A total of 660 patients who had at least one TH visit between August 2021 and May 2024 were included in the analysis. Median age was 56 (range 20-98), 49% were female, and 92% were white. Most patients resided in the US Midwest (84%), followed by the South (8%), West (5%), Northeast (1%), and US Territories (< 1%). Less than two percent were international patients. The most common primary visit diagnosis was glioblastoma (GBM, 26%), followed by astrocytoma, IDH-mutant (17%), meningioma (17%), oligodendroglioma, IDH-mutant, 1p/19q codeleted (7%). Of 6657 visits reviewed, 2745 (41%) were conducted via TH. Telehealth visits served various purposes, including consultation for newly diagnosed tumors or abnormal MRIs (n = 26), second opinion for an established tumor diagnosis (n = 119), discussion about clinical trial participation (n = 108), tumor-related treatment discussions (n = 719), chemotherapy education (n = 161), new symptom assessment (n = 117), symptom management (n = 366), and tumor surveillance (n = 1694). Outcomes from telehealth visits included enrollment in clinical trials (n = 28), proceeding with tumor-directed surgery (n = 46), initiation of radiation therapy (n = 88), starting or changing systemic therapy (n = 377), continuing existing systemic therapy (n = 932), transition to supportive care (n = 45), tumor diagnostic workup (n = 28), continuation of tumor surveillance (n = 1254). Acute care utilization, defined as an emergency department visit or hospitalization within one month of an appointment, was the same following telehealth visits compared to in-person visits (6.9% for IP vs 5% for TH, p = 0.507). Conclusions: Our findings demonstrate that telehealth can effectively support all aspects of neuro-oncology care, ranging from initial diagnosis discussions to systemic therapy management and transitions to supportive care. Telehealth offers a convenient and accessible method of care delivery option for patients faced with neurologic illness. Additionally, THs do not lead to increased acute care utilization compared to IP evaluations.

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.