Bi, Wenya Linda

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Abstract Background Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a “rate of probable interest” to inform future clinical trial design and development on behalf of the Response Assessment in Neuro-Oncology meningioma group. Methods PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I2 indices. Results The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2 = 80%) and 21.7% (95% CI: 6.2-53.9%, I2 = 76%), and for grades 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2 = 68%). In the targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2 = 58%) and 49.0% (I2 = 63%) for grade 1, while for grades 2-3 tumors, the PFS-6 rates with targeted therapy and immunotherapy were 42.1% (I² = 60%) and 46.0% (I² = 0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grades 2-3 tumors. Conclusions Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.

Abstract BACKGROUND Leveraging external data has the potential to increase efficiency and precision of drug development in glioblastoma by complementing or replacing data from in-trial controls. We used an external control arm (ECA) to re-analyze data of the abemaciclib, neratinib and CC-115 arms of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. METHODS INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. The initial experimental arms (abemaciclib, neratinib, CC-115) have not shown a survival benefit relative to the shared control arm. We re-analyzed the experimental arm data and replaced the shared control arm with an ECA. The ECA was developed from a collection of trial datasets and real-world data available through the Glioblastoma External (GBM-X) Data Platform (). Propensity score matching was used to adjust for possible differences between pretreatment covariates (age, sex, resection, KPS) in the ECA and shared control arm. Cox proportional hazards models were used to estimate treatment effects. RESULTS On INSIGhT, patients were randomized to abemaciclib (n = 74), neratinib (n = 80), and CC-115 (n = 12). There were 687 unmethylated MGMT patients in the GBM-X ECA. After propensity score matching, there was no significant treatment effect associated with abemaciclib (HR 1.091, 95%CI:0.834-1.433, p = 0.536), neratinib (HR = 1.043, 95%CI:0.787-1.383, p = 0.770), or CC-115 (HR 1.088, 95%CI:0.834-1.433, p = 0.794) compared to the ECA. CONCLUSION In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.

Objective The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications. Study Design Survey. Setting A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery. Results House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting. Conclusions Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland.

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 Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Abstract Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

Abstract BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

Abstract BACKGROUND EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

Abstract BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade &gt; 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to &lt; 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.