bluuebunny/crossref_metadata_2025 huggingface dataset:
Time to access to novel anticancer drugs in Europe, a case study in seven European countries.
Authors: Post Colinda , Van Laarhoven Hanneke W.M. , Hollak Carla
Published: June 2022

1586

Background: After European Medicines Agency Marketing Authorization (EMA-MA) different national reimbursement processes may contribute to unequal access throughout the EU. The aim of this study is to investigate the access time to new anticancer medicines in seven high-income Northern European countries and factors influencing the reimbursement process. Methods: We performed a retrospective database study. New anticancer medicines were included with a positive CHMP advice between January 2016 and January 2020, leading to EMA-MA followed by an application for national reimbursement approval in Germany, UK, France, The Netherlands, Belgium, Norway and Switzerland. The relevant Health Technology Assessment (HTA) - and reimbursement websites for each country were used to identify reimbursement dates. Time to access was defined as the time between EMA-MA and date of inclusion in the relevant reimbursement list. In addition we investigated the differences in national approval process and study-, medication- and patient- related factors which might influence the time to reimbursement. Results: We found that for the thirty-six new anticancer medicines, national reimbursement came on average 289 days after EMA-MA, with a variety of -125 in Switzerland (i.e. non EU-member) to 1415 days. Of these EMA-MA new anticancer medicines 42% were reimbursed in all countries. The average number of cancer medicines reimbursed in the examined countries was 27 (75%), with a range of 24 (67%) in Belgium to 36 (100%) in Germany. The shortest average time from EMA-MA to reimbursement were in Germany, 2.33 days, France and Switzerland following with 207 days and 279 days respectively. The median time to reimbursement was 227 days with a range of 3 days in Germany to 553 days in Belgium. In Germany, where there is no pricing and reimbursement approval required when launching a pharmaceutical, 100% of the cancer medicines are reimbursed within five days. After one year, In the UK 56% of the medicines are reimbursed, followed by 53% in the Netherlands, France and Switzerland. Belgium and Norway have a one year reimbursement rate of 14% and 11% respectively. Access to anticancer medicines is dependent on regulatory procedures, HTA and price regulations. Germany has a fast market access for anticancer medicines with a price regulation one year after launching the medicines. In the other countries, price regulation is part of the launching process. Other factors which might accelerate the time to reimbursement we are examining are high clinical benefit score (ESMO-MCBS), (non-)orphan status of the medicines and submission by big pharmaceuticals. Conclusions: This study shows that after EMA-MA, except for Germany, on average it takes a long time for anticancer medicines to be reimbursed in Northern European countries. There is a considerably variety both within and among countries.
Novel use of clinical pathways to identify poor prognosis lung cancer patients: Implementation and outcomes.
Authors: Jackman David Michael , Rice Matthew , Virkler Nicholas , Desravines Belinda , Selesnick Victoria H. , Scalzo Michael , Siegel Jocelyn H. , Tulsky James A. , Jacobson Joseph O.
Published: June 2022

1589

Background: Cancer patients in the last year of life have different clinical needs and evolving goals of care. Using our oncology decision-support pathways to help clinicians consistently identify such patients in a systematic and prospective fashion, at a discrete moment in the care trajectory, may be an important step towards matching the care of these patients with their stated goals. Methods: Medical oncologists from each disease group at the Dana-Farber Cancer Institute (DFCI) were tasked with identifying clinical settings in each oncology care pathway associated with an expected median survival of < 12 months. This information was embedded into the underlying data model of the pathways platform, allowing us to determine how often clinicians navigated through each poor prognosis node. Results: From 3/1/20 – 6/30/21, there were 264 navigations in 205 unique lung cancer patients receiving standard of care (i.e., not on clinical trial) for a clinical condition associated with poor prognosis. Overall, the median overall survival from the time of a patient’s first navigation through a poor prognosis node during the defined study period was 6.4 months. Table lists outcomes for each specific setting. Patients with squamous or small cell lung cancer being treated in or beyond the third-line setting had notably poor outcomes, with less than a third of these patients surviving 6 months from the time of navigation. Conclusions: A clinical pathways platform can be a key tool in designating clinical scenarios associated with poor prognosis and identifying patients who may be particularly at risk. Pathways analytics provide real-world evidence corroborating the expected poor prognosis based on published studies and can identify specific clinical subsets for whom specific resources are warranted. By embedding this into the pathways data model, we aim to alert physicians to conduct goals of care conversations, offer supportive care resources, and match patients to appropriate treatment options and clinical trials. [Table: see text]
Utilization of telemedicine among patients newly diagnosed with cancer.
Authors: Pan I-Wen , Yen Tina W.F. , Shih Ya-Chen Tina
Published: June 2022

1595

Background: The use of telemedicine among cancer patients remains limited. Because of the COVID-19 pandemic, CMS expansion of telehealth with 1135 waiver was enacted in March 2020, broadening the opportunities to provide patient care using telemedicine. This study examined the impact of the CMS expansion on the use of telemedicine among cancer patients. Methods: We identified newly diagnosed patients with 5 common cancers (breast, prostate, lung, colorectal, and lymphoma) between 3/2019 and 12/2020 from Optum’s de-identified Clinformatics Data Mart Database. Patients who had 6 months of full enrollment (3 months before and 3 months after the first [index] cancer diagnosis date), had cancer claims on 3 separate dates within 3 months of the index date for the specific cancer diagnosis, and no prior history of cancer were included. We defined telemedicine use as patients who had a telemedicine procedure code within 1 month of their index diagnosis and had the cancer diagnosis on the telemedicine claim. We conducted an interrupted time series analysis to examine the impact of CMS expansion on telemedicine use. A multivariable logistic regression model was used to identify factors associated with telemedicine use during the post-expansion period. Results: Of 96,632 patients included, the average crude rate of telemedicine use was 0.12% before and 14.2% after the expansion in March 2020 (see Table). There was a significant impact of expansion on telemedicine use (21% increase; p<0.001). The peak rate (adjusted) was 28% in April 2020, decreasing and plateauing in July/August 2020, with rates staying in the range of 10-12% between August and December 2020. During the post-expansion period, lymphoma, prostate, and lung cancer patients (adjusted rates: 14.6%, 15.7%, and 15.9%, respectively) were more likely to use telemedicine compared to patients who had breast (12.7%) or colorectal (12.3%) cancer. Patients who were older (adjusted rates: ≥65 years, 13.8%; 50-64, 14.2%; 20-49, 18.6%), Black (12.4% vs 14.4% for White, 15.5% for Hispanic and 16.6% for Asian), resided in East South Central census division (8.4% vs 23.5% in New England) and had Medicare (12.2% vs 20.3% for commercial insurance) were less likely to use telemedicine (all p<.001). Conclusions: After the CMS telehealth expansion, the use of telemedicine among newly diagnosed cancer patients increased significantly. Telemedicine use varied by patient age, geographic location, race/ethnicity, and payer. Further research is needed to understand the pattern of telemedicine use.[Table: see text]
Baseline tumor genomic and gut microbiota association with clinical outcomes in newly diagnosed glioblastoma (GBM) treated with atezolizumab in combination with temozolomide (TMZ) and radiation.
Authors: Weathers Shiao-Pei S. , Zhu Haifeng , Knafl Mark , Damania Ashish , Kamiya-Matsuoka Carlos , Harrison Rebecca A. , Lyons Larry , Yun Cindy , Darbonne Walter C. , Loghin Monica , Penas-Prado Marta , Majd Nazanin , Yung W. K. Alfred , O'Brien Barbara Jane , Wistuba Ignacio Ivan , Futreal Andrew , Wargo Jennifer Ann , Ajami Nadim J. , Woodman Scott Eric , de Groot John Frederick
Published: June 2022

2006

Background: Checkpoint inhibitor (CPI) therapy has demonstrated overall limited efficacy in the treatment of GBM. Sixty newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. Methods: Genomic (WES with somatic mutation and SCNA determination N = total 42 samples, 33 baseline, 9 TP-2), transcriptomic (RNA seq N = total 72 samples, 54 baseline, 18 TP-2), and metagenomic sequencing of fecal samples (N = total 45 samples, 26 pre samples, 13 post RT samples, six 6m samples) analyses were conducted on pre-treatment samples. Findings were correlated with clinical outcome including OS and PFS. Twenty of the 60 patients underwent re-resection for suspected recurrent disease of which nine patients had WES and RNA seq performed successfully on paired pre and post treatment samples. Results: Somatic mutation, copy number and ploidy profiles were consistent with known aberrations in GBM. An unsupervised molecular network-based stratification of pre-treatment tumor mutations resulted in patients being grouped in 3 clusters with survival difference. Patients with GBM harboring an EGFR aberrancy were associated with a relatively worse mOS following treatment compared to patients with tumors enriched with PTEN alterations, while patients with IDH1 mutations had the longest mOS. Gene set enrichment analysis of gene expression in tumors from patients ( < mOS vs ≥mOS) identified genes associated with lymphocyte activation and immune response in patients with longer survival (p < 0.01) Unsupervised hierarchical clustering of bacterial taxa demonstrated two distinct clusters with significant difference by OS. Survival analysis and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC) revealed distinct taxa associated with OS ( Ruminococcus spp.) and response to treatment ( Eubacterium spp.), respectively. Conclusions: In this small CPI-treated GBM cohort, WES, SCNA and RNA seq identified pre-treatment tumor features that separated patients by survival. The fecal microbiome observations in our GBM cohort warrants further investigation. Clinical trial information: NCT03174197.
CA-4948 for the treatment of melanoma brain metastasis.
Authors: Doonan Bently Patrick , Von Roemeling Christina , Klippel Kelena , Hoang-Minh Lan , Mitchell Duane Anthony
Published: June 2022

2011

Background: Melanoma is a growing clinical health concern where the incidence has doubled over the last 30 years. A major driver of melanoma associated deaths is the development of brain metastases (MBM). It is estimated that 40-60% of patients with metastatic melanoma will develop MBM. Current treatment strategies have a great local control rate, but do not prevent recurrent disease, with a distant intracranial failure rate of 50% at 1 year. Novel treatments and an improved understanding of the MBM tumor microenvironment are needed. Toll-like receptor signaling is activated in cutaneous melanoma, triggering innate inflammatory activation downstream through the adapter proteins MyD88 and interleukin (IL)-1 receptor-associated kinase (IRAK-1 and -4). Increased expression of IRAK-4 stimulates transcription of multiple cellular kinases and transcription factors, and production of inflammatory chemokines and cytokines. This places IRAK-4 as a central driver of both intrinsic tumorigenicity and immune evasion in melanoma. In this study we examine IRAK-4 activation in MBM, as well as preclinical responsiveness to CA-4948, an oral first-in-class small molecule inhibitor of IRAK-4 that has demonstrated clinical activity and has an acceptable safety in cancer patients. Methods: Using multiparameter IHC and proteomics analysis IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient MBM tissues and compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for CA-4948 drug concentration following single oral high dose in a murine model. Using an aggressive preclinical model of MBM, B16F10, downstream biomarker response to treatment including phospho-NF-κB, phospho-ERK1/2, and phospho-P38 was measured in control and CA-4948 treated animals using multi-parameter IHC. Survival response was also tested using the B16F10 model. Results: Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient MBM. We also demonstrate that CA-4948 is capable of achieving therapeutically relevant concentrations in the brain parenchyma, and shows single agent activity in an aggressive preclinical model of MBM. We further confirm decreased ERK1/2, MAPK and NF-κB activation in response to CA-4948 treatment. Conclusions: We present here for the first time that IRAK-4 is a strong candidate for targeted therapy in MBM. We further validate CNS penetrance of the oral IRAK-4 inhibitor CA-4948, where single agent markedly reduces the proliferative capacity of aggressive preclinical MBM, resulting in improved survival. These data warrant further investigation of CA-4948 for the treatment of melanoma brain metastases, with far reaching potential as an adjunct to standard of care.
Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and to better predict intracranial tumor response in patients with non–small cell lung cancer with brain metastases: A prospective cohort study.
Authors: Li Meichen , Hou Xue , Chen Jing , Zhang Baishen , Yu Juan , Wang Na , Li Delan , Shao Yang , Zhu Dongqin , Liang Chuqiao , Ou Qiuxiang , Ma Yutong , Chen Likun
Published: June 2022

2023

Background: Cerebrospinal fluid (CSF) can be used as a type of liquid biopsy to detect brain tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor response and monitor mutational evolution during systemic treatment in non-small cell lung cancer (NSCLC) patients with brain metastases. Methods: We conducted aprospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and at disease progression. Primary extracranial tumor samples were available for 58 patients and all samples underwent targeted next generation sequencing of 425 cancer-related genes. Results: At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of heterogeneity was observed between paired CSF and plasma samples, while concordance in driver mutations was also observed. A higher number of unique copy number variations (CNVs) were detected in CSF ctDNA than in plasma. CtDNA-positivity in baseline CSF samples was associated with poor outcomes (HR = 2.565, P = 0.003). Moreover, patients with increased concentrations of ctDNA in CSF after 8 weeks of treatment had significantly shorter intracranial progression-free survivals (PFS) than patients with decreased concentrations of CSF ctDNA (6.13 months vs 13.27 months, HR = 3.92, P = 0.007). Increased concentrations of plasma ctDNA were associated with shorter extracranial PFS (6.13 months vs 11.57 months, HR = 2.626, P = 0.032). From clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of systemic treatment. The clonal mutations remained more than 80% in CSF after 8-weeks of treatment also predicted a shorter intracranial PFS (HR = 3.785, P = 0.039). Conclusions: CSF ctDNA revealed unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor response and track clonal evolution during treatment in NSCLC patients with brain metastases.
Changing recognition of breast cancer–related leptomeningeal disease and response to therapy: A retrospective single institution review.
Authors: Wallace Gerald Carter , Ahmed Kamran A. , Soyano Muller Aixa Elena , Forsyth Peter A. J.
Published: June 2022

2027

Background: Breast cancer related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5-8% of breast cancer patients with overall survival (OS) measured in weeks without treatment. As new treatments prolong survival with breast cancer, the risk of developing BC-LMD may be increasing. We hypothesized that the rate of BC-LMD diagnosis increased significantly with time. We also predicted that OS with BC-LMD had changed with time and in relationship to molecular subtype and treatment following BC-LMD diagnosis. Methods: With approval of the local Scientific Research Committee and IRB, we conducted a retrospective analysis of medical records for patients treated or diagnosed with breast cancer at MCC from 2011-2020. Patient demographics, tumor characteristics, treatments, and outcomes were collected. Kaplan Meier survival curves were used to determine median overall survival (OS), progression of disease, and differences by molecular subtype. Univariate and multivariate analyses were used to determine characteristics of primary tumors and treatments which affected OS. Results: Of the 133 cases identified, significantly more were diagnosed between 2016-2020 than 2011-2015 (p < 0.01). Significant increases were seen in HER2+ and TNBC patients (p < 0.05) but not for ER/PR positive (HR+) disease (p = 0.058). HER2+ LMD associated with longest overall survival (OS; 7mths) followed by HR+ disease (3mths) and TNBC with the shortest OS (2mths). Systemic metastases preceded BC-LMD diagnosis in 72% of cases and CNS metastases in 85% of cases. HER2+ disease also conferred increased survival after CNS metastases were diagnosed until progression to LMD (8mth vs 2mth for HR+ and 1mth for TNBC LMD; p < 0.05). Positive impact on survival by HER2 targeted therapies may account for improved OS in this population. Other factors which increased OS generally were: WBRT, continuation of systemic therapy, delivery of intrathecal chemotherapy, and participation in clinical trials. Having TNBC and decision to defer treatment were associated with reduced OS. Conclusions: This study highlights the importance of identifying patients with BC-LMD early and with the intention to treat. Prospective clinical trials and population-based studies are needed to advance treatment of BC-LMD.
Convection-delivered adenoviral gene therapy reprograms the immunosuppressive glioblastoma microenvironment.
Authors: Young Jacob S , Cho Nam Woo , Casey-Clyde Ti , Santos Raquel , Seo Kyounghee , Phillips Joanna J. , Berger Mitchel S. , Ozawa Tomoko , Raleigh David R.
Published: June 2022

2039

Background: Immune checkpoint inhibition has not improved outcomes for glioblastoma patients, and single- cell approaches reveal the glioblastoma microenvironment is largely comprised of immunosuppressive cells. We hypothesized intratumor convection enhanced delivery (CED) of adenoviral gene therapy could recruit and activate anti-tumor immune cells in the glioblastoma microenvironment. Methods: Syngeneic GL261 (3x105 cells/mouse) or SB28 glioblastoma (3 x 104) cells were implanted into the frontal lobe of immunocompetent C57BL/6J mice (18 mice/arm). Intracranial bioluminescence (BLI) and body weight (BW) measurements were used to assess glioblastoma growth and treatment toxicity, respectively. After tumor engraftment, glioblastomas were treated with conformal ionizing radiation mimicking stereotactic radiosurgery (SRS) in human patients as a positive control for tumor inhibition (18Gy/1Fx). Attenuated adeno-associated virus 9 (AAV9) vectors encoding Gfp as a negative control, or encoding experimental cytokines driving recruitment and activation of anti-tumor immune cells in other intracranial tumors ( Ccl4, Il1b, or Apoa1) were delivered using CED (2x1011 vg/mouse). Glioblastomas were collected for histologic, single-cell, and molecular analyses 5 days after treatment (6 mice/arm) and at endpoints after monitoring for survival (12 mice/arm). CED targeting was validated using AAV9-GFP and confocal microscopy. Treatment responses were assessed using H&E, IHC, multiplexed cytokine assays, and single cell mass cytometry (CyTOF) to define immune cell types in the glioblastoma microenvironment. Results: Histologic analyses revealed AAV9-CCL4, AAV9-IL1B, or SRS induced glioblastoma macrophage infiltration, and AAV9-IL1B, AAV9-APOA1, or SRS induced glioblastoma T cell infiltration. AAV9-APOA1 (18.5 days versus 15 days, p < 0.001) or AAV9-IL1B (16.5 days versus 15 days, p = 0.001) CED treatments prolonged median survival from SB28 allografts. Glioblastoma cytokine analysis revealed inhibition of pro-tumor cytokines (IL6, LIF) after experimental CED treatments. Systemic cytokines were minimally changed by CED treatments. CyTOF showed decreased immunosuppressive macrophage infiltration and increased CD8+ T cell or microglia infiltration of the glioblastoma microenvironment after experimental CED treatments. There was no evidence of systemic or central toxicity in any treatment condition. Conclusions: Convection-enhanced delivered of adenoviral gene therapy reprograms the glioblastoma immune microenvironment and improves survival in an immunologically “cold” syngeneic glioblastoma model.
Impact of EGFRA289T/Vmutation on relapse pattern in glioblastoma.
Authors: Maxime Fontanilles , Noeuveglise Alexandra , Vasseur Nasrin , Beaussire Ludivine , Marguet Florent , Modzelewski Romain , Hanzen Chantal , Alexandru Cristina , Magne Nicolas , Langlois Olivier , Di Fiore Frédéric , Clatot Florian , Thureau Sébastien
Published: June 2022

2046

Background: The prediction of the relapse pattern is an important issue in glioblastoma for personalized approach. Molecular factors, such as MGMT promoter methylation, influence relapse in- or out-field of the initial radiotherapy volume. Recently, a recurrent mutation located at position 289 of the extracellular domain of the epidermal growth factor receptor ( EGFRA289mut) has been associated with a more infiltrative phenotype in glioblastoma. The primary objective of the present study was to explore the impact of EGFRA289mut on the pattern of relapse after a chemo-radiotherapy based treatment of patients suffering from glioblastoma. Methods: An ancillary study from a monocentric prospective cohort of patients suffering from glioblastoma was conducted. All patients received radiotherapy and concomitant temozolomide. The population was divided into two groups according to EGFRA289 status (mutated versus wild-type). Primary endpoint was the overlap score (varying from 0 to 1) between initial irradiated tumor volume (Vinit) and relapse volume (Vr). Vinit was the initial 95% isodose of the radiotherapy and Vr was delineated using the enhanced MRI T1-weighted part of the relapse tumor. Secondary endpoints explored the impact of other EGFR extracellular mutations, EGFR amplification and EGFRvIII on the relapse pattern, as well as the impact of EGFRA289mut on survival. EGFR alterations were identified using next-generation sequencing or droplet-digital PCR based methods on formalin-fixed paraffin-embedded samples collected at initial diagnosis. Results: One hundred patients were included: 11% of the population had EGFRA289mut glioblastoma (n = 11/100). EGFRA289mut glioblastomas had a relapse pattern more marginal compared to EGFRA289wt glioblastomas: a mean overlap score Vinit/Vr of 0.78 was observed in the EGFRA289mut group versus 0.94 in the EGFRA289wt group (p = 0.021). The proportion of EGFR A289mut glioblastomas in the outfield relapse (overlap score < 0.8) has a trend to be higher than in the infield relapse (overlap score > 0.8): 25% (n = 2/8) versus 9.8% (n = 9/92) for the EGFRA289wt population, p = 0.21. Neither EGFR amplification nor EGFRvIII did influence overlap score Vinit/Vr. In our population, EGFRA289mut did not influence survival. Conclusions: EGFR A289mut influences the relapse pattern in a population of patients suffering from glioblastoma. The role of EGFRA289mut as a decision-making biomarker for personalized radiotherapy should now be investigated in dedicated clinical trial. Clinical trial information: NCT02617745.
Comparison of survival outcomes of patients with newly diagnosed glioblastoma treated with standard chemoradiation in and outside of clinical trials.
Authors: Rahman Rifaquat , Youssef Gilbert , Ventz Steffen , Redd Robert , McDunn Jon , Louv William , Alexander Brian Michael , Wen Patrick Y. , Trippa Lorenzo
Published: June 2022

2051

Background: Randomized clinical trials use stringent eligibility criteria to select patients which can raise concerns about generalizability of study results. Recent interest in external controls and new trial designs has increasingly focused on the possible use of real-world data sources. We examined potential differences of survival outcomes in clinical trial and real-world datasets in newly diagnosed glioblastoma. Methods: Patient-level data from 4 independent datasets were analyzed. Non-trial data were derived from an institutional dataset of 453 patients with newly diagnosed glioblastoma treated outside of a clinical trial with standard radiation therapy with concurrent and adjuvant temozolomide at a large academic center. Trial patients included patients on the control arm of several multi-institutional trials (NCT00689221, n = 273; NCT00813943, n = 89; NCT00943826; n = 459) and patients treated on trial at our institution (n = 210). Non-trial patients were compared with each of the 4 clinical trial datasets in pairwise comparisons with Cox regression with adjustments for age, sex, extent of resection, KPS and MGMT status. Results: Patient-level data from 1,484 patients were analyzed. Non-trial patients were older compared to patients in the multi-institutional trials (mean 58.6 vs. 56.1 years (NCT00943826), 53.9 years (NCT00813943), 55.7 years (NCT00689221); p < = 0.001). The non-trial cohort had fewer women (43.5% vs. 35.9%, p = 0.02), greater proportion of lower KPS patients (47% KPS <90 vs. 31% KPS <90, p < 0.001) and greater proportion of MGMT methylated patients (49% vs. 33%, p < 0.001) compared to NCT00943826 patients. There were no other significant differences between patient characteristics of non-trial patients and the 4 trial datasets. Trial participation was not associated with improved survival in multivariable analysis after adjustments for clinical covariates (non-trial patients vs. each trial dataset; Table, P > 0.05). Conclusions: Glioblastoma patients treated on multi-institutional clinical trials that were included in our analysis did not have statistically significant differences in survival compared to patients treated outside of a clinical trial at a large academic center after adjustment for relevant variables. Our findings support the possible use of real-world data in the development of external control arms for future trials in newly diagnosed glioblastoma. [Table: see text]
Clinical characteristics and outcome of a large cohort of patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.
Authors: Lamoureux Audrey-Anne , Fisher Michael J. , Lemelle Lauriane , Pfaff Elke , Pfister Stefan M. , Sturm Dominik , Jones David T.W. , Orbach Daniel , Raskin Scott , Drilon Alexander E. , Zapotocky Michal , Coleman Abadi Christina , Barritault Marc , Leblond Pierre , Tabori Uri , Hansford Jordan R. , Erker Craig , Doz Francois , Laetsch Theodore Willis , Perreault Sébastien ,   CNSonTRK
Published: June 2022

2052

Background: TRK fusions are detected in less than 3% of central nervous system (CNS) tumors. Given their rarity, there are limited data on the clinical course of affected patients. Methods: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatment modalities and outcomes. Results: Ninety-two patients with TRK fusion-driven primary CNS tumors were identified including 76 pediatric patients (82.6%), 15 adults (16.3%) and 1 not specified (1.1%). Median age at diagnosis was 4.4 years (range 0.0–78.3) and 58.7 % were male. NTRK2 gene fusions were found in 45 patients (48.9%), NTRK1 and NTRK3 aberrations were detected in 27 (29.3%) and 20 (21.7%), respectively. Tumor types included 56 high-grade gliomas (HGG; 60.9%), 20 low-grade gliomas (LGG; 21.7%), 4 embryonal tumors (4.3%) and 12 others (13.0%). Median follow-up was 40.5 months (range 3–226). During the course of their disease, 75 (81.5%) patients underwent surgery with a treatment intent, 67 (72.8%) patients received chemotherapy, 50 (54.3%) patients received radiation therapy, while 47 (51.1%) patients received NTRK inhibitors (6 as first line treatment). There were significant differences in the median progression-free (PFS) and overall survival (OS) between pediatric patients compared to adults. The pediatric median PFS was 32 months (95% CI: 15.5–48.5) compared to 8 months for the adult (95% CI: 4.5–11.5, p = 0.015). The pediatric median OS was 182 months (95% CI: 25.1–338.9) compared to 24 months (95% CI: 18.3–29.7 p < 0.001) for adult patients. There was no difference in the PFS of LGG compared to HGG. However, the OS was significantly worse for the HGG when compared to LGG (p = 0.039). The median OS for LGG was not reached and the median OS for HGG was 70 months (95% CI 7.5–132.5). Nineteen patients with HGG (38.0 % 19/50 evaluable patients) died compared to only one patient with LGG (5.6% 1/18 evaluable patients, p = 0.014). Conclusions: We report the largest cohort of patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.
Preliminary results of a phase II study of retifanlimab (PD-1 inhibitor) plus or minus epacadostat (IDO1 inhibitor) in combination with bevacizumab and hypofractionated radiotherapy for recurrent glioblastoma: NCT03532295.
Authors: Campian Jian Li , Butt Omar H. , Huang Jiayi , Luo Jingqin , Tao Yu , Strowd Roy E. , Hissim Deanna C , Kizilbash Sani Haider , Abraham Christopher , Ansstas George , Johanns Tanner Michael , Kim Albert H. , Ciorba Matthew A. , Chheda Milan G
Published: June 2022

2058

Background: Immunotherapies targeting the programmed cell death-1 (PD-1) pathway in recurrent glioblastoma (rGBM) have failed. We hypothesize that combining therapies targeting multiple immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. Here, we evaluate the safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an oral IDO1 inhibitor (epacadostat), in patients with rGBM in a nonrandomized, noncomparative sequential two-arm Phase II study. Methods: This is an open-label Phase II study of 2 sequential cohorts (Table). Cohort A first examines retifanlimab + bevacizumab + HFRT in patients with IDH1/2-WT rGBM. After a toxicity monitoring period, Cohort B, which adds epacadostat, starts enrolling. Key inclusion criteria includes dexamethasone ≤ 4 mg/day at registration and candidacy for reirradiation. Previous bevacizumab use for radiation necrosis is permitted. The primary endpoint is OS probability at 9 months (OS-9). Secondary endpoints include PFS, OS, and toxicity. Exploratory endpoints include immunological phenotyping of blood and tissue. An increase of OS-9 from 38% (bevacizumab alone) to 60% is considered clinically relevant. Results: From 6/2020 to 12/2021, we have completed accrual for cohort A and the interim analysis results are presented here: 25 patients with rGBM enrolled, with 23 evaluable. Median age is 64.3 years (42.1-81.8), 30.4% female, 30.4% MGMT promotor methylated, median KPS 90 (range 70-100), baseline dexamethasone 0 mg (range 0-4) with 52.2% of patients on dexamethasone during the first 3 cycles, median baseline ALC 1,000 cells/µl (range 300-3,700). Patients received a median of 6 cycles to date (range 2-20). Median follow-up is 11.97 months per the reverse Kaplan-Meier method. Interim analysis shows a median PFS of 9.9 months (95%CI: 5.5 to not reached (NR)) and median OS of 12.2 months (95%CI 7.3-NR). Notably, Cohort A met the primary endpoint with an OS-9 of 71.4% (95%CI: 46.7% -86.1%). No dose limiting toxicities have been yet observed. Two treatment-related grade 3 toxicities have occurred (myositis, hypertension). Cohort B enrollment is ongoing, and correlative studies pending. Conclusions: Interim analysis suggests retifanlimab combined with HFRT and bevacizumab in patients with rGBM is well-tolerated and had encouraging OS and PFS at the time of data cutoff. Cohort B, which adds epacadostat, is currently enrolling. Clinical trial information: NCT03532295. [Table: see text]
3D-volumetric assessment of response to ivosidenib in IDH-mutant gliomas.
Authors: Puri Sushant , Shi Jessica , Blair Lindsay , Blakeley Jaishri O'Neill , Laterra John , Kamson David
Published: June 2022

2063

Background: Isocitrate Dehydrogenase (IDH) mutant gliomas represent a distinct class of primary brain tumors. Mutant IDH is a driver mutation implicated in gliomagenesis and a potential therapeutic target. Ivosidenib, an inhibitor of mutant IDH1, is currently being evaluated to treat gliomas. In the present study we assess our single-institutional experience with the off-label use of ivosidenib to reduce tumor growth rate in patients with IDH mutant gliomas. Methods: We have longitudinally analyzed the imaging of patients with histology-proven radio- and chemotherapy-naïve IDH-mutant WHO Grade 2 and 3 astrocytomas (AS) and oligodendrogliomas (OG) treated with off-label ivosidenib between 2019 and 2022. First, each patients’ FLAIR images were anonymized, bias-corrected, co-registered and semi-automatically segmented for volumetric analysis using 3D Slicer 4.11. MR acquisition dates were hidden, and the order of scans was randomized to prevent expectation bias. Volumetric trends and PFS were analyzed. Progressive disease was defined as a ≥40% increase in volume from baseline as per modified RANO criteria. Results: Eleven patients were included in the analysis (median age 46 years [range 26-62], 2F, 8AS/3OG, 7 Grade 2). Mean±SD follow-up time on ivosidenib was 16.1±15.5 months. Tumor volume reduction was noted in 82% of patients at least at one time point. Average volume change at best response was -11.4±12.8%. Mean time to best response was 12.1±9.3 months. PFS-6 and PFS-12 were 91% (n = 11), and 88% (n = 8), respectively. Mean PFS was 24.4 months (CI95% 18.8-29.9). Median PFS was not reached. Patients older than 45 years had significantly higher volume reduction compared to younger patients (18.9±6.3% vs. -2.4±13.2%;-p = 0.047, 2-tailed T-test). Ivosidenib was discontinued in in 2 patients for 2D radiographic changes, and in one for increased seizure frequency. Conclusions: The use of ivosidenib in treatment-naïve gliomas was associated with a high response rate; however, on average it required longer than a year to achieve best response. In this cohort, older patients had higher volume reduction. The drug was well tolerable. Further analysis of an expanded cohort is underway.
Examination of mutation signature and mutation spectrum as predictors of response to immune checkpoint blockade therapy.
Authors: Bowen Danae , Capone Stephen , In Gino Kim , Buisson Rémi
Published: June 2022

2537

Background: In recent years, there has been promising progress in the use of immune checkpoint blockade (ICB) as a treatment for various cancer types such as lung, kidney, bladder, skin, colon, and breast cancer. In order for this modality to have increased success, more precise selection tools are needed to predict which patients will benefit from treatment. Tumor Mutational burden (TMB) has been implicated as a biomarker for ICB response due to the increased tumor immunogenicity present in high TMB samples. However, we hypothesize that the quality of mutations may also have an impact in determining immune response, rather than just the quantity of mutations alone. Methods: A retrospective analysis of 2041 patients across multiple solid tumor types was conducted using an open-access, open-source cancer genomics database (Gao, Sci Signal, 2013), with the goal of assessing the influence of mutational signature on patient response to ICB (including CTLA-4, PD-1, and PDL-1). Patient demographics, treatment variables/outcomes, and tumor variables, including mutation spectrum, and mutation count, were evaluated. A paired two sample test for means was used to analyze data with p < 0.05 considered statistically significant. Response outcomes were determined per RECIST v 1.1. Results: Our data demonstrate that mutational spectrum profiles show distinct patterns when considering response to ICB, independent of TMB. Patients with breast invasive ductal carcinoma who responded to ICB had less C > A mutations ( p = 0.020) and more C > T mutations ( p = 0.017) compared to non-responders. Lung adenocarcinoma responders had less C > T mutations ( p = 0.003) and more C > A mutations ( p = 0.0003) compared to non-responders. Furthermore, both head and neck squamous cell carcinoma and glioblastoma multiforme responders had more T > A mutations ( p = 0.047 and p = 0.011, respectively) than non-responders. However, in other cancer types studied (urothelial, colon, renal, lung squamous, and melanoma), there were no obvious trends to distinguish responders from non-responders. Preferentially mutated gene targets were also considered for all 10 cancer types (including CARD11, SMARCA4, GLI1, PIK3R1, PTPRT, among others), many of which were also tied to the unique mutational signatures observed and which may be separately identified as novel ICB therapy targets. Conclusions: We found that specific mutation type may impact response to ICB in at least 4 cancer types, including breast, lung adenocarcinoma, head and neck squamous cell carcinoma and glioblastoma multiforme. Of note, this trend was not found in other cancer types which are typically found to have higher TMB. Moving away from solely considering the magnitude of mutations in tumor samples and towards identifying specific mutational signatures may aid in providing necessary specificity for selecting patients for ICB cancer therapy.
Phase 1b study of GS-3583, a novel FLT3 agonist Fc fusion protein, in patients with advanced solid tumors.
Authors: Tolcher Anthony W. , Brody Joshua , Rajakumaraswamy Nishanthan , Lakhani Nehal J. , Kuhne Michelle R. , Trowe Torsten , Jiang Deyuan , Dauki Anees , Kummar Shivaani
Published: June 2022

2566

Background: We have previously shown that systemic administration of GS-3583, a Fms-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein leads to expansion of conventional dendritic cells (cDC), both subtype 1 (cDC1) and subtype 2 (cDC2), in the periphery of healthy volunteers (Rajakumaraswamy N, et al. J Clin Oncol. 2021;39[suppl_15]:2559.). This mechanism may increase cDC in the tumor microenvironment and promote T cell mediated antitumor activity in patients with solid tumors. Methods: This ongoing, Phase 1b, open label study is investigating the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of escalating multiple doses of GS-3583 monotherapy in adult patients with advanced solid tumors using a standard 3 + 3 design. GS-3583 was administered intravenously on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 52 weeks or until progressive disease or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 therapy at each dose level. Results: At the time of the Dec 3, 2021 data cut-off, 9 patients have enrolled in 3 dose escalation cohorts. Median (range) age was 71 (44-79); 4 (44%) patients were male. Tumor types were pancreatic (n=3), ovarian (n=4), and rectal (n=2). To date, no DLTs or discontinuation due to adverse events (AE) have been observed. Three patients had Grade ≥3 AEs which were also recorded as serious AEs, none of which were considered related to GS-3583. Dose dependent increase in GS-3583 exposure was observed in the evaluated dose range 2 to 12 mg with target-mediated drug disposition appearing to be saturated at doses above Dose Level 2. GS-3583 accumulation was observed at higher dose levels. GS-3583 treatment resulted in expansions of cDC1 and cDC2 at all 3 doses (Table); a dose-dependent trend in the magnitude and the durability of cDC expansion was observed. At the highest dose evaluated, GS-3583 produced ≥100-fold expansion of both cDC1 and cDC2 at multiple time points. Dose escalation on the study is still ongoing. Conclusions: GS-3583 was safe and well tolerated and induced dose-dependent expansion of cDCs in the periphery in patients with advanced solid tumors up to doses of 12 mg. These findings support further dose escalation and clinical development of GS-3583 in combination with agents that would stimulate the expanded cDCs to produce anti-tumor responses. Clinical trial information: NCT04747470. [Table: see text]
Artificial intelligence-powered pathology image analysis merged with spatial transcriptomics reveals distinct TIGIT expression in the immune-excluded tumor-infiltrating lymphocytes.
Authors: Park Gahee , Song Sanghoon , Kim Sukjun , Ahn Sangheon , Kim Hyunjoo , Lee Jaegeun , Ro Juneyoung , Park Woomin , Chung Taiwon , Kang Cholmin , Lee Chunggi , Kim Huijeong , Shin Jisoo , Lee Seungje , Baek Eunji , Lee Sumin , Seo Melody SeungHui , Choi Hyojung , Yoo Donggeun , Ock Chan-Young
Published: June 2022

2570

Background: TIGIT is a promising emerging immunotherapeutic target. However, the specific sources of TIGIT expression within the tumor microenvironment are largely unknown. Here, we present an AI-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer, Lunit SCOPE IO, to integrate image analysis from whole slide images with single-cell molecular profiling. Methods: We used The Cancer Genome Atlas (TCGA) RNA expression data across 23 cancer types (n=6,930). Lunit SCOPE IO was developed, trained, and validated based on >17k H&E whole-slide images, to segment cancer area (CA) and cancer-associated stroma (CS) and to detect tumor cells and TILs. The intra-tumoral TIL, stromal TIL, and tumor cell purity (TCP) in the CA+CS area were calculated. The public spatial transcriptomics (ST) dataset for breast cancer was downloaded from the 10X Visium web page. Lunit SCOPE IO was applied to the associated H&E WSIs to match distinct TIGIT expression to single cells identified in the WSIs. Results: TIGIT was highly expressed in TGCT (3.45±0.11; median±SEM), LUAD (3.07±0.05), and HNSC (2.89±0.06), and was highly enriched in samples with microsatellite instability-high or tumor mutational burden-high (≥ 10/Mb) compared to those without them (fold change = 1.30, p < 0.001). At a macroscopic, bulk-level in the TCGA dataset, TIGIT expression was positively correlated with intra-tumoral TIL density (R=0.37, p<0.001) and stromal TIL density (R=0.42, p<0.001), but it was negatively correlated with TCP (R=-0.27, p<0.001). Lunit SCOPE IO analyzed the images from ST analysis and calculated intra-tumoral TIL, stromal TIL, and TCP of each region of interest, containing 2 (IQR 0-7) cells. Interestingly, at a microscopic, cell-level, TIGIT expression was still higher in areas of enriched stromal TIL (P < 0.001) and lower in tumor cell-dense areas, but it was not significantly correlated with enriched intra-tumoral TIL areas, meaning that TIGIT expression is likely derived from the excluded TILs in the CS area. Conclusions: Interactive analysis of spatial transcriptomics with AI-powered pathology image analysis revealed that TIGIT expression in the tumor microenvironment is exclusive to confined areas with stromal TIL enrichment, reflecting the exclusion of TIL from the tumor nest. [Table: see text]
Radiotherapy-immunotherapy related pneumonitis prediction from pre-treatment CT using a deep graph-based integrative model.
Authors: Yang Linlin , Cui Hui , Duan Yanan , Yao Yueyuan , Zou Bing , Wang Linlin
Published: June 2022

2580

Background: Early prediction of symptomatic pneumonitis (grade ≥ 2) could potentially assist the comprehensive management for non-small cell lung cancer (NSCLC) patients who received radiotherapy combined with immunotherapy. A more accurate integrative model for symptomatic pneumonia prediction using CT images is needed. Methods: This retrospective study contains 243 NSCLC patients (62 symptomatic pneumonitis) who underwent radiotherapy combined with immunotherapy between January 2015 and June 2021. Five-fold cross-validation was performed for training and testing. There were 195 cases in the training set (50 symptomatic pneumonitis) and 48 cases in the validation set (12 symptomatic pneumonitis) in each fold. The deep graph integrative model (DG) was composed of two pre-trained 3D UNet encoders to extract deep features from tumor and lung volumes of pre-treatment CT images, respectively, and a graph attention layer (GAT) for integration and classification. The encoders were fine-tuned using manually segmented tumor and lung CT volumetric patches from the training set. Evaluation measures include area under ROC curve (auc), sensitivity (sen), and specificity (spe). Results: Our new DG achieved auc, sen, and spe of 0.823, 0.767, and 0.810, which outperformed conventional CT radiomics model (auc 0.743, sen 0.620, spe 0.752), 3D UNet based deep radiomics model (auc 0.761, sen 0.746, spe 0.737), and our model without GAT (auc 0.796, sen 0.762, spe 0.782). The improvement was statistically significant (p < 0.001). Conclusions: Our DG model improved symptomatic pneumonia prediction using CT images, which can be used as a tool to effectively improve the safety and personalized treatment of combined radiotherapy with immunotherapy for NSCLC patients.