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PURPOSE The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid–dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS Patients with newly diagnosed O 6 -methylguanine–DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780 ). RESULTS Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05). CONCLUSION The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Abstract BACKGROUND The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. MATERIAL AND METHODS Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, the RANO working group developed updates to the RANO criteria (RANO 2.0). RESULTS Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment. CONCLUSION These criteria represent a work in progress that will hopefully improve the assessment of response in glioma trials. Future updates will incorporate novel developments, advanced imaging techniques, and endpoints as they become validated.

Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Abstract The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve the reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, we propose updates to the RANO criteria (RANO 2.0). Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment.

Abstract Introduction Prospective data about quality of life (QoL) in men with breast cancer (BC) are lacking. A prospective registry (EORTC10085) of men with all BC stages, including a QoL correlative study, was performed as part of the International Male Breast Cancer Program. Methods Questionnaires at BC diagnosis included the EORTC QLQ-C30 and BR23 (BC specific module), adapted for men. High functioning and global health/QoL scores indicate high functioning levels/high QoL; high symptom-focused measures scores indicate high symptoms/problems levels. EORTC reference data for healthy men and women with BC were used for comparisons. Results Of 422 men consenting to participate, 363 were evaluable. Median age was 67 years, and median time between diagnosis and survey was 1.1 months. A total of 114 men (45%) had node-positive early disease, and 28 (8%) had advanced disease. Baseline mean global health status score was 73 (SD: 21), better than in female BC reference data (62, SD: 25). Common symptoms in male BC were fatigue (22, SD: 24), insomnia (21, SD: 28), and pain (16, SD: 23), for which women’s mean scores indicated more burdensome symptoms at 33 (SD: 26), 30 (SD: 32), and 29 (SD: 29). Men’s mean sexual activity score was 31 (SD: 26), with less sexual activity in older patients or advanced disease. Conclusions QoL and symptom burden in male BC patients appears no worse (and possibly better) than that in female patients. Future analyses on impact of treatment on symptoms and QoL over time, may support tailoring of male BC management.

2017 Background: Response Assessment in Neuro-Oncology (RANO) criteria for high-grade and low-grade glioma (HGG and LGG) were developed to improve reliability of response assessment in glioma trials. Several limitations of the original RANO criteria have been reported. Methods: To address limitations of the original RANO criteria, a large cohort of patients with newly diagnosed and recurrent glioblastoma were evaluated comparing RANO-HGG with modified RANO (mRANO) and immunotherapy RANO (iRANO) criteria to inform the following proposed updates (RANO 2.0). Results: Based on the 2021 WHO classification of glioma, we recommend a single common set of criteria for all gliomas regardless of WHO grade and IDH mutational status. These criteria will be used for all trials regardless of the treatment modalities being evaluated. In newly diagnosed glioblastoma, the post-radiotherapy MRI, usually obtained approximately 4 weeks after completion of radiotherapy, rather than the post-surgical MRI as proposed in original RANO criteria, will be used as the baseline for comparison of subsequent scans. Since the incidence of pseudoprogression is high in the first 3 months following radiotherapy, confirmation of progression during this period with a repeat MRI (in 4-8 weeks) will be required for determining radiographic progression of disease (PD) if the patient is clinically stable. However, confirmation scans are not mandatory after this period nor for recurrent tumors since these scans do not appear to improve reliability in determining progression. For agents with a high likelihood of producing pseudoprogression such as viral therapies and some other immunotherapies, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement will remain the 2-dimensional maximum cross-sectional area of tumor as the simplest method, but where resources are available, volumetric measurements are an option. For IDH wild-type tumors with contrast enhancement, non-enhancing tumor will no longer be evaluated with the possible exception of patients receiving antiangiogenic therapies. However, in tumors with a significant non-enhancing component, both the contrast enhancing and non-enhancing components will be evaluated as target lesions. Conclusions: We hope that these and other proposed changes by the RANO working group will improve response assessment in glioma clinical trials and help the development of more effective therapy for patients.

Advances in molecular profiling have led to improved understanding of glioma heterogeneity. Results have been used to inform diagnostic classification and targeted treatment strategies. Validation of these tests is necessary in the development of biomarkers that can aid in treatment decision, allowing for personalized medicine in neuro-oncologic diseases. Although not all populations have benefitted equally from awareness of and access to testing, opportunities arise regarding incorporating this testing into the standard of care for patients with glioma.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2–3 oligodendroglioma [1p19q codeleted, IDH- mutant], WHO grade 2–4 IDH- mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of gliomas.

Abstract Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.