bluuebunny/crossref_metadata_2025 huggingface dataset:
Pivotal trial endpoints and prices of cancer drugs in the US and Europe.
Authors: Vokinger Kerstin Noëlle , Daniore Paola , Hwang Thomas J , Lee ChangWon C , Kesselheim Aaron S
Published: May 2020

2077

Background: A key clinical outcome for new cancer drugs is improvement in overall survival (OS), defined as time from the date of randomization to the death from any cause. However, many cancer drugs are approved by regulators based on changes to surrogate measures of OS, such as progression-free survival or overall response rate. When surrogate measures are not validated, they can provide misleading information about drug efficacy. We categorized pivotal trial endpoints for recently-approved cancer drugs in the US and Europe as showing improvements in OS vs non-OS surrogates, and evaluated the correlation with drug prices. Methods: We identified new drugs FDA-approved between 2009 and 2018 that were indicated to treat solid and hematologic tumors in adults and that had also been approved by the EMA and Swissmedic by December 2019. Launch prices were extracted and adjusted to average sales prices for monthly treatment costs in the US and compared to currency-adjusted ex-factory monthly treatment costs in Germany, Switzerland, and England. Pivotal clinical trial primary endpoints were collected from the drug labeling and FDA medical reviews for the US, and the EMA public assessment reports for Europe, and categorized as OS in any trial vs. not. Pearson’s correlation tests assessed the association between launch prices and OS vs non-OS endpoints in each country. Results: 54 drugs were approved by the FDA, EMA, and Swissmedic during the study period. In the US, 30 (56%) were approved based on OS by contrast to 35 (65%) in the EMA. The number of cancer drugs approved by the FDA based on OS decreased in the past years. By contrast, the number of approved cancer drugs by the EMA based on OS were stable. There was no association for the US (p = 0.05), Germany (p = 0.13) and England (p = 0.12), while Switzerland revealed an association (p = 0.03) between OS endpoint and price. Conclusions: Reductions in use of OS endpoints as the basis for cancer drug approval in the US is concerning. Drug pricing should be better aligned with the benefit that drugs provide to patients, as measured by clinical trial outcomes such as OS.
Understanding practice variation with a clinical pathways system: Differences by physician and practice factors, and changes in practice over time.
Authors: Foster Emily , Stuver Sherri Oliver , Tremonti Carole Kathleen , Bunnell Craig A. , Hamilton Joanna M. , Jacobson Joseph O. , Jackman David Michael
Published: May 2020

2079

Background: Clinical oncology pathways aim to support clinical decision-making and reduce unwarranted practice variation across an enterprise. The Dana-Farber Cancer Institute (DFCI) implemented web-based oncology pathways with DFCI-customized content in each disease center and at each of its satellites. Our pre-specified aim was an on-pathway rate of 70-85%. Methods: Treatment decisions were electronically captured as on- or off- pathway. Monthly metrics about usage and on-pathway rate were shared with users on a monthly basis. Physicians were categorized into quintiles based on the calculated on-pathway performance during the first 90 days of each individual’s use of the platform. On-pathway rates were then calculated for days 91-360 to study changes in behavior over time. Physician and practice factors were examined to determine any differences by initial on-pathway quintile classification. Results: 122 physicians were eligible for inclusion in this analysis (minimum 5 navigations in each study period). On-pathway rates showed significant variability in the initial 90-day period: quintile 1 median 100%, quintiles 2-4 80.2%, and quintile 5 50% (Table). In the follow-up period, median on-pathway rates shifted into the pre-specified goal range for all groups. Physicians in quintiles 1 or 5 of initial on-pathway rate were more likely to have fewer total navigations than were physicians in quintiles 2-4 (p=0.003). While no other physician or practice characteristic differed significantly by on-pathway rate group, physicians in the first or last quintile were more likely to be in an academic setting, have a PhD, or navigate fewer pathways. Conclusions: Over time, the deployment of a web-based clinical pathways program resulted in greater uniformity in physician practice, based on on-pathway rate. Familiarity with the pathways platform and its navigation, monthly feedback about usage, and evolution of content over time are some factors that might have played a role. [Table: see text]
Association of financial conflicts of interest with academic success among junior faculty in hematology and oncology.
Authors: Fought Angela J. , Davis Andrew A. , Shaw Melissa M. , Prasad Vinay , Kamath Suneel Deepak
Published: May 2020

2080

Background: Financial conflict of interest (COI) represents a complex issue in hematology and oncology. Little is known about when COIs develop during a career and if these correlate with early career success. We evaluated self-reported COIs for junior faculty members at 10 academic cancer centers and examined if these financial relationships with industry correlated with measures of academic career success. Methods: The study evaluated 229 assistant professors from the top 10 cancer centers based on the 2018 US News Cancer rankings. Faculty characteristics were determined from hospital websites including the number of years since completing fellowship. Data regarding National Institute of Health (NIH) funding were obtained. Industry funds (Sunshine Act funds; SAF) were identified from the Centers for Medicare & Medicaid Services (CMS) Open Payments database from 2013-2017. Self-reported COIs were obtained from the American Society of Clinical Oncology (ASCO) or American Society of Hematology (ASH) disclosures databases, and through review of disclosures from recent publications. Measures of academic success included h-index and number of publications. We assessed the influence of number of COIs and SAF received on measures of academic success. Results: Of the 229 included faculty, 45% were female, 39% graduated fellowship in 2015 or later, 35% were double-boarded, 40% had dual degrees and 15% received NIH funding. Approximately 46% of faculty had at least 1 COI. COIs (ASCO/ASH) were positively correlated with COIs self-reported in publications and total SAF (Spearman correlations 0.57 and 0.54, both P < 0.01). The development of COIs and the number of SAF increased with years in practice (Spearman correlations 0.37 and 0.28, both P < 0.01). COIs and SAF correlated with h-index (Spearman correlation 0.40 and 0.41, both P < 0.01). After adjusting for years since fellowship, linear regression demonstrated that log-transformed h-index and number of publications were associated with SAF (P < 0.01) and COIs (ASCO/ASH) (P = 0.01). Conclusions: Financial COIs were present in nearly half of the faculty and increased with more time since completing fellowship. Measures of academic success were positively correlated with COIs (ASCO/ASH) and SAF. These data suggest that cultivating industry relationships may aid faculty in establishing early academic success.
Telemedicine visits reduce time to biopsy, travel time and costs for interventional radiology patients.
Authors: Shah Suken , Erinjeri Joseph , Guan Qiu Xia , Otto Christian , Solomon Stephen Barnett
Published: May 2020

2082

Background: Telemedicine has been utilized to increase access to care for patients in primary care practices and more recently, specialty practices. The purpose of the study was to test the hypothesis that adding a telemedicine clinic practice could decrease the time to biopsy, travel time and cost for interventional radiology (IR) clinic patients. Methods: Telemedicine visits were performed by a physician or advanced practice provider (PA or NP) at a single institution, academic medical center to patients at 3 MSK regional locations in NY and NJ. Total patient encounters and data from November 2017 to October 2019 were analyzed. Primary outcome measures were wait time from the IR referral to biopsy procedure visits, patient travel time and travel cost, stratified by in-person vs telemedicine visit. Round-trip travel distance and costs for patients were calculated by determining the offset travel. Cost (economic) benefit was the sum of: Federal cost per mile for travel, toll and parking costs, and doctor visit lost wages. Results: There were 172 MSK Regional site telemedicine visits. There was a significant reduction in time from referral to biopsy for telemedicine visits compared to in-person visits (12 vs 17 days, p < 0.0001). Additionally, there was a significant reduction in travel time for telemedicine visits vs travel time to Manhattan for an in-person visit (p < 0.0001). Telemedicine visit patients had to travel 367 less hours than an in-person visit and saved a total of 11,222 in miles that they did not have to travel. Telemedicine patients accrued $14,652 in economic benefits due to reduced travel costs and lost wages from work. Conclusions: Telemedicine significantly reduced the time to biopsy, travel time and cost for Interventional Radiology patients compared to in-person visits. Telemedicine for IR patients increases access to care for patients and allow for more efficient use of physician time and resources.
Controlled IL-12 in combination with a PD-1 inhibitor subjects with recurrent glioblastoma.
Authors: Chiocca E. Antonio , Lukas Rimas Vincas , Chen Clark C , Rao Ganesh , Amidei Christina , Buck Jill Yannetti , Hadar Nira , Demars Nathan A. , Miao John , Estupinan Taylor , Loewy John W. , Wang Yunxia , Gelb Arnold Bruce , Cooper Laurence JN
Published: May 2020

2510

Background: Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (“Controlled IL-12”), was shown in a phase 1 study (NCT02026271) to elicit a new and sustained intra-tumoral infiltration of T cells with co-expression of PD-1. We report updated findings following completion of enrollment (with follow-up ongoing) for a phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, Controlled IL-12 in combination with nivolumab (nivo) in adults with recurrent glioblastoma (rGBM). Methods: Multicenter, open label, dose-escalation phase 1 trial to evaluate safety and tolerability of local, Controlled IL-12 with nivo in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles, Day 0 at time of resection) plus V (10 or 20 mg) PO QD x 15 with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Results: 21 subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n = 3; Cohort 2: V 10 mg, nivo 3 mg/kg, n = 3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n = 3 + 12 expansion). Safety data were similar to Ad+V monotherapy. Adverse reactions during follow-on nivo dosing were consistent with anti-PD-1 labeling, manageable, and generally reversible with no synergistic toxicities. Focusing on the 20mg V cohort (recommended phase 2 dose), serum IL-12 mean ± SEM (screening, 0.4 ± 0.1 pg/mL; Day 0, 0.6 ± 0.1 pg/mL), increased after Ad+V to 8.7 ± 3.3 pg/mL on Day 3. Similarly, serum IFN-g levels did not increase due to nivo alone (screening, 0 ± 0 pg/mL; Day 0, 0 ± 0 pg/mL), increasing after Ad+V to 6.2 ± 2.3 pg/mL on Day 7. Additionally, nivo alone did not significantly increase circulating T cells (CD3+ CD8+%) (paired differences comparison, Day 0 to screening) 3.1%, p =0.13, whereas Ad+V significantly increased peripheral T cells (Day 28 - Day 0) 3.6%, p =0.02. Pseudoprogression followed by a decrease in size (SPD) has been shown as evidenced by serial MRIs in a subgroup of subjects. Preliminary overall survival findings will be presented. Conclusions: Controlled IL-12 with PD-1 inhibition is a rational combination with initial data consistent with immune-mediated effects, a favorable safety profile, and early evidence of anti-tumor effects. An additional phase 2 study combining Controlled IL-12 with cemiplimab-rwlc in adults with rGBM is ongoing. Clinical trial information: NCT03636477 .
Inefficiencies in the phase II to phase III transition as a modifiable factor that is impeding successful drug development for glioblastoma.
Authors: Balasubramanian Adithya , Gunjur Ashray , Hafeez Umbreen , Menon Sid , Cher Lawrence , Parakh Sagun , Gan Hui Kong
Published: May 2020

2516

Background: Improving the outcomes of patients with glioblastoma (GBM) represents one of the most significant challenges in neuro-oncology. We have observed inefficiencies in the availability and use of phase 2 data when planning phase 3 studies, and have undertaken a detailed review of key design parameters of phase 2 and 3 trials in GBM to identify and quantify the impact of this phenomenon. Methods: Studies between 2005-2019 inclusive were identified though MEDLINE search using keywords and MeSH terms, and manual bibliography searches. P2Ts were restricted to those referenced by the corresponding P3Ts. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&AG). For each P3T, corresponding Phase 2 trial (P2T) data was “optimally matched” (OM) where same drug was used in similar schedule and similar GBM population; “partially matched” (PM) where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. The statistical data used in the P2/3 transition were compared by Pearson Correlation, Fisher’s Exact or Chi-square testing as appropriate. Results: Of 20 P3Ts identified, 6 (30%) lacked any phase 2 data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). Further, there were 13 OM dyads and 7 PM dyads. OM dyads showed strong concordance for mPFS (r2= 0.95, p < 0.01) and mOS (r2= 0.84, p < 0.01), whilst PM dyads did not (p > 0.05). We identified several inefficiencies in translation from P2T to P3T. Firstly, 3 P3T had statistical assumptions of primary endpoint that may have been too optimistic. 2 of these P3Ts aimed for an expected endpoint that was higher than the actual outcomes from a matched P2T. 1 P3T was unable to reach the desired sample size. We note that 4 P3Ts had actual primary endpoint HRs that were < 0.9 but with P > 0.05. Finally, we investigated whether there were absolute thresholds for efficacy in P2Ts to inform whether to proceed with P3Ts. For P2Ts in the newly diagnosed setting, all those with mPFS < 14 months and/or mOS < 22 months had subsequent negative P3Ts. For P2Ts in recurrent disease, all those with mPFS < 6 months and mOS < 12 months had negative P3Ts. Applying these thresholds to the studies in our review, 10 of the 12 negative P3Ts (83%) with matched P2Ts need not have been initiated, sparing 4739 patients’ from unnecessary trial participation. Conclusions: Our data strongly supports the vital role of properly designed P2Ts in informing P3Ts for drug development for primary CNS tumours.
Immune microenvironment profiling of breast cancer brain metastases using multiplex immunofluorescence.
Authors: Griguolo Gaia , Tosi Anna , Guarneri Valentina , Dieci Maria Vittoria , Fineberg Susan , Ventura Annavera , Bauchet Luc , Jacob Jack , Rigau Valerie , Jacot William , Rosato Antonio , Darlix Amelie , Conte Pier Franco
Published: May 2020

2526

Background: Despite clinical implications, the complexity of brain metastases (BM) immune microenvironment in breast cancer (BC) patients is poorly understood. Multiplex immunofluorescence (mIF), a novel imaging technique allowing simultaneous visualization and quantification of several IF labeled proteins while maintaining spatial information, holds promise to comprehensively describe BCBM immune microenvironment, potentially providing valuable information to improve treatment. Methods: Clinical data and archival BM samples were collected for 60 BC patients undergoing neurosurgery (2003-2018) at three institutions. BM immune contexture was characterized using a custom mIF panel, including cell subtyping (CD4, CD8, FOXP3, CD68), activation (Granzyme B) and localization (keratin for tumor recognition) markers. Mean immune cell density (cells/mm2) for each sample was determined by digital image analysis and classified in tumor and stroma areas. Associations between immune subpopulations, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Up to date, 30 BCBM samples have been analyzed; 33% HR+/HER2-, 20% HR-/HER2+, 10% HR+/HER2+, 37% HR-/HER2-. At a median follow-up of 46 months, BC subtype was the only clinical variable associated with OS (longest for HER2+ and shortest for HR-/HER2-, log-rank p = 0.002). In the total sample area, no significant difference in immune cell densities was observed according to BC subtype. In the tumor area, HR+/HER2- tumors showed higher densities of CD8+ and CD68+ cells compared to other subtypes (p = 0.036 and p = 0.016, respectively). In stroma, HR-/HER2- tumors presented numerically higher densities of CD4+ and FOXP3+ cells and higher ratio of CD4/CD8 and FOXP3/CD8 ratio (not statistically significant). Higher CD4/CD8 and FOXP3/CD8 ratio in the stroma was significantly associated with worse OS, even after correction by BC subtype (Table). Conclusions: In BCBM, immune infiltrate differs according to BC subtype. Preliminary results suggest that a more tolerogenic immune microenvironment is associated with worse OS and might represent a target for optimization of immunotherapy for these patients. Updated results for all 60 patients will be presented. [Table: see text]
Clinical outcome of patients experiencing central nervous system progression on first-line pertuzumab and trastuzumab for HER2-positive metastatic breast cancer in a real-life cohort.
Authors: Collet Laetitia , Eberst Lauriane , Fraisse Julien , Debled Marc , Levy Christelle , Mouret-Reynier Marie-ange , Desmoulins Isabelle , Goncalves Anthony , Campone Mario , Ferrero Jean-Marc , Brain Etienne , Dieras Veronique , Petit Thierry , Simon Gaetane , Leheurteur Marianne , Dalenc Florence , Vanlemmens Laurence , Darlix Amelie , Arnedos Monica , Bachelot Thomas
Published: May 2020

2527

Background: Isolated central nervous system (CNS) progression on first-line systemic therapy with Trastuzumab (T) and Pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) is a therapeutic challenge. Our aim was to describe the clinical outcome and current treatment strategies for such patients in a large retrospective cohort. Methods: Patients (pts) were selected among all MBC pts included in the French Epidemiological Strategy and Medical Economics (ESME) database involving 18 specialized cancer centers (NCT03275311). CNS progression-free survival (CNS-PFS), progression-free survival (PFS) and overall survival (OS) from diagnostic of brain metastases (BM) were estimated using the Kaplan-Meier method. Results: Between January 2008 and December 2016, 995 pts were treated with first-line T and P for their HER2-positive MBC. They were 55 years old in median, with tumors expressing hormone-receptors in 62%. A total of 132 pts (13%) experienced isolated CNS progression on T and P, with a median time from metastatic diagnosis to CNS progression of 12 months. It was the first CNS progression for 108 pts (82%) while 24 (18%) already had BM at time of metastatic relapse. After CNS progression, T and P were continued for 58% of pts (n = 73). The remaining 47 pts were switched to another HER2-directed therapy (T-DM1 for 57%, T alone or combined with chemotherapy for 36% and lapatinib for 21%). Among those 132 pts, 37% received whole-brain radiotherapy, 18% stereotactic radiation therapy, and 11% surgery. Systemic treatment was combined with CNS-directed therapy for 50% of pts. Median follow-up is 21 months (95%CI: 14.9-25.5) from the diagnosis of CNS metastases. Median OS (mOS) of the 132 pts is 35 months (95%CI: 29.2-53,6), and median PFS 7 months (95%CI: 6.3- 9.2). A total of 77 pts (58.3%) experienced a new CNS progression with a median CNS-PFS of 9 months (95%CI: 7.6-12,0). Patient who stayed on T and P had a significantly better OS in comparison to pts who were switched to another systemic HER2-directed therapy (mOS not evaluable vs23 months), whereas PFS and CNS-PFS were similar between groups. Conclusions: In this real life setting, isolated CNS progression occurred among 13% of pts with HER2+ MBC on first-line treatment with T and P, after a median time of 12 months. Following current ASCO recommendations, continuation of T and P after CNS-directed therapy, seemed to be adequate. Nevertheless, time to subsequent progression is short and better therapeutic options are needed.
Radiation-induced changes in the inflammatory microenvironment composition of lung cancer brain metastases.
Authors: Steindl Ariane , Mair Maximilian , Starzer Angelika Martina , Dieckmann Karin , Widhalm Georg , Hainfellner Johannes A. , Schmidinger Manuela , Preusser Matthias , Berghoff Anna Sophie
Published: May 2020

2528

Background: Radiotherapy was postulated to impact the inflammatory microenvironment composition in patients with lung cancer brain metastases (BM). Methods: Formalin fixed and paraffin embedded BM specimens from treatment naïve patients (group 1) and from patients treated with radiation therapy including whole brain radiotherapy and/or stereotactic radiosurgery (group 2) or prophylactic cranial irradiation (group 3) before BM resection were identified from the Vienna Brain Metastasis Registry. T cell subsets (CD3+,CD8+,CD45RO+,FOXP3+,PD-L1+) were investigated using the Ventana Benchmark Ultra system Definiens software. Results: Specimens from 41 patients (28/41;68.3% NSCLC, 13/41;31.7% SCLC) were included in the study. A significant difference in CD3+TIL density between group 1 (median: 964.5cells/mm2) and group 2 (median: 283.4cells/mm2; p-value=0.021; Mann-Whitney-U test), as well as group 3 (median: 168.8 cells/mm2; p-value= 0.028; Mann-Whitney-U test) were observed. Furthermore, CD8+ and FOXP3+TIL densities of group 2 (CD8+ median: 172.1cells/mm2; FOXP3+ median: 210.7cells/mm2) were numerically lower compared to group 1 (CD8+ median: 190.1 cells/mm2; FOXP3+ median: 221.2 cells/mm2). Of 10/41 (24.4%) patients further resected BM tissue specimens after initial resection were available. Here, the inflammatory microenvironment of BM treated with radiation therapy between the resections was significantly associated with lower densities of CD3+ (median: 105.1 cells/mm2) and CD8+ (median: 20.3cells/mm2) compared to radiation-naïve patients (CD3+ median: 825.4cells/mm2; CD8+median: 105.5cells/mm2; p=0.037; Mann-Whitney U-test). Conclusions: Radiation treatment was associated with lower densities of TIL subsets in our BM cohort. Although results have to be interpreted with caution due to the limited sample size, further studies investigating the sequencing of radiotherapy and immune modulating therapies might be of interest. [Table: see text]
Application of machine learning algorithms for the diagnosis of primary brain tumors.
Authors: Khammad Vasilii , Otero Jose Javier , Cabello Izquierdo Yolanda , Garagorry Guerra Francisco , Becker Aline P. , Kharchenko Nataliy , Zapirov Gadzhimurad
Published: May 2020

2533

Background: Primary lesions of the CNS refer to a heterogeneous group of benign or malignant tumors arising in different parts of the brain and spinal cord. According to the 2016 CNS WHO classification, the accurate diagnosis of primary brain tumors requires a layered approach of histologic, anatomic and molecular features to generate an integrated diagnosis with clinical and prognostic significance. However, in the US and worldwide, scarce resources are available to perform all the required tests routinely, so methods that improve pre-test probabilities and decrease false positive results have significant clinical and financial impact. Aims: 1) validate new diagnostic workflows with implementation of modern machine learning/artificial intelligence approaches; 2) design a reliable and interactive computational platform for primary CNS tumor diagnosis. Methods: To achieve these goals we have developed a population model in Rstudio, “La Tabla”, based on the articles from open resources of MEDLINE database and the latest version of WHO classification of CNS tumors. The data of “La Tabla” is comprised of more than 100,000 adult and pediatric cases, including rare brain tumor diagnoses, such as Gangliocytoma, Diffuse Midline Glioma and etc. Results: Boruta package and weights function in R have been used to distinguish the most important features for diagnosis prediction. To visualize correlation between these features (age, ki67 level, tumor location, presence of myxoid areas, calcifications, necrosis and etc.) and all diagnoses in two-dimensional space, we used a t-SNE algorithm. Models trained with decision tree algorithms (randomForest, XGBoost and C5.0) showed high overall accuracy in predicting diagnoses of “La Tabla” (95%, 94% and 92%) and 300 patients at OSUCCC-James (93%, 74% and 87%) in the absence of IHC and molecular data. Neural networks provided by keras and nnet packages predicted diagnoses using just clinical and histological findings with 94% and 88% accuracy on “La Tabla” and James patient databases respectively. Currently, we are building “Shiny” applications with R to deliver easily operated platform for pathologists and physicians. Conclusions: In conclusion, we managed to generate models that are able to diagnose primary brain lesions using basic clinical data (age, gender, tumor location), ki67 levels and distinct features of histological architecture. Most of the models distinguish brain tumors and associated molecular status with high accuracy and will serve as a reliable tool for second opinion in clinical neuro-oncology.
Clinical outcomes of the combination of bevacizumab and ttfields in patients with recurrent glioblastoma: Results of a phase II clinical trial.
Authors: Fallah Jaleh , Chaudhary Rekha T. , Rogers Lisa R. , Wei Wei , Brewer Cathy J. , Peereboom David M. , Ahluwalia Manmeet Singh
Published: May 2020

2537

Background: Clinical trials of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients (pts) with recurrent glioblastoma (GBM), with median progression-free survival (PFS) of 2-4 months and median overall survival (OS) of 6-9 months with either treatment modality. In a single-arm phase II clinical trial, the efficacy of the combination of bevacizumab and TTFields in pts with recurrent GBM was investigated. Methods: Pts with histologically confirmed GBM or other grade IV gliomas, who had disease progression after chemoradiation were enrolled in a phase II trial of the combination of bevacizumab and TTFields. Bevacizumab was given at a dose of 10 mg/Kg intravenously every 2 weeks and TTFields was worn by the pts continuously for more than 18 hours per day. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints were PFS at 6 months and OS at 12 months. Survival outcomes were assessed using the Kaplan-Meier method and compared by log rank test. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria. Results: From April 2013 to December 2017, 25 pts were enrolled and 23 were evaluable: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 pts were Caucasian, 1 was African American and 1 of unknown race. After a median follow up of 31.6 months (range: 4.1-59.0 months), 21 out of 23 pts died (4 women and 17 men). The median PFS was 4.1 months (95%CI, 3.6-9.5) and the median OS was 10.5 months (95% CI, 8.2-14.9). The PFS rate at 6 and 12 months were 33% and 19%, respectively. The OS rate at 6 and 12 months were 82% and 46%, respectively. Women had better OS and PFS compared to men, however, the difference was not statistically significant which can be due to the small study population (table). Grade 3 and 4 toxicities considered definitely or probably related to the treatment included hypertension (n = 1) and cerebral infarction (n = 1). Other reported grade 3-4 toxicities (n = 7) included cough, dysphagia, muscle weakness, hyperglycemia, psychosis, seizure, lymphopenia, transaminitis, and muscle weakness considered unlikely to be treatment-related. Conclusions: The combination of bevacizumab and TTFields in is safe and feasible and has clinical efficacy in pts with recurrent GBM. Clinical trial information: NCT01894061 . [Table: see text]
Phase Ib clinical trial of OKN-007 in recurrent malignant glioma.
Authors: Battiste James D. , Ikeguchi Alexandra , Woo Sukyung , Sharan Satish , Zhao Yan D. , Cohoon Andrew , Sung Sarah , Wright Deborah , Teague April M. , Jensen Randy L. , Kim Eun Ha , Yang Won S. , Towner Rheal A.
Published: May 2020

2538

Background: Despite therapeutic advances, the median overall survival for patients with recurrent, high-grade gliomas remains poor. Thus, there is an urgent need for efficacious new therapies. The nitrone compound, OKN-007 (disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is a promising novel anti-cancer agent. In orthotopic glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. Methods: NCT01672463 is a phase Ib trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. Patients with recurrence, adequate performance status and organ function, receiving clinically appropriate doses of steroids, with a life expectancy greater than 8 weeks were eligible. OKN-007 was administered by IV. The study comprised a 3+3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until recurrence (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Median age was 51 years (range, 25-62). No dose-limiting toxicities were observed and 60 mg/kg was chosen for the expansion dose. Of 123 adverse events (AE), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAE were fatigue (4.1%) and headache (3.3%). No drug-attributable grade 4 or 5 AE were observed. Grade 3 TEAE included headache, urinary tract infection, and increased prothrombin time (0.8% each). Only two grade 1 AE, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. Conclusions: OKN-007 appears safe for patients with recurrent glioma. The MTD was not reached. Our data suggest that, compared to standard therapy, OKN-007 may prolong OS in recurrent glioma. Based on new data, a trial of OKN-007 plus temozolomide is underway in patients with newly diagnosed glioblastoma (NCT03587038). Clinical trial information: NCT01672463 .
Post-marketing safety surveillance of tumor treating fields (TTFields) in patients with high-grade glioma in clinical practice.
Authors: Shi Wenyin , Blumenthal Deborah T. , Oberheim Bush Nancy Ann , Kebir Seid , Lukas Rimas Vincas , Muragaki Yoshihiro , Zhu Jay-Jiguang , Glas Martin
Published: May 2020

2542

Background: Tumor Treating Fields (TTFields) are an antineoplastic treatment delivering low intensity, intermediate frequency, alternating electric fields through two pairs of transducer arrays locoregionally applied to tumor bed. TTFields are FDA-approved for glioblastoma (GBM; 200 kHz) and mesothelioma (150 kHz). Safety and effectiveness were demonstrated in the phase III EF-11 and EF-14 trials in recurrent GBM (rGBM) and in newly diagnosed GBM (ndGBM), respectively. The main TTFields-related adverse event (AE) was array-associated manageable skin irritation. We report AEs from TTFields-treated patients in the real-world, clinical practice setting. Methods: Unsolicited, global, post-market surveillance data from TTFields-treated patients (October 2011–February 2019) were retrospectively analyzed using MedDRA v21.1, stratified by region (US, EMEA [Europe, Middle East, Africa], or Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma and anaplastic oligodendroglioma, or other brain tumors that includes brain metastases from different cancer types), and years of age (<18, pediatric; 18 to 64, adults; or ≥65, elderly). Results: Of 11,029 patients, 53% had ndGBM, 39% had rGBM (at any line of recurrence), 6% had anaplastic astrocytoma/oligodendroglioma, and 1% had other brain tumors. Most were adults (73%) and 26% were elderly (≥65 years of age). The majority of patients were males (66.3%) compared to females (33.7%), with a ratio representative of a typical GBM population. The most reported TTFields-related AE was array-associated local skin reaction, with an incidence of 38% in ndGBM, 29% in rGBM, 38% in anaplastic astrocytoma/oligodendroglioma, 31% in other brain tumors, 37% in pediatric, 34% in adults, and 36% in elderly patients. Most skin AEs were mild to moderate and resolved with no treatment or over the counter topical ointments. Incidence of other TTFields-related AEs in patients with ndGBM and rGBM, respectively, included heat sensation (under-array warmth; 11%, 10%), electric sensation (under-array tingling; 11%, 9%), and headache (7%, 6%). Conclusions: This retrospective, global, TTFields safety surveillance analysis revealed no new safety signals, with favorable safety and tolerability comparable to published TTFields/GBM trials. The most common TTFields-related AE was array-associated local skin reaction. The safety profile remained consistent among subgroups (diagnosis, age, or region) and total cohort, indicating feasibility in multiple subpopulations, including elderly patients.
Molecular features of gliomas with high tumor mutational burden.
Authors: Xiu Joanne , Walsh Kyle M , Pandey Manjari , Lou Emil , Fonkem Ekokobe , Newton Herbert B. , Dunbar Erin M. , De La Fuente Macarena Ines , Glantz Michael J. , Mittal Sandeep , Ashley David M. , Korn Wolfgang Michael , Sumrall Ashley Love
Published: May 2020

2549

Background: TMB-H in gliomas is caused by molecular alterations or alkylator treatment- induced genomic changes characterized by a large number of G:C>A:T transitions. Our study describes the molecular features of TMB-H gliomas. Methods: Gliomas were tested with NextGen sequencing (592 genes), MGMT promoter methylation (MGMT-m) fragment analysis and IHC at Caris Life Sciences. Microsatellite instability (MSI) was test by NGS, FA/IHC. The GC:AT transition rate was calculated as the prevalence of G:A and C:T changes seen in each tumor and > 80% was regarded as high transition(TR-H). TMB values were compared using Wilcoxon Rank Sum. TMB-H was defined as the top quartile of all TMB values (TMB>9). Results: TMB in the 3129 gliomas ranged from 0 to 372 mutations/MB (mean: 8.5, median: 6). TMB-H was observed in 31% of glioblastomas, 16% of astrocytomas (astro) (22% of grade III, 7% of grade I/II) and 22% of oligodendrogliomas (oligo) (32% of grade III and 15% of grade I/II). MGMT-m (58% vs. 47%; p=0.0001), pathogenic (p) or likely p (lp) EGFR (14% vs 10%, p=0.004) and PIK3CA mutations (13% vs. 9%, p=0.002), as well as p/lp in 30 other genes were more prevalent in TMB-H cases (p<0.01). In the 613 TMB-H tumors, TR-H was seen in 12% (73) and was strongly associated with increased TMB (median TMB 52 in TR-H vs. 9 in TR-L,) and MSI-H (7.3% vs. 1.1%), both p<0.0001. Tumors with both TR-H and MSI-H had a mTMB of 114 vs. 49 in TR-H /MSS tumors. MSI-H and TR-L tumors had an mTMB of 23 vs. 9 in MSS /TR-L tumors (p<0.0001). All 5 POLE-MT tumors had TMB of >100 (median 264) and TR-L; 4 of the 5 were also MSI-H. PDL1 IHC had no correlation with TMB, MSI or transition rates. In 89 paired samples taken >150 days apart (regardless of intervening treatment), acquisition of TMB-H was seen in 11 pairs: 8 glioblastomas, 2 grade II/III astro and 2 oligo. In the paired tumors that acquired TMB-H status compared to those that did not, a significantly higher prevalence of MGMT-m (82% vs. 37%, p=0.008) and IDH mutation (64% vs. 19%, p=0.004) were seen. 10 of the 11 recurrent tumors with acquisition of TMB-H had TR-H while none in the other 78 pairs. Conclusions: TMB varies significantly in gliomas and associates with POLE, TR-H and MSI-H, but not with an increase of PD-L1. POLE-mutated tumors had the highest TMB levels. TR-H, an indicator of alkylator-induced phenotype, is associated with a higher TMB than MSI-H, however, TR-H may synergize with MSI-H to further increase TMB. Tumors with an IDH mutation and MGMT-m are more prevalent in tumors with high TMB gain. Further understanding of molecular and immune profile of the TMB-H may facilitate more individualized treatment planning.
Tumor treating fields effects on the blood-brain barrier in vitro and in vivo.
Authors: Salvador Ellaine , Kessler Almuth , Hoermann Julia , Domroese Dominik , Schaeffer Clara , Burek Malgorzata , Tempel- Brami Catherine , Voloshin Tali , Giladi Moshe , Ernestus Ralf-Ingo , Loehr Mario , Foerster Carola , Hagemann Carsten
Published: May 2020

2551

Background: The greatest hurdle, which even potent and effective drugs targeting central nervous system (CNS) tumors and other disorders face, is the blood brain barrier (BBB). The inability to cross the tight regulatory mechanism renders these drugs futile. Of late, administration of tumor treating fields (TTFields) as part of a combined treatment modality for glioblastoma demonstrated increased overall patient survival. Still, the effects of TTFields on the BBB have not yet been investigated. Here, we report the potential of TTFields application to open up the BBB. Methods: Murine brain endothelial cells were treated with 100-300 kHz TTFields for 24-96 h. Cells were also allowed to recover from 24-96 h after treatment. Subsequently, changes in cell morphology, integrity, and permeability were observed via staining of intercellular junction proteins (IJP) as well as transendothelial electrical resistance (TEER)and permeability assays. In vivo, rats were treated with 100 kHz TTFields or heat for 72 h after which they were IV injected with Evan´s Blue (EB)/ TRITC-dextran (TD) which was later quantified from the brain. Rat brain cryosections were also stained for IJPs as well as immunoglobulin G (IgG) to assess vessel structure. Finally, serial dynamic contrast-enhanced (DCE) MRI with gadolinium (Gd) contrast agent was performed pre- and post- TTFields. Results: Upon TTFields application, IJPs such as claudin-5 were delocalized from the cell membrane to the cytoplasm with maximal effects at 100 kHz. In addition, BBB integrity was significantly reduced and permeability for 4 kDa molecules was significantly increased. Cell morphology recovery was first observed at 48 h post-treatment and completely restored to normal after 96 h, indicating a reversibility of the TTFields effect on the BBB. In addition, EB and TD permeated the rat brain post-TTFields treatment. Brain cryosections displayed IJPs delocalization as well as IgG accumulation in the brain parenchyma. Confirming these observations, increased Gd in the brain was shown by DCE-MRI post-TTFields application. A reversion to normal conditions was detected 96 h after end of treatment, which was demonstrated by no difference in contrast enhancement between control and treated rats. Conclusions: TTFields application both in vitro and in vivo points towards its ability to transiently open the BBB. This presents TTFields as a novel aid for drug delivery geared towards treatment of CNS tumors and other related diseases. Hence, it is indicative of the possibility of an enhanced and more effective combinatorial therapeutic strategy.
Clinical, radiological, and genomic features of BRAF V600E-mutated adult glioblastoma.
Authors: Lim-Fat Mary Jane , Song Kun Wei , Wen Patrick Y. , Reardon David A. , Gerstner Elizabeth Robins , Arrillaga-Romany Isabel
Published: May 2020

2554

Background: Although uncommon, detection of a BRAF V600E mutation in adult patients with glioblastoma has become relevant given the increased availability of NGS and encouraging therapeutic activity of BRAF/MEK inhibitors. The clinical course, radiological characteristics and genetic mutations in this patient population has, however, not been well described. Methods: Adult patients treated at Dana-Farber Cancer Institute or Massachusetts General Hospital with glioblastoma diagnosed from 2013-2019 and an identified BRAF V600E mutation on immunohistochemistry staining or institutional NGS platform were included. Patient demographics, treatments and outcomes were collected retrospectively. Molecular diagnostics (Oncopanel or SNaPSHOT) and cytogenetics (array CGH) were reviewed for relevant mutations or copy number variants (CNV). Qualitative MRI data was analyzed using Visually Accessible Rembrandt Images (VASARI) feature set. Response assessment was performed using the RANO criteria. Results: Nineteen glioblastoma patients had a BRAF V600E mutation (16 on NGS and 19 on IHC). The median age at diagnosis was 41 (22-69) years; 13/19 were female, 12/19 were Caucasian. Only 1/19 had an IDH mutation; 10 of the 17 with known methylation status had MGMT unmethylated tumors. The most frequent mutations on NGS or CNV on array-CGH were TERT (12/16), CDKN2A (10/16), EGFR (7/16), PIK3R1 (6/16) and CKDN2B (6/16). Most tumors were well circumscribed (12/19) and all were contrast-enhancing on MRI. While no patient had clear leptomeningeal involvement at diagnosis, 11/19 eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following progression after standard of care therapy, with 3/6 patients showing partial response and 2 showing stable disease as their best response. PFS after BRAF/MEK inhibition ranged from 1.9 to 19 months. Grade 1 skin rash was present in 1 patient, but no other adverse events were reported. Median OS for the patients with confirmed deaths (15/19) was 22.6 (14.5 – 39.0) months. Conclusions: Compared to the general glioblastoma population, adult patients with BRAF V600E mutations are younger, more frequently female, and have a higher median OS despite a much higher incidence of leptomeningeal dissemination. Outcome following BRAF/MEK targeted therapy was encouraging. Understanding the natural history and features of these tumors may help better screen patients for BRAF/MEK inhibition and identify novel therapeutic strategies.
Targeting glioblastoma with novel immunocytokines.
Authors: Roth Patrick , Weiss Tobias , Puca Emanuele , Silginer Manuela , Hemmerle Teresa , Pazahr Shila , Bink Andrea , Neri Dario , Weller Michael
Published: May 2020

2558

Background: There is an urgent need for novel treatment options for patients with glioblastoma, the most frequent malignant primary brain tumor. In contrast to other types of cancer, immunotherapeutic approaches have so far not been successful against glioblastoma. Converting the glioma microenvironment from a "cold" and immunosuppressive status into a more "hot" and immunopermissive phenotype may allow for clinically meaningful anti-tumor immune responses. Methods: We explored the activity of novel immunocytokines based on the L19 antibody, specific to a tumor-associated epitope of extracellular fibronectin, for the targeted delivery of three pro-inflammatory cytokines (IL-2, IL-12, TNF) to the microenvironment of gliomas. Following an extensive preclinical assessment in 2 orthotopic immunocompetent mouse glioma models, we used a fully-human L19-hTNF fusion protein to treat human patients with recurrent glioblastoma. Results: Intravenous administration of L19-mIL12 or L19-mTNF prolonged survival and cured a proportion of tumor-bearing mice while no effect was seen with L19-IL2. When L19-mIL12 or L19-mTNF were administered to glioma-bearing RAG−/− mice, no therapeutic activity was observed which suggests adaptive immunity as an underlying mechanism. On a mechanistic level, both immunocytokines induced the infiltration of the tumor site with lymphocytes and promoted the expression of pro-inflammatory cytokines in the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Based on these preclinical findings, we initiated a phase I/II clinical trial with a fully-human L19-hTNF fusion protein for patients with isocitrate dehydrogenase (IDH1R132H) wildtype WHO Grade III or IV glioma at first relapse (NCT03779230). Treatment was safe and well tolerated in the first three glioblastoma patients. Administration of L19-hTNF resulted in reduced regional blood perfusion in the tumor region and was associated with more necrotic areas within the tumor as well as an increased number of tumor-infiltrating CD4 and CD8 T cells. Conclusions: The data obtained with the comprehensive preclinical characterization and subsequent clinical translation form the basis for future studies with immunocytokines as novel treatment option for patients with malignant brain tumors. Clinical trial information: NCT03779230 .
Amide proton transfer MRI can accurately stratify gliomas according to their IDH mutation and 1p/19q co-deletion status.
Authors: Bisdas Sotirios , Casagranda Stefano , Roettger Diana , Brandner Sebastian , Thorne Lewis , Mancini Laura
Published: May 2020

2561

Background: Amide proton transfer (APT) MRI provides sensitive metrics at the amides and amines offsets from the water resonance and has been shown in small cohorts to differentiate low from high grade gliomas with better diagnostic performance than diffusion- and perfusion-weighted MRI. The purpose of our study was to assess APT-MRI performance to stratify gliomas according to their IDH mutation and 1p/19q status. Methods: Forty-five patients with primary gliomas and diffuse astrocytomas (26 WHO grade II, 11 WHO grade III, 8 WHO grade IV) underwent prospectively multi-parametric MRI with APT imaging at 3T scanner. The molecular classification identified 9 patients with IDH-wildtype, 1p/19q retained and 36 with IDH-mutant (22 had 1p/19q-retained, 14 had 1p/19q-codeleted). Tumour segmentations were manually created and the masks were superimposed on the calculated magnetisation transfer ratio asymmetry (MTRasym) spectra and proton transfer ratio APT maps. Individual and group analysis was conducted to analyse the statistical differences between quantitative imaging parameters for the IDH mutation and 1p/19q codeletion statuses. Results: The MTRasym spectra showed a clear difference between IDH-wildtype and IDH-mutant gliomas, with the IDH-mutant gliomas presenting a stronger contribution in the amines (p < 0.001). In IDH-mutant 1p/19q-retained and IDH-mutant 1p/19q-codeleted, the MTRasym spectra showed similarities in shape with higher intensity (approx. 60%) for the IDH-mutant 1p/19q-retained gliomas over the entire spectrum indicating an increased content in amines and amides in IDH-mutant 1p/19q-retained (p < 0.01). Notably, the latter entities showed higher amides levels than the IDH-wildtype gliomas (p < 0.03). Conclusions: APT-MRI shows a remarkable potential to disentangle the protein metabolism in gliomas, to link metabolic patterns to the IDH and 1p/19q status and hence provide robust surrogate biomarkers for non-invasive histomolecular classification with potential use as treatment monitoring tools.