Galanis, E.

Abstract Background Meningiomas lack effective therapies for recurrent or aggressive disease. NF2 inactivation, commonly in meningioma, may sensitize tumors to FAK inhibition and interact with MAPK signaling. This study investigated the therapeutic activity of defactinib (FAK inhibitor) and avutometinib (RAF/MEK inhibitor) alone and in combination in preclinical meningioma models. Methods MAPK-altered meningioma cell lines, IOMM-Lee (NF2 wild-type, BRAF p.V600E) and CH157-MN (NF2 mutant, NRAS p.Q61K), BenMen-1 (NF2 mutant, MAPK wild-type), and three patient-derived NF2 mutant cell lines were cultured in matrigel and treated with defactinib and avutometinib in 3D cell viability assays. In vivo, flank and intracranial xenograft models of IOMM-Lee and CH157-MN were treated with VS-4718 (FAK inhibitor, superior pharmokinetics in mice), avutometinib, or combination. Tumor growth, survival, and pharmacokinetic/pharmacodynamic properties were assessed. Results In vitro, combination therapy showed synergistic or additive effects in CH157-MN and IOMM-Lee cells, respectively. Defactinib alone demonstrated activity in NF2-mutant patient-derived and BenMen-1 cells, while avutometinib did not. In vivo, avutometinib monotherapy suppressed tumor growth and extended survival in both flank and intracranial xenograft models, with evidence of favorable pharmacokinetic properties and target pathway inhibition in intracranial tumors. Combination therapy provided enhanced and sustained control of flank CH157-MN meningioma compared to avutometinib alone but did not significantly improve survival over avutometinib alone in intracranial models. Conclusions Avutometinib demonstrated robust anti-tumor effects in flank and intracranial models of MAPK-altered meningioma. Combination benefits were context dependent. Defactinib activity in NF2-mutant patient-derived cells without targetable MAPK-kinase alterations highlights the importance of genomic biomarkers to guide personalized strategies.

TPS2103 Background: Treatment for newly diagnosed IDH-mutant astrocytoma, WHO grade 3, is based on the results of the CATNON study, demonstrating benefit of radiotherapy followed by 12 months of adjuvant temozolomide. While temozolomide and radiotherapy significantly improved survival, the prognosis for these patients remains limited and more effective therapies are required. This trial will evaluate the benefit of the addition of the IDH1 and IDH-2 inhibitor vorasidenib to adjuvant temozolomide versus placebo following standard radiotherapy to evaluate possible improvement in outcomes. Methods: Alliance A072301 (NCT07215910) is a multicenter, double-blinded phase 3 randomized study to determine if the addition of vorasidenib to adjuvant temozolomide significantly improves progression-free survival (PFS), based on blinded central review in patients with newly diagnosed, IDH-mutant astrocytoma, WHO grade 3. Key inclusion criteria include age ≥ 12 years old, histological confirmation of astrocytoma (absence of 1p/19q codeletion), WHO grade 3, presence of any IDH mutation, plan for radiation and chemotherapy and surgery within 6 months. The presence of CDKN2A/B homozygous deletion, spinal or leptomeningeal disease, as well as prior chemotherapy, cranial irradiation or IDH inhibitor therapy, is exclusionary. 408 patients will be randomized 1:1 to receive vorasidenib 40 mg or placebo daily with 12 cycles of temozolomide following radiotherapy and then continued as monotherapy until disease progression or unacceptable toxicity. Stratification factors include age (< 40 years old vs ≥ 40 years old) and residual disease (< 2 cm vs ≥ 2 cm). Tumor assessments with MRI will be every three months for the first two years, every four months for the next two years and then every six months thereafter as per blinded independent central review using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria. Key secondary endpoints include PFS by local review, time to next treatment, safety and tolerability, quality of life measures. Exploratory measures will include seizure frequency. The trial will have 85% power to detect a hazard ratio of 0.625 with one-sided type I error rate of 0.025. Enrollment for the trial commenced February 2026. Support: U10CA180821, U10CA180882, U24CA196171. https://acknowledgments.alliancefound.org.

e13661 Background: The process of data abstraction and curation represents a significant proportion of clinical trial costs, requiring up to $30,000 per patient depending on the data complexity. Research variables such as stage, performance status (PS), and cancer disease status are typically present in the electronic health record (EHR) in free text but require abstraction for research use. Structuring these real-world data (RWD) in an exportable format utilizing minimum common oncology data elements (mCODE) could reduce the need for abstraction and the potential for erroneous transcription that has been shown to be 5.51-7.72% in a meta-analysis. We assessed the feasibility, availability, and accuracy of RWD for use across Alliance for Clinical Trials in Oncology sites by comparing RWD to matched electronic case report form data (CRF data) at 2 sites where EHR-integrated tools collect structured RWD for all solid tumor patients. Methods: Stage, PS, and cancer disease status (CDS) were extracted from the EHR as RWD and from eCRFs for 100 patients enrolled in National Clinical Trials Network trials across multiple disease sites from 2022 through 2025. Data from baseline and day 1 of cycles 1-4 were compared (500 encounter timepoints). Results: Stage, PS, and CDS were available from RWD more often than CRFs (85 vs 70 / 100 patients, 436 vs 416 / 500 encounters, and 345 vs 83 / 500 encounters respectively). When stage was present in both (n = 58), there were 5 mismatches (8.6%). PS had 22 mismatches (4%) and CDS had 45 mismatches (11.4%). After correcting for differences in CRF vs RWD definitions, CDS mismatches dropped to 1.2% (n = 4). Discordance between RWD and CRF data was related to differences in the timepoint of data collection (e.g., systemic staging scans completed after the initial consult), CRF data obtained from other EHR notes (e.g., oncology research nurse notes containing PS), inherent discordance between RWD and CRF data choices (e.g., responding vs complete or partial response), and failure to update EHR data capture tool fields. RWD were available 21 days (median) before CRF data. Conclusions: Our results suggest that RWD captured directly within clinical notes match CRF data, are more often present, and are available sooner. RWD could serve as a data source for trials, decreasing the need for manual curation and cost. Although some discordance exists, overall rates are low and close to the published error rate for abstraction.