Publications by authors named "Patrick Y Wen"

423 Publications

Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative.

Neurooncol Pract 2021 Aug 13;8(4):417-425. Epub 2021 Feb 13.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.

Methods: A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.

Results: A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).

Conclusion: Many different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
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http://dx.doi.org/10.1093/nop/npab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278354PMC
August 2021

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

J Immunother Cancer 2021 Jul;9(7)

Duke Cancer Institute, Duke University, Durham, North Carolina, USA

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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http://dx.doi.org/10.1136/jitc-2021-002459DOI Listing
July 2021

The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications.

Neuro Oncol 2021 Jun 29. Epub 2021 Jun 29.

Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC, USA.

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http://dx.doi.org/10.1093/neuonc/noab120DOI Listing
June 2021

SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

Neuro Oncol 2021 Jun 26. Epub 2021 Jun 26.

Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA and Harvard Medical School, Boston, MA, USA.

Objective: To update the 2000 American Academy of Neurology (AAN) practice parameter on anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

Methods: Following the 2017 AAN methodologies, a systematic literature review utilizing PubMed, EMBASE, Cochrane, and Web of Science databases was performed. The studies were rated based on the AAN therapeutic or causation classification of evidence (Class I-IV).

Results: Thirty-seven articles were selected for final analysis. There were limited high level, Class I studies and mostly Class II and III studies. The AAN affirmed the value of these guidelines.

Recommendations: In patients with newly diagnosed brain tumors who have not had a seizure, clinicians should not prescribe anti-epileptic drugs (AEDs) to reduce the risk of seizures (Level A). In brain tumor patients undergoing surgery, there is insufficient evidence to recommend prescribing AEDs to reduce the risk of seizures in the peri- or postoperative period (Level C). There is insufficient evidence to support prescribing valproic acid or levetiracetam with the intent to prolong progression-free or overall survival (Level C). Physicians may consider use of levetiracetam over older AEDs to reduce side effects (Level C). There is insufficient evidence to support using tumor location, histology, grade, molecular/imaging features, when deciding whether or not to prescribe prophylactic AEDs (Level U).
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http://dx.doi.org/10.1093/neuonc/noab152DOI Listing
June 2021

Deep Learning-Based Automatic Tumor Burden Assessment of Pediatric High-Grade Gliomas, Medulloblastomas, and Other Leptomeningeal Seeding Tumors.

Neuro Oncol 2021 Jun 26. Epub 2021 Jun 26.

Department of Diagnostic Imaging, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.

Background: Longitudinal measurement of tumor burden with MRI is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors.

Methods: A preoperative and postoperative cohort were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO criteria (AutoRAPNO) was determined. Performance was compared to that of two expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared.

Results: A total of 794 pre-operative MRIs from 794 patients and 1,003 post-operative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with ICCs of 0.912 and 0.960 for the two preoperative and 0.947 and 0.896 for the two postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC=0.909; Rater 3 ICC=0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions.

Conclusions: Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.
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http://dx.doi.org/10.1093/neuonc/noab151DOI Listing
June 2021

The Use of External Control Data for Predictions and Futility Interim Analyses in Clinical Trials.

Neuro Oncol 2021 Jun 9. Epub 2021 Jun 9.

Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA.

Purpose: External control data from completed clinical trials and electronic health records can be valuable for the design and analysis of future clinical trials. We discuss the use of external control data for early stopping decisions in randomized clinical trials (RCTs).

Methods: We specify interim analyses (IAs) approaches for RCTs, which allow investigators to integrate external data into early futility stopping decisions. IAs utilize predictions based on early data from the RCT, possibly combined with external data. These predictions at IAs express the probability that the trial will generate significant evidence of positive treatment effects. The trial is discontinued if this predictive probability becomes smaller than a pre-specified threshold. We quantify efficiency gains and risks associated with the integration of external data into interim decisions. We then analyze a collection of glioblastoma (GBM) datasets, to investigate if the balance of efficiency gains and risks justify the integration of external data into the IAs of future GBM RCTs.

Results: Our analyses illustrate the importance of accounting for potential differences between the distributions of prognostic variables in the RCT and in the external data to effectively leverage external data for interim decisions. Using GBM datasets, we estimate that the integration of external data increases the probability of early stopping of ineffective experimental treatments by up to 25% compared to IAs that don't leverage external data. Additionally, we observe a reduction of the probability of early discontinuation for effective experimental treatments, which improves the RCT power.

Conclusion: Leveraging external data for IAs in RCTs can support early stopping decisions and reduce the number of enrolled patients when the experimental treatment is ineffective.
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http://dx.doi.org/10.1093/neuonc/noab141DOI Listing
June 2021

Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.

Clin Cancer Res 2021 Jun 2. Epub 2021 Jun 2.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.

Patients And Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant (m) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.

Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.

Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0611DOI Listing
June 2021

Lessons learned from contemporary glioblastoma randomized clinical trials through systematic review and network meta-analysis: part 2 recurrent glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab029. Epub 2021 Feb 12.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Background: There exists no consensus standard of treatment for patients with recurrent glioblastoma (GB). Here we used a network meta-analysis on treatments from randomized control trials (RCTs) to assess the effect on overall survival (OS) and progression-free survival (PFS) to determine if any consensus treatment can be determined for recurrent GB.

Methods: We included all recurrent GB RCTs with at least 20 patients in each arm, and for whom patients underwent standard of care at the time of their GB initial diagnosis. Our primary outcome was OS, with secondary outcomes including PFS and adverse reactions. Hazard ratio (HR) and its 95% confidence interval (CI) of the comparison of study arms regarding OS and PFS were extracted from each paper. For comparative efficacy analysis, we utilized a frequentist network meta-analysis, an extension of the classic pair-wise meta-analysis. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses.

Results: Fifteen studies were included representing 29 separate treatment arms and 2194 patients. In our network meta-analysis, combination treatment with tumor-treating field and Vascular endothelial growth factor (VEGF) inhibitor ranked first in improving OS ( = .80). Concomitant anti-VEGF and Lomustine treatment was superior to Lomustine alone for extending PFS (HR 0.57, 95% CI 0.41-0.79) and ranked first in improving PFS compared to other included treatments ( = .86).

Conclusions: Our analysis highlights the numerous studies performed on recurrent GB, with no proven consensus treatment that is superior to the current SOC. Intertrial heterogeneity precludes drawing strong conclusions, and confidence analysis was low to very low. Further confirmation by future trials is recommended for our exploratory results.
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http://dx.doi.org/10.1093/noajnl/vdab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134527PMC
February 2021

Activity of PD-1 blockade with Nivolumab among patients with recurrent atypical/anaplastic meningioma: Phase II trial results.

Neuro Oncol 2021 May 20. Epub 2021 May 20.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Programmed death-1 ligand (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death-1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy.

Methods: Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.

Results: Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected AEs. PFS-6 was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was > 10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased post-treatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO.

Conclusion: Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.
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http://dx.doi.org/10.1093/neuonc/noab118DOI Listing
May 2021

Epidemiology of Brain Metastases and Leptomeningeal Disease.

Neuro Oncol 2021 Apr 28. Epub 2021 Apr 28.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.

Brain metastases affect a significant percentage of patients with advanced extracranial malignancies. Yet, the incidence of brain metastases remains poorly described, largely due to limitations of population-based registries, a lack of mandated reporting of brain metastases to federal agencies, and historical difficulties with delineation of metastatic involvement of individual organs using claims data. However, in 2016, the Surveillance Epidemiology and End Results (SEER) program released data relating to the presence versus absence of brain metastases at diagnosis of oncologic disease. In 2020, studies demonstrating the viability of utilizing claims data for identifying the presence of brain metastases, date of diagnosis of intracranial involvement, and initial treatment approach for brain metastases were published, facilitating epidemiologic investigations of brain metastases on a population-based level. Accordingly, in this review, we discuss the incidence, clinical presentation, prognosis, and management patterns of patients with brain metastases. Leptomeningeal disease is also discussed. Considerations regarding individual tumor types that commonly metastasize to the brain are provided.
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http://dx.doi.org/10.1093/neuonc/noab101DOI Listing
April 2021

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and F-FMISO PET.

Sci Rep 2021 Apr 7;11(1):7632. Epub 2021 Apr 7.

Mays Cancer Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (r = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (r = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.
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http://dx.doi.org/10.1038/s41598-021-84331-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027395PMC
April 2021

Report of National Brain Tumor Society Roundtable Workshop on Innovating Brain Tumor Clinical Trials: Building on Lessons Learned from COVID-19 Experience.

Neuro Oncol 2021 Apr 2. Epub 2021 Apr 2.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.
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http://dx.doi.org/10.1093/neuonc/noab082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083574PMC
April 2021

IDH-mutant gliomas with additional class-defining molecular events.

Mod Pathol 2021 Jul 26;34(7):1236-1244. Epub 2021 Mar 26.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

The 2016 WHO classifies IDH-mutant gliomas into oligodendroglioma or diffuse astrocytoma based on co-occurring genetic events. Recent literature addresses the concept of stratifying IDH-mutant gliomas based on prognostically significant molecular events. However, the presence of a second class-defining driver alteration in IDH-mutant gliomas has not been systematically described. We searched the sequencing database at our institutions as well as The Cancer Genome Atlas (TCGA) and cBioPortal for IDH-mutant gliomas with other potentially significant alterations. For each case, we reviewed the clinical information, histology and genetic profile. Of 1702 gliomas tested on our targeted exome sequencing panel, we identified 364 IDH-mutated gliomas, four of which had pathogenic FGFR alterations and one with BRAF V600E mutation. Five additional IDH-mutant gliomas with NTRK fusions were identified through collaboration with an outside institution. Also, a search in the glioma database in cBioPortal (5379 total glioma samples, 1515 cases [28.1%] with IDH1/2 mutation) revealed eight IDH-mutated gliomas with FGFR, NTRK or BRAF pathogenic alterations. All IDH-mutant gliomas with dual mutations identified were hemispheric and had a mean age at diagnosis of 36.2 years (range 16-55 years old). Co-occurring genetic events involved MYCN, RB and PTEN. Notable outcomes included a patient with an IDH1/FGFR1-mutated anaplastic oligodendroglioma who has survived 20 years after diagnosis. We describe a series of 18 IDH-mutant gliomas with co-occurring genetic events that have been described as independent class-defining drivers in other gliomas. While these tumors are rare and the significance of these alterations needs further exploration, alterations in FGFR, NTRK, and BRAF could have potential therapeutic implications and affect clinical trial design and results in IDH-mutant studies. Our data highlights that single gene testing for IDH1 in diffuse gliomas may be insufficient for detection of targets with potential important prognostic and treatment value.
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http://dx.doi.org/10.1038/s41379-021-00795-wDOI Listing
July 2021

Positron emission tomography imaging of drug concentrations in the brain.

Authors:
Patrick Y Wen

Neuro Oncol 2021 04;23(4):537-538

Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1093/neuonc/noab025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041320PMC
April 2021

Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma.

J Neurooncol 2021 May 1;152(3):515-522. Epub 2021 Mar 1.

Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.

Purpose: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors.

Methods: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed.

Results: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9).

Conclusion: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.
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http://dx.doi.org/10.1007/s11060-021-03719-5DOI Listing
May 2021

Adult precision medicine: learning from the past to enhance the future.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa145. Epub 2020 Oct 24.

Department of Oncology, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.

Despite therapeutic advances for other malignancies, gliomas remain challenging solid tumors to treat. Complete surgical resection is nearly impossible due to gliomas' diffuse infiltrative nature, and treatment is hampered by restricted access to the tumors due to limited transport across the blood-brain barrier. Recent advances in genomic studies and next-generation sequencing techniques have led to a better understanding of gliomas and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in the management of gliomas, with encouraging results in preclinical studies and early clinical trials. However, molecular characterization of gliomas revealed significant heterogeneity, which poses a challenge for targeted therapeutic approaches. In this context, leading neuro-oncology researchers and clinicians, industry innovators, and patient advocates convened at the inaugural annual Remission Summit held in Orlando, FL in February 2019 to discuss the latest advances in immunotherapy and precision medicine approaches for the treatment of adult and pediatric brain tumors and outline the unanswered questions, challenges, and opportunities that lay ahead for advancing the duration and quality of life for patients with brain tumors. Here, we provide historical context for precision medicine in other cancers, present emerging approaches for gliomas, discuss their limitations, and outline the steps necessary for future success. We focus on the advances in small molecule targeted therapy, as the use of immunotherapy as an emerging precision medicine modality for glioma treatment has recently been reviewed by our colleagues.
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http://dx.doi.org/10.1093/noajnl/vdaa145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846182PMC
October 2020

Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma.

Sci Rep 2021 Jan 27;11(1):2306. Epub 2021 Jan 27.

Dana Farber Cancer Institute, Boston, MA, USA.

Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m in combination with Bevacizumab 10 mg/kg IV every 2 weeks. Assessments included adverse events, response, and survival. Median age of patients was 47 (range 19-76) and 24 (69%) were male. At the time of study entry, 9 (26%) had ongoing corticosteroid use. ECOG performance status was 0 or 1 in 83% of patients. Patients were mostly heavily pretreated with 77% have three or more prior regimens. A total of 12 patients (36%) suffered grade 3-4 drug associated adverse event (AE); no grade 5 AE were reported. Of the 33 evaluable patients, best response was PR in 3 (9%), SD in 14 (43%), and PD in 16 (48%) with responses confirmed by a second reviewer. Median time to progression of disease was 53 days (95% CI 42-113) and Median time to death was 129 days (95% CI 86-199 days). Progression free survival at 4 months (PFS-4) on Evo-Bev was 31%, which was a statistically significant improvement over the historical rate of 3%. The median overall survival of patients receiving Evo-Bevacizumab was 4.6 months (95% CI 2.9-6.6). The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation.
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http://dx.doi.org/10.1038/s41598-021-81841-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841164PMC
January 2021

Seizures Among Patients with Brain Metastases: A Population- and Institutional-level Analysis.

Neurology 2021 Jan 5. Epub 2021 Jan 5.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.

Objective: To test the hypothesis that subets of patients with brain metastases (BrM) without seizures at intracranial presentation are at increased risk for developing seizures, we characterized the incidence and risk factors for seizure development among seizure-naïve patients with brain metastases (BrM).

Methods: We identified 15,863 and 1,453 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women's Hospital/Dana Farber Cancer Institute (2000-2015) institutional data, respectively. Cumulative incidence curves and Fine/Gray's competing risks regression were used to characterize seizure incidence and risk factors, respectively.

Results: Among SEER-Medicare and institutional patients, 1,588 (10.0%) and 169 (11.6%) developed seizures, respectively. On multivariable regression of the SEER-Medicare cohort, African American vs. White race (hazard ratio [HR]=1.45 [95% CI, 1.22-1.73], p<0.001), urban vs. non-urban residence (HR=1.41 [95% CI, 1.17-1.70], p<0.001), melanoma vs. NSCLC as primary tumor type (HR=1.44 [95% CI, 1.20-1.73], p<0.001), and receipt of brain-directed stereotactic radiation (HR=1.67 [95% CI, 1.44-1.94], p<0.001) were associated with greater seizure risk. On multivariable regression of the institutional cohort, melanoma vs. NSCLC (HR=1.70 [95% CI, 1.09-2.64], p=0.02), >4 BrM at diagnosis (HR=1.60 [95% CI, 1.12-2.29], p=0.01), presence of BrM in a high-risk location (HR=3.62 [95% CI, 1.60-8.18], p=0.002), and lack of local brain-directed therapy (HR=3.08 [95% CI, 1.45-6.52], p=0.003) were associated with greater risk of seizure development.

Conclusions: The role of antiseizure medications among select patients with BrM should be re-explored, particularly for those with melanoma, a greater intracranial disease burden, and/or BrM in high-risk locations.
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http://dx.doi.org/10.1212/WNL.0000000000011459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055345PMC
January 2021

Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank.

Neuro Oncol 2021 03;23(3):356-375

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.
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http://dx.doi.org/10.1093/neuonc/noaa277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992879PMC
March 2021

Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa124. Epub 2020 Sep 17.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs.

Methods: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6).

Results: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated.

Conclusion: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.
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http://dx.doi.org/10.1093/noajnl/vdaa124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668489PMC
September 2020

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma.

Clin Cancer Res 2021 Feb 16;27(4):1048-1057. Epub 2020 Nov 16.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.

Patients And Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, = 50) or pembrolizumab monotherapy (cohort B, = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.

Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant , unmethylated , and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284901PMC
February 2021

Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials.

Neuro Oncol 2021 02;23(2):189-198

UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, University of California Los Angeles, Los Angeles, California, USA.

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.
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http://dx.doi.org/10.1093/neuonc/noaa253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906061PMC
February 2021

A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma.

Neuro Oncol 2021 03;23(3):468-477

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Background: No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.

Methods: Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected.

Results: The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.

Conclusions: This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.
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http://dx.doi.org/10.1093/neuonc/noaa240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992893PMC
March 2021

Population-based estimates of survival among elderly patients with brain metastases.

Neuro Oncol 2021 04;23(4):661-676

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Prognostic estimates for patients with brain metastases (BM) stem from younger, healthier patients enrolled in clinical trials or databases from academic centers. We characterized population-level prognosis in elderly patients with BM.

Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified 9882 patients ≥65 years old with BM secondary to lung, breast, skin, kidney, esophageal, colorectal, and ovarian primaries between 2014 and 2016. Survival was assessed by primary site and evaluated with Cox regression.

Results: In total, 2765 versus 7117 patients were diagnosed with BM at primary cancer diagnosis (synchronous BM, median survival = 2.9 mo) versus thereafter (metachronous BM, median survival = 3.4 mo), respectively. Median survival for all primary sites was ≤4 months, except ovarian cancer (7.5 mo). Patients with non-small-cell lung cancer (NSCLC) receiving epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-based therapy for synchronous BM displayed notably better median survival at 12.5 and 20.1 months, respectively, versus 2.8 months exhibited by other patients with NSCLC; survival estimates in melanoma patients based on receipt of BRAF/MEK therapy versus not were 6.7 and 2.8 months, respectively. On multivariable regression, older age, greater comorbidity, and type of managing hospital were associated with poorer survival; female sex, higher median household income, and use of brain-directed stereotactic radiation, neurosurgical resection, or systemic therapy (versus brain-directed non-stereotactic radiation) were associated with improved survival (all P < 0.05).

Conclusions: Elderly patients with BM have a poorer prognosis than suggested by prior algorithms. If prognosis is driven by systemic and not intracranial disease, brain-directed therapy with potential for significant toxicity should be utilized cautiously.
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http://dx.doi.org/10.1093/neuonc/noaa233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041328PMC
April 2021

Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas.

Cell Rep 2020 09;32(13):108196

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110α and p110β, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110α for proliferation and p110β for migration. Genetic ablation of either isoform delays tumor progression in mice, but only ablating both isoforms completely blocks GBM driven by the concurrent ablation of Pten and p53. BKM120 (buparlisib) treatment only modestly prolongs survival in mice bearing intracranial Pten/p53 null tumors due to partial pathway inhibition. BKM120 extends the survival of mice bearing intracranial tumors in which p110β, but not p110α, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110β effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110β and indicates a need to develop brain-penetrant p110α/β inhibitors.
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http://dx.doi.org/10.1016/j.celrep.2020.108196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571617PMC
September 2020

Exploring Predictors of Response to Dacomitinib in -Amplified Recurrent Glioblastoma.

JCO Precis Oncol 2020 8;4. Epub 2020 Jun 8.

Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Purpose: Despite the high frequency of genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial.

Patients And Methods: We retrospectively explored whether previously described extracellular domain (ECD)-sensitizing mutations in the context of gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration.

Results: We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of or ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression.

Conclusion: While dacomitinib was not effective in most patients with -amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, and ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.
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http://dx.doi.org/10.1200/PO.19.00295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446412PMC
June 2020

Response to Letter to Editor.

Neuro Oncol 2020 11;22(11):1706-1707

UCLA Brain Tumor Imaging Laboratory, Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

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http://dx.doi.org/10.1093/neuonc/noaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690353PMC
November 2020

Dabrafenib plus trametinib in patients with BRAF-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.

Lancet Oncol 2020 09 17;21(9):1234-1243. Epub 2020 Aug 17.

Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA.

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAF-mutated biliary tract cancer.

Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAF-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.

Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAF-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.

Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF mutations should be considered in patients with biliary tract cancer.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(20)30321-1DOI Listing
September 2020

Highlights of the 2019 Society for Neuro-Oncology Inaugural Brain Metastases Conference: establishing a dedicated meeting to address an unmet need in the field.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa036. Epub 2020 Jan 28.

Division of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Brain metastases comprise the majority of central nervous tumors in adults and confer poorer survival for patients with primary cancer. Systemic disease control is improving with advances in treatment for primary tumors and the complexity of brain metastases management is increasing with multimodality approaches incorporating combinations of surgery, radiotherapy, chemotherapy, targeted therapies, and immunotherapy. Accordingly, the Society for Neuro-Oncology established an annual brain metastases conference to unite colleagues from multiple disciplines with content spanning a range of timely topics relevant to improving our understanding of brain metastases and how they are optimally treated. The inaugural meeting on August 16-17, 2019 was very successful with 163 impactful presentations being delivered to a large multidisciplinary audience on current research advances in the field of neuro-oncology. This review summarizes the major themes of the meeting and highlights the main findings presented.
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http://dx.doi.org/10.1093/noajnl/vdaa036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415252PMC
January 2020