Citations

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 Vorasidenib is Food and Drug Administration‐approved for treatment of grade 2 isocitrate dehydrogenase (IDH)–mutant gliomas and has demonstrated a benefit in progression‐free survival compared to a placebo. This study assessed the cost‐effectiveness of this treatment strategy compared to standard treatment: observation or chemoradiation (CRT). Methods The authors used an integrated Markov model to compare quality‐adjusted life‐years (QALY) gained and cost‐effectiveness of patients with IDH‐mutated low‐grade glioma (LGG) treated with vorasidenib, observation, or CRT. Outcomes were expressed as incremental cost‐effectiveness ratios (ICERs) per QALY gained. Treatment is considered cost‐effective if it meets the commonly accepted willingness‐to‐pay threshold of $100,000 per QALY gained. Results Based on model parameters, vorasidenib demonstrated an ICER of $356,756 per QALY when compared to CRT. When compared to observation, vorasidenib demonstrated an improved ICER of $215,191 per QALY. On one‐way sensitivity analysis compared to observation, median cost of vorasidenib and median overall survival were most likely to affect ICER with only marginal changes on analysis of other model factors. For ICER to become ≤$100,000 compared to observation, the cost of vorasidenib would need to drop to below $14,072 monthly or have a median survival gain of at least 11.9 years. The probabilistic sensitivity analysis demonstrated that vorasidenib was favored in none of 5000 Monte Carlo iterations. Conclusion Using the best available data, the current price of vorasidenib does not meet commonly accepted cost‐effectiveness thresholds in treatment of IDH‐mutated LGGs.

OBJECTIVE Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond 3 months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluated prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. METHODS The authors retrospectively analyzed a cohort of 1546 patients who underwent Gamma Knife SRS for brain metastases at their institution between 2015 and 2023. One hundred seventy patients who survived less than 90 days after SRS were identified and case matched to 170 patients who survived over 90 days. Measured variables included patient demographic characteristics, tumor characteristics, treatment history, functional status, and control of the primary cancer. The authors modeled post-SRS 90-day survival using binomial and multivariate logistic regression. RESULTS Multivariate analysis highlighted Karnofsky Performance Score (KPS) < 70 (OR 17.4, p < 0.001), prior whole-brain radiation (OR 6, p = 0.004), and focal neurological deficits (OR 3.02, p = 0.003) as significant predictors of poor survival, whereas CNS progression before SRS (OR 0.22, p < 0.001) and control of systemic cancer (OR 0.556, p = 0.002) were associated with survival < 90 days. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. CONCLUSIONS Key predictors of 90-day survival after SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurological deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

Abstract Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond three months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluates prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. We retrospectively analyzed a cohort of 1,546 patients who underwent Gamma Knife SRS for brain metastases at our institution between 2015 and 2023. One hundred seventy patients who survived fewer than 90 days post-SRS were identified and case-matched to 170 patients who survived over 90 days. Measured variables included patient demographics, tumor characteristics, treatment history, functional status, and control of the primary cancer. We modeled post-SRS 90-day survival using binomial and multivariate logistic regression. Multivariate analysis highlighted Karnofsky Performance Status (KPS) &lt; 70 (OR: 17.4, p &lt; 0.001), prior whole brain radiation (OR: 6, p = 0.004), and focal neurological deficits (OR: 3.02, p = 0.003) as significant predictors of early deaths, while CNS progression before SRS (OR: 0.22, p &lt; 0.001) and control of systemic cancer (OR: 0.556, p = 0.002) were associated with a less than 90-day survival. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. Key predictors of 90-day survival following SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurologic deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

Background: Post-treatment prognosis and monitoring are critical for determining the timing of salvage treatment in glioblastoma patients but has been challenging due to difficulties differentiating progression from treatment effects in conventional images. This exploratory study aimed to establish the correlation of radiomics image features from time series of amino acid tracer 18F-DOPA PET images, with outcomes, using machine learning and dimension reduction analysis. Methods: 18F-DOPA PET images were collected for a patient cohort with wild-type IDH and unmethylated MGMT who underwent dose-escalated radiation therapy. Quantitative features were derived from the high uptake region (T/N > 2.0) in pre- and post-radiation therapy follow-up 18F-DOPA PET images. A customized workflow was utilized for pre-selecting predictive features, followed by manifold learning. Machine learning algorithms were employed to establish associations between imaging features and remaining survival (RS), defined as the time between a follow-up scan and date of death. Results: The ML models exhibited 81–83% ROC_AUC in predicting RS evaluated on an independent test dataset. A RS map is proposed for monitoring tumor alterations through serial 18F-DOPA PET scans, demonstrating superior sensitivity and better correlation with survival compared to the RANO criteria. Conclusions: Our study demonstrates that ML models utilizing FU 18F-DOPA PET images have the potential to effectively predict future survival outcomes in patients with glioblastoma treated with dose-escalated radiation therapy. The capability to assess changes in tumor over time through imaging can potentially assist in patient stratification and the selection of salvage treatments, while also aiding in distinguishing treatment effects from genuine tumor progression.

Abstract Background Dasatinib is an oral inhibitor of the Src kinase family, with preclinical data indicating impact on gliomagenesis, tumor invasion, and radiosensitivity. Methods North Central Cancer Treatment Group N0877 is a phase 1 dose escalation and phase II randomized study evaluating the maximum tolerated dose (MTD), safety, and efficacy of dasatinib with radiation and temozolomide (TMZ) for glioblastoma. Following identification of the MTD, adult patients with a histologic diagnosis of glioblastoma were randomized 2:1 between dasatinib given with standard concurrent and adjuvant TMZ, versus placebo with standard concurrent and adjuvant TMZ. Radiation dose was 60 Gy in 30 fractions. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), toxicity, and quality of life. Results Thirteen patients were enrolled in the phase I component and established the MTD and phase II dose of 150 mg given daily. A total of 204 patients were enrolled in the phase II component. OS was not different between arms (median OS 15.6 months for dasatinib compared to 19.3 months for placebo, hazard ratio:1.21 favoring placebo, 95% CI: 0.88–1.65, log-rank P-value: .238). Similarly, PFS was not significantly different between the dasatinib and placebo arms. There was a significant increase in anemia, nausea, and creatinine elevation with dasatinib, but significantly more grade 3 lymphopenia with placebo. Conclusions The addition of dasatinib to standard chemoradiation did not improve outcomes for patients with glioblastoma. Clinical Trial Identifier NCT00869401.

TPS2092 Background: Glioblastoma (GBM) is the most common primary brain malignancy in adults. GBM is universally recurrent and associated with dismal outcomes. Re-irradiation (reRT) is ideal for evaluating combination therapy for recurrent GBM (rGBM) due to its multifactorial mechanism of action, including downstream immunomodulatory activity. RT (especially multi-fraction) increases immunogenicity in preclinical models by promoting immune activation, immune migration, and antigen uptake. Additionally, a recent study demonstrated enhanced PD-L1 expression in the glioma tumor microenvironment (TME) following RT, and combining stereotactic RT with a PD-1 inhibitor improved survival in murine models. Retifanlimab is a humanized monoclonal anti-PD1 IgG4 antibody that received FDA approval for adults with metastatic or recurrent locally advanced Merkel cell carcinoma. Bevacizumab, an anti-VEGF antibody, is a treatment for radiation necrosis/cerebral edema with less immune suppression than corticosteroids. In a previous Phase 2 study, hypofractionated RT (HFRT), retifanlimab, and bevacizumab was associated with a 9-month overall survival (OS) rate of 71.4%. To demonstrate the efficacy of this regimen compared to HFRT and bevacizumab, we have designed a new randomized controlled Phase 2 trial. We hypothesize that combination reRT with retifanlimab will produce a more robust anti-tumor immune response and improve OS compared to reRT without retifanlimab. Methods: This is a multicenter, open-label, randomized, controlled Phase 2 study of retifanlimab, bevacizumab, and HFRT for adult patients with rGBM. Patients are randomized 1:1 to the experimental (bevacizumab + retifanlimab + HFRT) or control cohort (bevacizumab + HFRT). Key eligibility criteria include age ≥ 18 years, Karnofsky performance status ≥ 60, ≥ 4 months since administration of any prior bevacizumab, and dexamethasone dose ≤ 4 mg at the time of randomization. The primary endpoint is 9-month OS. Secondary endpoints include OS, progression-free survival, objective response rate, neurologic assessment by NANO criteria, and adverse events profile. Protocol treatment will continue up to two years, or until progression or intolerable toxicity. Survival follow up will continue every two months, up to four years. Seven of the planned 94 patients have been enrolled as of submission on 1/28/25. Clinical trial #: NCT06160206. Funding provided by Incyte. Clinical trial information: NCT06160206 .

Abstract BACKGROUND BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi. METHODS Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed. RESULTS Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi. CONCLUSIONS In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.

Stenosis of the left main coronary artery (LM stenosis) is associated with significant mortality and morbidity due to the large area of affected myocardium. Evidence on the use of percutaneous coronary intervention (PCI) for the treatment of LM stenosis is growing. However, the role of Western guidelines on patients in the Asian-Pacific region is unclear due to anatomical variations, substantial heterogeneity in healthcare resources and infrastructure, and the lack of consensus on the optimal management of LM stenosis in the Asia-Pacific region. Hence, an Asian Pacific Society of Cardiology (APSC) working group developed consensus recommendations on the use of PCI in the management of LM stenosis in the Asia-Pacific region. The APSC expert panel reviewed and appraised the available evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed and put to an online vote. Consensus was reached when 80% of votes for a given recommendation were in support of ‘agree’ or ‘neutral’. The resulting 12 statements provide guidance for clinical practitioners in the region on the use of PCI in the treatment of patients with LM stenosis.