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 O6-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.

Engineering macrophages with chimeric antigen receptors is emerging as a promising cancer therapeutic. Chimeric antigen receptor-expressing macrophages (CAR-Ms) engineered to recognize tumor-specific antigens have been shown to inhibit tumor growth and activate adaptive immune responses, leading to robust tumor control in animal studies. Based on this work, clinical trials have been initiated. While the trials have shown promise, challenges remain. The dynamic interactions between CAR-Ms and cancer cells and the exact mechanisms driving anti-tumor effects remain poorly defined. Defining the dynamic interactions between CAR-Ms and cancer cells will provide critical insights for optimizing future CAR-M design and improving therapeutic efficacy. We sought to directly visualize CAR-M interactions with glioblastoma cells at high-resolution and in real-time using CAR-Ms engineered to recognize Neural-Glial Antigen 2 (NG2), an antigen expressed on glioblastoma cells. Using patient-derived glioblastoma cells, we formed glioblastoma spheroids and embedded them in a 3D matrix together with CAR-Ms. Using time-lapse microscopy, as expected, we found that NG2-targeting CAR-Ms engulfed glioblastoma cells. However, excitingly, we found that NG2-targeting CAR-Ms blocked >85% of glioblastoma cell invasion in 3D. This inhibition of glioblastoma invasion was not due to a significant change in CAR-M polarization states. Together, these data suggest that NG2-targeting CAR-Ms both engulf glioblastoma cells and block glioblastoma invasive behavior.

Background Early identification of malnutrition is critical for improving clinical outcomes in oncology patients. However, there are no established biomarkers for malnutrition screening. Objectives This study aimed to identify circulating lipid species associated with malnutrition risk among oncology patients through lipidomic analysis. Methods A cross-sectional study was conducted using plasma samples from oncology patients classified as at risk (n = 90) or not at risk (n = 90) for malnutrition using the Malnutrition Screening Tool (Malnutrition Screening Tool score = 0 compared with ≥2). All participants had head and neck, lungs, or gastrointestinal cancer. Targeted lipidomics were conducted using liquid chromatography-mass spectrometry. Elastic net regression adjusted for confounding variables identified lipids associated with malnutrition risk. A weighted lipid malnutrition risk score was derived and evaluated using the receiver operating characteristic area under the curve. Conditional multivariable logistic regression assessed the association of the lipid score with malnutrition risk. Lipid enrichment analysis was performed using the lipid ontology enrichment framework. Results Elastic net regression identified 12 lipids species that were inversely associated with malnutrition risk: cholesterol ester 20:0, ceramide 18:2;O2/26:0, lysophosphatidylcholine 26:0/0:0, lysophosphatidylinositol 18:2/0:0, phosphatidylcholine 34:5, phosphatidylcholine 40:8, phosphatidylethanolamine (PE) P-18:0/20:3, PE P-18:1/18:2, PE P-18:1/20:4, sulfated hexosylceramide 18:1;O2/16:0, sphingomyelin 18:2;O2/23:0, and triglyceride (O-50:1). One lipid, dihexosylceramide 18:1;O2/20:0, was positively associated with malnutrition risk. The weighted lipid malnutrition risk score was associated with increased risk for malnutrition [odds ratio: 3.57; 95% confidence interval (CI): 1.97, 6.47, P < 0.001]. Addition of the lipid score to established malnutrition risk factors improved model predictive performance, increasing the receiver operating characteristic area under the curve from 0.78 (95% CI: 0.71, 0.84) to 0.90 (95% CI: 0.86, 0.94). Lipid ontology enrichment analysis indicated downregulation of membrane structure and signaling lipids and upregulation of storage lipids. Conclusions This study highlights the potential of lipidomics to identify biomarkers of malnutrition risk among oncology patients. Large, prospective studies are warranted to validate these findings.

Glioblastoma is the most common and deadly brain cancer in adults. Although the disease disrupts the blood-brain barrier and exposes the tumor to the systemic circulation, using circulating cell-free DNA as a non-invasive biomarker for diagnosing glioblastoma remains elusive. The main obstacles are the confounding effects from artifactual variants in cell-free DNA caused by errors during next-generation sequencing and real variants in cell-free DNA originating from white blood cells that acquired somatic mutations during normal aging. Here, we developed and validated TrueR sequencing to overcome next-generation sequencing-related false positives in cell-free DNA. Subsequently, TrueR identified molecular features unique to tumor-derived cell-free DNA (i.e., circulating tumor DNA) that are detectable in blood during a tumor-naïve search. Specifically, variants associated with glioblastoma circulating tumor DNA were exclusively present in cell-free DNA (i.e., absent in white blood cell DNA) and showed gene-specific subclones. These features were uncommon in low-grade glioma, stroke, and age-related somatic mosaicism of white blood cells. We also detail a variant-agnostic method, demonstrating that copy number gains and losses in short cell-free DNA fragments (<90 bp) support the detection of glioblastoma. Finally, we present evidence that our findings extend beyond glioblastoma, supporting the broader advancement of the liquid biopsy.

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.

Background:Glioblastoma (GBM) has limited effective salvage therapy options. The combination of the Type 1B topoisomerase/HIF1α inhibitor topotecan and the tyrosine kinase inhibitor pazopanib has shown promise in solid tumors and may be effective in recurrent GBM. Methods:Patients with recurrent GBM who were bevacizumab-naïve (Group A, 9 patients) or had previous bevacizumab (BEV) (Group B, 22 patients) started daily oral pazopanib (600 mg) and topotecan (0.25 mg). The primary objective was progression-free survival (PFS) at 6 months for Group A and 3 months for Group B patients. Secondary objectives included median progression-free and overall survival (OS), safety, tolerability, and toxicity as measured by patient-reported outcomes (PROs) and adverse event documentation. Results:Group A enrolled 9 evaluable patients and closed to accrual early when interim primary objectives were not met (PFS-6 11%). Group B enrolled 22 evaluable patients and narrowly met its primary objective (PFS-3 18%). Median PFS and OS endpoints demonstrated equivalent to slight improvement upon historical metrics, respectively. The regimen was tolerable and safe save for high frequency of hypertension, with PROs data showing stability or worsening in parallel with tumor stability or progression, respectively. Conclusions:These findings suggest the regimen is safe and tolerable to GBM patients. The regimen was ineffective in bevacizumab-naïve patients and only narrowly met its predetermined endpoint in patients with prior BEV. These results do not support the combination regimen as tested in this protocol for further investigation in GBM.

Background:This multi-institutional phase I trial aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and preliminary antitumor activity of berubicin (WP744 or RTA744), designed to cross the blood-brain barrier, in patients with primary brain cancers. Methods:Thirty-five patients with recurrent or refractory primary brain cancers, including glioblastoma multiforme, received berubicin infusions over 2 h for 3 consecutive days (one course) every 21 days. Daily doses escalated from 1.2 to 9.6 mg/m2 using an accelerated titration design. Plasma levels of berubicin were measured via high-performance liquid chromatography-tandem mass spectrometry to estimate pharmacokinetic parameters. Results:The daily MTD was determined to be 7.5 mg/m2. Nonhematological toxicities were minimal; no cardiotoxicity was observed. In the intention-to-treat population (n = 35), 1 patient had a durable complete response, 1 had a partial response, and 9 had stable disease, corresponding to an objective response rate of 5.7% and a disease control rate of 31.4%. In the response-evaluable subset (n = 25), the corresponding rates were 8% and 44%, respectively; these secondary estimates should be interpreted with caution as patients who discontinued early were excluded. Pharmacokinetic analysis determined a mean half-life of 32.8 h. The area under the curve increased proportionally with dose. Conclusions:The tolerability and efficacy of berubicin, including one durable complete response, warrant continued development of the molecule. Berubicin shows activity over a range of doses, including a durable response at 2.4 mg/m2. The recommended phase II dose is 7.5 mg/m2 infusions over 2 h for 3 days every 3 weeks. Trial registration:NCT00526812.

Meningiomas are the most common primary central nervous system tumors in adults, posing a significant burden to society. Although a large percentage of lower-grade meningiomas are curable by surgery or radiation alone, high-grade and a subset of low-grade meningiomas demonstrate recurrences and complications from treatment. Systemic therapies for meningioma remain ineffective, and no targeted treatments are approved. Despite the central role of YAP1/TAZ-TEAD signaling in NF2-deficient/mutant tumors, no studies have systematically examined TEAD inhibition across molecularly defined meningioma subtypes or investigated mechanisms of resistance in this disease. We have recently shown that YAP1/TAZ signaling is an oncogenic driver of meningioma. Here, using established and patient-derived meningioma cell lines, we demonstrate that genetic ablation of YAP1/TAZ suppresses growth in both NF2 mutant and NF2 wild type cell lines, establishing YAP1/TAZ-TEAD signaling as a shared oncogenic dependency. Pharmacologic TEAD inhibition suppressed growth of benign NF2 mutant and a subset of higher-grade NF2 mutant meningiomas, whereas NF2 wild type meningiomas were generally more resistant. RNA-Seq and Western Blot analysis identified compensatory activation of MEK-ERK, mTOR-S6, and FAK signaling in resistant lines exhibit. Importantly, co-targeting these pathways was able to overcome resistance to TEADi and was superior to MEK/mTOR/FAK inhibition alone. These studies provide a compelling proof-of-concept that TEADi represents a novel therapeutic vulnerability in meningioma and reveal adaptive signaling responses that can be therapeutically exploited.

Chondrosarcomas are rare cartilaginous neoplasms with limited treatment options. Isocitrate dehydrogenase 1/2 (mIDH1/2) mutations occur in 65

Over a decade ago, collaborating academic cancer centers formed the Oncology Research Information Exchange Network® (ORIEN) to develop a patient-driven, federated infrastructure for oncology research. Aster Insights is the network’s operational, commercial, and research partner. Together ORIEN and Aster Insights have built a unique multimodal dataset on the active engagement and consent of patients who opted into the Total Cancer Care® (TCC) protocol to contribute their data and biospecimens for research. Over 400,000 cancer patients have been enrolled in TCC, >32,500 of which have an in silico “Avatar” generated to represent their individual patient experience and molecular profile to support a broad range of network and industry research use cases. We provide an overview of ORIEN’s evolution, demonstrate the power of our data resources through a landmark analysis of >37,000 tumors across all cancer types collected for the Avatar program, and provide a vision for ORIEN to fuel collaborative research.

Background:GBM is one of the most common and most aggressive brain tumors in adults, and upfront standard of care treatment has limited efficacy. Immune checkpoint inhibitor strategies have significantly improved outcomes in various solid tumors but have not proven effective in GBM, suggesting other strategies may be needed to realize their full potential. Methods:GBM patients were treated with upfront standard of care chemoradiation with temozolomide and pembrolizumab, followed by adjuvant temozolomide and pembrolizumab for six nine-week cycles. Depending on production of sufficient vaccine, patients were randomized into HSPPC-96 vaccine or placebo group (q4 weeks) while those with failed vaccine production continued on study unblinded as an ancillary group. The primary objective was overall survival at one year, and secondary endpoints were progression-free survival at six months, overall and progression-free survival, radiographic response, and tolerability by patient-reported outcomes and adverse event documentation. Results:90 patients were screened, 32 were treated (8 vaccine, 9 placebo, 15 ancillary), and 26 were evaluable for radiographic responses prior to accrual termination. The study did not meet its primary endpoint of overall survival at one year (65.5% in vaccine group, 75% in placebo). Progression-free endpoints were mildly improved in the vaccine group but were not significant, and response rates were not significantly different. The regimen was well-tolerated and safe. Conclusions:Though limited by early discontinuation, these findings do not support the combination of pembrolizumab and HSPPC-96 vaccine with standard of care therapy. Trials Registration:ClinicalTrials.gov identifier: NCT03018288.

GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a multi-arm, international, seamless Phase 2/3 response adaptive randomization (RAR) platform trial designed to efficiently identify investigational therapies that improve overall survival and confirm efficacious therapies and biomarker signatures to support registration. GBM AGILE is a collaboration among academic investigators, patient organizations, and industry to support new drug applications for newly diagnosed and recurrent glioblastoma. The primary objective of GBM AGILE is to identify therapies that improve overall survival in patients with newly diagnosed or recurrent glioblastoma. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different companies to be evaluated simultaneously and/or over time against a common control. Investigational therapies are added as information about promising drugs is identified, while other therapies are removed as they complete evaluation. RAR is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE has screened over 2300 patients and enrollment continues to be robust. In addition to the efficient evaluation of investigational arms, a goal of GBM AGILE is to expand knowledge of glioblastoma to support advancements in treatment using the data collected within the trial (learning environment). Over 7 million data points are currently available for inclusion in the development of a longitudinal model. Such a model may be able to inform randomization by providing earlier and continuous information regarding patient and arm performance. In addition, serial magnetic resonance imaging scans and biospecimens from baseline through patient progression are being collected for further analysis. An initial 500 baseline tissue samples are being characterized by genome sequencing and transcriptome analysis. NCT number: NCT03970447.

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

AIMS:Cancer diagnosis may increase the risk of developing prediabetes/diabetes and subsequently worsen survival in cancer patients. However, it is unclear whether this association is influenced by the timing of hyperglycemia onset or the use of antihyperglycemic medications. MATERIALS AND METHODS:This study leveraged a retrospective cohort, constructed using electronic health record data, of solid tumour patients at the Huntsman Cancer Institute, a comprehensive cancer centre in Utah, USA. Adjusted Cox proportional-hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the association between new-onset prediabetes/diabetes and overall survival. RESULTS:Of the 7300 patients included, 23% developed prediabetes/diabetes after cancer diagnosis (mean time-to-onset = 2.6 years). Patients with new-onset prediabetes/diabetes had worse overall survival compared to patients without prediabetes/diabetes [HR (95% CI): 2.97 (2.48-3.55)]. Compared to patients without prediabetes/diabetes, patients who were not prescribed antihyperglycemic medications had poorer survival than those who were prescribed antihyperglycemic medications (n = 665) [HR (95% CI): 2.52 (2.17-2.93) and 1.70 (1.40-2.06), respectively]. Ever use of metformin was associated with better survival [HR (95% CI): 0.32 (0.15-0.66)] compared to individuals with prescriptions of other non-insulin antihyperglycemic medications, while ever use of insulin was associated with worse survival [HR (95% CI): 1.67 (1.16-2.42)], compared to individuals with prescription of non-insulin antihyperglycemic medications. CONCLUSIONS:Improving clinical practice guidelines for appropriate hyperglycemia monitoring and management, especially in the first 3 years after cancer diagnosis, may improve cancer survival. Early intervention with non-insulin antihyperglycemic medications for control of new-onset prediabetes/diabetes may be crucial in preventing the need for insulin prescription and worsening of survival.

Pamiparib, a small-molecule poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor, demonstrates strong PARP-DNA complex trapping, antitumor activity, and blood–brain barrier penetration. This phase Ib/II dose-escalation study (NCT03150862) investigated pamiparib’s tolerability/safety and efficacy when combined with radiotherapy and/or low-dose temozolomide (TMZ) in patients with treatment-naïve (Arms A and B) and recurrent/refractory (Arm C) glioblastoma. The recommended phase II dose for Arm A was pamiparib 60 mg twice daily (BID) for 6 weeks with 6–7 weeks radiotherapy; the recommended dose for Arm C was pamiparib 60 mg BID plus 60 mg TMZ (days 1–7; 28-day cycle). The Arm B escalation cohort completed enrollment; the expansion cohort was not opened. Grade ≥3 treatment-emergent adverse events (TEAEs)/serious TEAEs were observed in 55.0%/36.7% (Arm A), 44.4%/22.2% (Arm B), and 66.0%/38.3% (Arm C) of patients. Disease control and objective response rates were 67.9% and 11.3%, respectively, for treatment-naïve patients in the dose-escalation and -expansion studies, and 40.9% and 13.6%, respectively, for recurrent/refractory patients. Median overall survival for treatment-naïve MGMT unmethylated patients was 12.8 months and 7.3 months for recurrent/refractory MGMT methylated and unmethylated patients. Pamiparib with radiotherapy and/or low-dose TMZ was tolerable for treatment-naïve or recurrent/refractory glioblastoma. Treatment-emergent cytopenia was manageable and reversible with dose reductions/interruptions. Combination regimens demonstrated antitumor activity.

Vorasidenib (VOR) is an inhibitor of mutant isocitrate dehydrogenase 1/2 (mIDH1/2). We previously reported outcomes from an expanded access program (EAP; NCT05592743) providing VOR to people with mIDH1/2 glioma. Enrollment closed after FDA approval (August 2024); participants then transitioned off the program. Here, we describe the EAP population to highlight real-world use of VOR. Eligible participants were aged ≥12 years with mIDH1/2 glioma who, per their treating oncologist, would potentially benefit from VOR. Safety assessments occurred every 2 weeks for the first two 28-day cycles, and monthly thereafter. As of April 30, 2025, 153 participants (median age, 39 [range: 12–83] years; 84 [54.9%] male) had entered the EAP. Eighty-two (53.6%) had astrocytoma, 115 (75.2%) had grade 2 tumors, 119 (77.8%) had mIDH1 tumors, and 87 (56.9%) had undergone subtotal resection or biopsy. Most (n=85 [55.6%]) had ≥1 prior systemic treatment(s), including radiation ± chemotherapy (n=54), IDH inhibitors (n=35), chemotherapy only (n=11), and vaccine (n=1). At program closure, 124 (81.0%) participants were receiving VOR, 26 (17.0%) had discontinued VOR (disease progression, n=19; adverse events [AEs], n=2; other, n=6), and 3 (2.0%) had died (disease progression, n=2; unrelated infection, n=1). Median (range) durations of treatment were 220 (2–762) days in the overall population, 220 (11–762) and 209 (2–540) days, respectively, in participants with grade 2 and 3 gliomas, and 221.5 (11–762) days in participants with progressive/recurrent disease at initiation. Forty-eight (31.4%) participants had ≥1 AE (any grade), 5 (3.3%) had serious AEs, 11 (7.2%) had AEs of special interest (≥grade 2 ALT/AST elevations). These data provide additional insight into the real-world use and safety of VOR in a heterogeneous population that, in contrast to the Phase 3 INDIGO study, included patients with grade ≥3 tumors, prior systemic treatment, and was enriched for mIDH2.