Schiff, David

2016 Background: Bevacizumab therapy (Bev) for recurrent glioblastoma (rGBM) has not demonstrated improved overall survival (OS) in randomized clinical trials. However, single-center and preliminary multi-center studies suggest that relative cerebral blood volume (rCBV) measured with dynamic susceptibility contrast MRI (DSC-MRI) at baseline or shortly after treatment initiation may predict response to Bev. The primary aim of ECOG-ACRIN EAF151 was to evaluate whether early binary change in rCBV, assessed 2–3 weeks after initiation of Bev-containing therapy, identifies patients with an OS benefit of ≥4 mos. Pre-specified secondary aims assessed baseline rCBV; post-hoc exploratory analyses examined early post-Rx rCBV. Methods: A prospective, phase II multi-center trial without randomization enrolled subjects with rGBM receiving their first Bev-containing therapy. Progression was determined by local sites (RANO criteria; MRI within 28 days of registration, ≥42 days since end of chemoradiation). Baseline (S0) and follow-up (S1) DSC-MRI were performed before the first Bev infusion (within 3 days), and 12-25 days post-infusion but before the second infusion. Anatomic MRI and DSC-MRI (double-dose Gadavist injection, full-dose preload) complied with recommended protocols. Mean normalized (nRCBV) and standardized (sRCBV) rCBV were extracted from contrast-enhancing tumor ROIs. A 2-sided logrank test (α=0.1) was used to test the primary aim (change in mean nRCBV from S0 to S1, ≥0 vs. <0). Cox regression with restricted cubic splines was used to assess the association between continuous rCBV markers and OS. Results: 146 subjects were accrued from 33 sites. 134 completed S0 and 118 completed both S0 and S1. After exclusion of uninterpretable scans, 107 were evaluable for change in rCBV, and 124 for baseline rCBV. There was no statistically significant difference in OS between subjects with binary increase (n=40; median OS 8.0 mos [90% CI 5.5–9.2]) vs. decrease (n=67; 7.9 mos [90% CI 6.3–10.3]) in mean nRCBV (p=0.67). Based on the spline fits, we observed a strong nonlinear association between OS and continuous nRCBV and sRCBV at both S0 and S1: low marker values are associated with lower risk, but beyond a threshold, higher values are not associated with greater risk. As an exploratory analysis, we estimated optimal cut points (nRCBV: S0=1.11, S1=1.16; sRCBV: S0=1.13, S1=0.99) and found that subjects whose S1 rCBV decreased below threshold had a median OS 2.7 mos (nRCBV, HR 0.61 [90% CI 0.41–0.88]) and 5.2 mos (sRCBV, HR 0.43 [90% CI 0.28–0.63]) longer than subjects whose rCBV either increased or did not decrease below threshold. Conclusions: EAF151 prospectively evaluated whether DSC-MRI markers predict OS in patients with rGBM treated with Bev. Although the change in these markers was not predictive, both baseline and early post-Rx markers were predictive of OS. Clinical trial information: NCT03115333 .

PURPOSE Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780 ). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score–matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

Abstract Current assessments of brain permeability rely predominantly on drug delivery to contrast-enhancing tumor regions. However, substantial portions of central nervous system (CNS) tumors reside within non-enhancing brain (NEB), where drug concentrations frequently remain subtherapeutic. This collaborative Adult Brain Tumor Consortium and Food and Drug Administration workshop aimed to identify criteria for defining NEB permeability to accomplish 2 critical objectives: (1) allocate clinical trial resources toward agents achieving therapeutic NEB concentrations and (2) minimize systemic toxicity when CNS benefit is improbable. The workshop systematically evaluated permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain. Methodological approaches to determine requisite NEB drug concentrations and approaches to measuring NEB pharmacokinetics and pharmacodynamics were examined. This culminated in developing the Non-Enhancing Brain Permeability Index (NEBPI), which assigns therapeutic agents to 3 categories: sufficiently permeable, insufficiently permeable, or impermeable. The NEBPI provides a standardized framework to assist investigators and regulatory agencies to evaluate NEB penetration before human efficacy studies are initiated for agents that require direct tumor contact. Assessing NEB drug penetration is critical to improving outcomes in CNS tumors and reducing the incidence of brain metastases in systemic malignancies.

Abstract BACKGROUND The phase III ECOG-ACRIN E3F05 trial tested whether combined therapy with radiation and concomitant followed by adjuvant temozolomide is more effective than radiation alone in patients with grade II gliomas. The study incorporated 1p/19q analysis but predated assessment of IDH mutational status. We previously reported that the addition of temozolomide to radiotherapy significantly improved overall survival in grade II gliomas, with similar hazard ratios in co-deleted (0.56) and non-codeleted (0.53) tumors. Herein we incorporate the results of DNA methylation profiling to examine outcomes in IDHmt, non-codeleted subjects as well as co-deleted ones. METHODS All 172 subjects underwent 1p/19q co-deletion analysis as a stratification factor, 1p and 19q deletion analysis was performed on formalin-fixed paraffin-embedded (FFPE) gliomas by Fluorescent In Situ Hybridization (FISH) following standard methods, 97/172 (56.3%) had tissue with 60% or more tumor content available for DNA methylation profiling using Heidelberg classifier v12 and Bethesda Classifier 2.0 to ascertain classification as IDH mutant glioma and alternative evaluation of 1p/19q co-deletion status. RESULTS Of the 172 subjects, 74 (43.0%) had 1p/19q codeletion by FISH, 38 (22.1%) were IDHmt without codeletion, 14 (8.1%) were IDHwt, and 46 (26.7%) were non-codeleted with unknown IDH status (these include n=4 pts originally classified as 1p/19q undetermined). With a median follow-up of 130 months, the addition of TMZ to RT improved OS in patients with IDHmt, non-codeleted tumors (HR 0.15 (0.03-0.74)) and 10-year OS from 39% to 80%. In codeleted tumors, the addition of TMZ improved OS (HR 0.51 (0.19-1.42)) and 10-year OS from 68% to 90%. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and IDHmt, non-co-deleted grade II gliomas.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children ≥2 years with NF1 who have symptomatic PN not amenable to complete resection. We report results from the phase 2b ReNeu trial (NCT03962543), including the LTFU. METHODS In ReNeu, mirdametinib was administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle treatment phase, patients could continue mirdametinib in an optional LTFU. We report results through June 12, 2024, approximately 9 months from the previous data cutoff. RESULTS Fifty-eight adults and 56 children received mirdametinib. Median (range) duration of treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered LTFU. Confirmed objective response rate (ORR, treatment+LTFU phases) was 47% (27/58; 95%CI, 33%, 60%) in adults and 55% (31/56; 95%CI, 42%, 69%) in children. Among confirmed responders, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of &gt;50%). Median (range) best percentage change from baseline in target PN volume was –41% (–90%, 13%) in adults and –43% (–98%, 48%) in children. Median duration of response (DoR) was not reached for either age cohort. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhea, nausea, and vomiting in adults; and diarrhea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and 14%, 14%, and 9%, respectively, of children. CONCLUSIONS Improved confirmed ORR was observed with longer duration of mirdametinib, with additional deep responses achieved in both adults and children. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals in the LTFU.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2y) with symptomatic NF1-PN. In ReNeu, symptomatic improvement and PN volume reductions were observed at the earliest assessments (~91 and ~152 days, respectively) and were sustained. This analysis evaluated time to first onset and resolution of commonly reported TRAEs in the ReNeu trial. METHODS Data cutoff (DCO) was September 20, 2023. Median time to first onset and resolution (days) for common TRAEs (≥15%) were evaluated for prepubescents (≥2 to &lt;12y, n=32), postpubescents (≥12 to &lt;18y, n=24), younger adults (≥18 to ≤50y, n=48), and older adults (&gt;50y, n=10). RESULTS Common TRAEs were mostly grades 1 to 2 (83%). In prepubescents, median day (range) of onset was 32 (14, 263) for vomiting, 71 (19, 386) for dermatitis acneiform, 123 (1, 663) for diarrhea, 124 (52, 775) for paronychia, and 127 (2, 663) for nausea. For postpubescents, median day (range) of onset was 8 (1, 438) for diarrhea, 8 (2, 574) for nausea, 12 (1, 252) for dermatitis acneiform, 28 (2, 354) for vomiting, and 110 (43, 245) for paronychia. In younger adults, median day (range) of onset was 5 (1, 352) for nausea, 8 (2, 15) for dermatitis acneiform, 9 (2, 73) for diarrhea, and 29 (1, 264) for vomiting. For older adults, median day (range) of onset was 4 (1, 286) for diarrhea, 9 (2, 15) for nausea, and 13 (2, 38) for dermatitis acneiform. Time to resolution was variable between TRAEs and among patients in all age groups; 90% resolved completely by DCO. Among all patients, 18 had a TRAE of asymptomatic ejection fraction decrease, with all but one resolving by DCO. CONCLUSIONS Overall, common TRAEs arose before treatment benefits and were generally resoluble by DCO. Proactively managing TRAEs may improve treatment experience and adherence.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of &gt;50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.

Abstract Glioblastoma is the most common type of malignant primary brain tumor and a major cause of morbidity and mortality. In 2021, the World Health Organization updated the classification of Central Nervous System (CNS) tumors to restrict glioblastomas to isocitrate dehydrogenase-wildtype (IDHwt) tumors, improving understanding of the prognosis and optimal therapy for these tumors. This revision also enables more homogeneous populations of patients to be enrolled in clinical trials, facilitating the evaluation of novel therapies. In this updated consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of patients with glioblastoma is discussed. In addition, novel therapies such as immunotherapies, viral therapies, targeted molecular therapies, theranostics, and antibody–drug conjugates will be reviewed, as well as the current challenges and future directions for research.

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.