tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of dabrafenib plus trametinib in BRAFV600E-mutant pediatric low-grade glioma: A microsimulation study.
Authors: Bryan Gascon, Alan Yang, Cindy Gauvreau, Julie Bennett, Liana Nobre, Uri Tabori, Cynthia Hawkins, Petros Pechlivanoglou, Avram Denburg
Journal: Journal of Clinical Oncology (2024)

2055 Background: BRAFV600E mutations, detected in 15-20% of pediatric low-grade gliomas (PLGGs), have emerged as a key therapeutic target for patients with unresectable, progressive, or recurrent PLGG. In a recent phase II clinical trial (NCT02684058), dabrafenib, a selective inhibitor targeting BRAFV600E, plus trametinib outperformed standard chemotherapy as first-line therapy, demonstrating significantly longer progression-free survival and improved safety in BRAFV600E-mutant PLGG. The aim of this study was to estimate the cost-effectiveness of dabrafenib+trametinib (Dab-Tram) versus standard chemotherapy as first-line therapy for patients with BRAFV600E-mutant PLGG. Methods: We constructed a microsimulation model, simulating a cohort of 10,000 patients with BRAFV600E PLGG. We populated the model using progression-free and overall survival estimates derived from the NCT02684058 trial, a hospital-based PLGG registry and treatment- and PLGG-related adverse events from published literature. The simulated cohort was assigned to either targeted therapy or chemotherapy as first-line therapy. Key parameters included treatment cost, dosage, inpatient and outpatient costs, and health-related quality of life. We assumed a lifetime duration of targeted therapy, a healthcare system perspective, lifetime horizon, and discount rate of 1.5%. Outcomes included life years, quality-adjusted life years (QALYs), lifetime costs (2022 CAD), and incremental cost-effectiveness ratios (ICERs).Sensitivity analysis included the use of alternative data sources, including those derived from independent assessment of NCT02684058 trial outcomes and real-world data from The Hospital for Sick Children (SickKids) in Toronto, Canada. Results: Modeled life years with Dab-Tram and chemotherapy were 34.91 and 32.68 years, respectively. Dab-Tram was associated with a 1.77 QALY increase at an incremental cost of $2,701,409 compared to standard chemotherapy. The resulting ICER was $1,526,265 per QALY gained. At a willingness-to-pay (WTP) threshold of $150,000 per QALY, a price reduction of approximately 80% is required to render it cost-effective. Scenario analysis varying effectiveness of targeted therapy using independent assessment of NCT02684058 trial outcomes and real-world data from SickKids demonstrated comparable clinical benefits and ICERs. Results were sensitive to changes in survival distributions. Conclusions: While clinical outcomes using Dab-Tram as first line therapy for BRAFV600E PLGG are promising, our model-based analysis demonstrates that at the present price, Dab-Tram is not cost-effective, and would require a considerable price reduction to enable equitable access and affordability. This work also provides an exemplar for economic evaluation of precision therapies based on emergent trial and real-world data for rare diseases.
Zotiraciclib for newly diagnosed or recurrent glioblastoma: Updated outcome and biomarker analysis.
Authors: Michael Weller, Thierry Gorlia, Joerg Felsberg, Joost Jongen, Claude-Alain Maurage, Francois Ducray, Dorothee Gramatzki, Peter Hau, Olivier L. Chinot, Matthias Preusser, Stephanie Cartalat, Patrick Roth, Martin J. Van Den Bent, Julia Furtner, Maike Collienne, Guido Reifenberger, Tobias Weiss, Emilie Le Rhun
Journal: Journal of Clinical Oncology (2024)

2058 Background: There has been little progress in the treatment of newly diagnosed glioblastoma in decades and standards of care for recurrent glioblastoma remain poorly defined. The multi-cyclin dependent kinase inhibitor Zotiraciclib (TG02) depletes short-lived survival proteins such as c-MYC and MCL-1 which are overexpressed in glioblastoma. The mode of action is thought to be specific inhibition of cyclin-dependent kinase (CDK) 9. Methods: EORTC 1608 was a three parallel group (A,B,C) phase Ib, non-randomized, multicenter study in isocitrate dehydrogenase wildtype newly diagnosed glioblastoma or anaplastic astrocytoma. In groups A and B, the maximum tolerated dose (MTD) of Zotiraciclib in elderly patients, in combination with radiotherapy alone (group A) or temozolomide alone (group B), stratified by O 6 -methylguanine DNA methyltransferase promoter methylation status, were determined. In group C, we explored single agent activity of TG02 at first relapse with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. Tumor-related extracellular vesicles were quantified according to the minimal information for studies of extracellular vesicles 2018 (MISEV2018) guidelines. Results: Main toxicities of zotiraciclib were neutropenia, gastrointestinal disorders and hepatotoxicity. The MTD was 150 mg twice weekly in group A (weekly) or twice weekly in alternating weeks in group B. PFS-6 in group C was 6.7%. The tumor expression of c-MYC and MCL-1 was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. The levels of tumor-related extracellular vesicles in the blood correlated with tumor volumes determined by MRI and increased from baseline to recurrence. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents which are the cornerstone of medical treatment for glioblastoma. Its single agent clinical activity in the recurrent setting was low. The role of c-MYC and MCL-1 as therapeutic targets and the diagnostic value of extracellular vesicles in peripheral blood in glioblastoma warrant further study.
SH2B3 mutation as a potential resistance mechanism to oncolytic virus therapy.
Authors: Philippos Apolinario Costa, Jeffrey Joseph Ishizuka, Kelly Olino, Alexander Frey, Daniel Lee
Journal: Journal of Clinical Oncology (2024)

2578 Background: Oncolytic viruses (OV) are viruses that preferentially destroy cancer cells while sparing healthy cells. Currently, talimogene laherparepvec (TVEC) is the sole FDA-approved OV product; however, resistance to therapy often emerges. To further understand OV resistance mechanisms, we performed transcriptome and mutational analysis on patient samples using a discordant lesion approach. Methods: An 80-year-old woman was diagnosed with Merkel cell carcinoma of the right lower extremity and underwent wide local excision. Her disease recurred, and she developed multiple metastatic lesions over three years. During that time, she was further treated with radiation, immunotherapy, and intralesional TVEC. Despite the different treatments, her disease eventually progressed, leading to her death. We analyzed the primary lesion and four discordant lesions that either persisted or recurred following treatment. Treatment data were extracted from medical records, and lesions were classified based on their resistance to therapies. DNA and RNA were extracted from tissue, and whole exome sequencing and bulk RNA sequencing were performed. Whole exome data was compared between specimens to determine mutation enrichment over time. Gene Set Enrichment Analysis was used to interpret bulk RNA sequencing data and compare transcriptional states of lesions. Results: Lesions four and five recurred following TVEC treatment and were, therefore, classified as TVEC resistant. Whole exome sequencing of all five lesions identified a heterozygous point mutation (P521L) in the SH2B3 gene in lesions four and five only. Additionally, the variant allelic fraction of this point mutation increased from 33% in lesion four to 44% in lesion five, where it was the highest frequency variant. When comparing lesion five to lesion one, Gene Set Enrichment Analysis showed an increase in both the hallmark inflammatory response gene signature and the hallmark interferon alpha response gene signature. SH2B3 is a gene that encodes the LNK protein, which functions as a negative regulator of the JAK-STAT signaling pathway and is, therefore, a negative regulator of interferon signaling. A mutation leading to a loss of function in SH2B3 would conceptually lead to upregulation of interferon signaling, which has previously been shown to promote an antiviral state within the tumor microenvironment and limit the effectiveness of OV treatment. Conclusions: Sequencing of discordant MCC lesions revealed enrichment in the mutational fraction of SH2B3 associated with an increase in interferon alpha and inflammatory signaling among lesions that were resistant to TVEC treatment. This is the first study to report a possible genetic driver for OV resistance. We introduced using CRISPR-HDR P521L SH2B3 in MCC cell lines to investigate its impact on LNK expression and its role as a mechanism of OV treatment resistance, with results to be presented.
Distribution and mutational landscape of inherited cancer susceptibility syndromes in central nervous system tumors.
Authors: Jie Gong, Chuanwei Wang, Ningning Luo, Tiantian Han, Xiangyu Yin, Dong-sheng Chen
Journal: Journal of Clinical Oncology (2024)

2051 Background: Inherited cancer susceptibility syndromes (ICSS) caused approximately 5%–10% of malignancies. The fifth edition of the World Health Organization Classification of Tumors emphasized that central nervous system (CNS) tumors are associated with various ICSS. Our understanding of CNS tumors, both at the systemic and germline levels, has significantly improved with the increasing popularity of next-generation sequencing (NGS) testing. Recognizing individuals with ICSS in primary CNS tumors is crucial for optimizing proper genetic counseling and improving therapeutics and clinical care, and may further directly enhance patient outcomes. Methods: We retrospectively analyzed the ICSS of 4,828 patients with CNS tumors in a Chinese cohort, including age, cancer type, and sex distribution, and further investigated the somatic and germline mutations of cancer-related genes. Additionally, we examined the molecular characteristics of CNS tumors with ICSS and their clinical significance for diagnostic and therapeutic purposes. Results: Our study identified 258 (5.34%) patients with ICSS among 4,828 patients with CNS tumors with 265 germline P/LP variants, and identified 34 categories of ICSS, including 20 types of ICSS occurring in 28% (72/258) of patients not listed in the WHO CNS 5 classification. The gene with the highest germline P/LP mutation frequency was TP53 (9.69%), followed by MSH2 (9.30%), NF1(8.91%), and BRCA2 (7.75%). These ICSS-associated genes were significantly enriched in the DNA repair and genomic stability signaling pathways (67%, 178/265). The two-hit events mainly focused on NF1, MSH6, and MSH2. The genes with the top five somatic mutation frequencies were TP53 (42.25%), TERT (30.23%), CDKN2A (28.68%), CDKN2B (27.52%), and PTEN (25.58%). The top five ICSS in CNS tumors were Lynch syndrome, BRCA-related cancer predisposition syndrome, Li-Fraumeni syndrome, Fanconi anemia, and neurofibromatosis type 1. ICSS analysis reclassifies CNS tumors of “NOS” and 53.88% (139/258) of patients diagnosed with ICSS harboring potential precision oncology therapy target mutations. Conclusions: Our study is the first to include a large-scale cohort of patients with CNS tumors with ICSS and analyze the clinical and genomic features as well as their clinical significance. Results in our study of CNS tumors with ICSS are expected to improve disease entire process management, which is an important application of DNA-based NGS in ICSS evaluation and management and provides a reference direction for the future design of clinical trials.
Phase 1 study (DRAGON) of SRK-181 (linavonkibart), a latent TGFβ1 inhibitor, combined with pembrolizumab in patients with anti-PD1 resistant advanced solid tumors: Updated results of expansion part.
Authors: Ulka N. Vaishampayan, Randy F. Sweis, Deepak Kilari, Ahmad A. Tarhini, Justin F. Gainor, Minal A. Barve, Guru P. Sonpavde, Meredith McKean, David J. Park, Sunil Babu, Yawen Ju, Lan Liu, Susan Henry, Lu Gan, Timothy A. Yap
Journal: Journal of Clinical Oncology (2024)

2507 Background: Linavonkibart (LKT), also known as SRK-181, a fully human IgG4 monoclonal antibody, selectively inhibits latent transforming growth factor-beta isoform 1 (TGFβ1). TGFβ1 drives tumor immune escape by promoting an immunosuppressive pro-tumor microenvironment, including reducing antigen presentation, impairing T-cell infiltration, and tumor-killing activity. Previously, results from the dose escalation phase (3+3 design) of the ongoing open-label, phase 1 DRAGON study (NCT04291079) have showed antitumor activity with LKT + pembrolizumab (P). The combination was well tolerated with no dose limiting toxicity and the recommended dose for LKT is 1500mg q3W. Methods: In the Part B (expansion phase), LKT (1500mg q3w) + P were administered in melanoma (MEL), urothelial carcinoma (UC), and non-small cell lung cancer (NSCLC) pts, who were non-responders to prior anti-PD-1; and in ccRCC and HNSCC pts, with disease progression on the most recent prior anti-PD-1.Biomarker analyses include immunohistochemistry and flow cytometry. Results: As of 12 Jan 2024, 72 pts (29% females, median age of 65 years) were enrolled in Part B. All pts received at least one anti-PD-1 therapy with median prior lines of therapies of 3 (range 1-9). All ccRCC and all but 2 HNSCC pts had a best response of SD or PD on prior anti-PD-1. All these patients had progressed on the most recent anti-PD-1. None of the MEL, UC and NSCLC pts had a response to prior anti-PD-1. The most common treatment-related AEs (TRAE, ≥10%) of any grade were rash (23.6%), pruritus (20.8%), fatigue (19.4%) and diarrhea (12.5%). Grade 3 TRAE (≥5%) were rash (8.3%). Only 1 grade 4 TRAE (dermatitis exfoliative generalised) occurred. No grade 5 TRAE and no treatment-related SAE (≥2% [1 pt]) was observed. Efficacy results are presented in the table below. Tumor assessments were based on RECIST 1.1 criteria by PI assessment. Biomarker results showed decreased circulatory myeloid derived suppressor cell levels and increased CD8+ infiltration into tumors across multiple tumor types, indicating enhanced proinflammatory microenvironment. Conclusions: Combination treatment with LKT+P is associated with enhanced proinflammatory microenvironment with promising efficacy in anti-PD-1 resistant pts across multiple tumor types with manageable safety profile. The result supports LKT as a potential treatment to overcome immune checkpoint inhibitor-associated resistance. Clinical trial information: NCT04291079 . [Table: see text]
Safety and efficacy of CyberKnife radiosurgery plus anlotinib hydrochloride in patients with recurrent glioblastoma: A prospective phase II single-arm study.
Authors: Yun Guan, Huaguang Zhu, Jing Li, Wei Zou, Li Pan, Yang Wang, Ying Liu, Enmin Wang, Xin Wang
Journal: Journal of Clinical Oncology (2024)

2050 Background: Glioblastoma (GBM) is a tumor known for its highly vascular nature and limited treatment options upon disease recurrence. While Bevacizumab which target VEGF-A has gained approval for treating recurrent glioblastoma, the multi-target tyrosine kinase inhibitor Anlotinib has the ability to directly target Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), and Fibroblast Growth Factor Receptor (FGFR). Theoretically, its anti-angiogenic effect may exceed that of Bevacizumab, and preliminary studies have shown its therapeutic efficacy in recurrent GBM (rGBM), indicating promising treatment potential. This study aims to present findings regarding the effectiveness and safety of combining Anlotinib with stereotactic radiosurgery (SRS) in treating patients with rGBM. Methods: Patients who underwent surgery, standard radiotherapy, and temozolomide chemotherapy and were diagnosed with recurrence based on Response Assessment in Neuro-Oncology (RANO) criteria and/or biopsy were eligible for inclusion. Each patient underwent CyberKnife SRS (25Gy/5fx) in combination with oral administration of Anlotinib (12 mg, daily, days 1–14/3 weeks) until encountering disease progression or experiencing intolerable adverse effects. The primary objective was the investigator-assessed median overall survival (OS) using the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Between December 2019 and July 2023, 22 patients (median age: 55 years; range: 28–70) were included. According to RANO criteria, 21 patients exhibited tumor response, with 6 achieving complete response, resulting in an objective response rate of 95.5%. Additionally, one patient maintained stable disease without progression. Median progression-free survival (PFS) was 9.1 months (95% CI, 7.5–24.7), with a 6-month PFS rate of 85.7% (95% CI, 71.9–100.0). Median overall survival was 19.5 months (95% CI, 10.6–46.8). Common adverse events included hand-foot skin reactions (40.9%), hypercholesterolemia (27.3%), and hypertension (22.7%). Four patients experienced grade 3 adverse events, accounting for an 18.2% incidence rate. Therapy discontinuation due to ischemic stroke (grade 3) occurred in one patient. No grade 4 events or treatment-related deaths were reported. Conclusions: The combination of salvage SRS with Anlotinib demonstrated promising outcomes and manageable toxicity in managing recurrent GBM. Currently, a phase II randomized controlled trial, supported by the Shanghai Municipal Commission of Health, is underway. This trial aims to compare the efficacy of Anlotinib combined with radiosurgery against Bevacizumab combined with radiosurgery for the treatment of rGBM patients, further exploring this therapeutic regimen. Clinical trial information: NCT04197492 .
Pharmacokinetics and biomarker analysis from a phase 1/2 open-label study of the anti-GPC3 T-cell engager SAR444200, in patients with advanced solid tumors.
Authors: Maxime Chenard-Poirier, Khaldoun Almhanna, Darren Wan-Teck Lim, Anthony B. El-Khoueiry, Jens Samol, Baek-Yeol Ryoo, Jung Yong Hong, ROBIN MENG, Giovanni Abbadessa, Serena Masciari, Asma Kefsi, Yiding Zhang, Helene Guillemin-Paveau, Benoit Pasquier, Lucie Lepine, Ecaterina Elena Dumbrava
Journal: Journal of Clinical Oncology (2024)

2579 Background: SAR444200 is a novel NANOBODY T cell engager that simultaneously binds TCRαβ and glypican-3 (GPC3) to co-engage T cells with GPC3-expressing tumor cells, resulting in T cell-dependent cellular cytotoxicity. Here we present updated safety, pharmacokinetics (PK) and biomarker data from 6 and 5 dose levels (DL), respectively in patients with advanced solid tumors in the dose escalation cohort (Part 1A) from the first-in-human Phase 1/2 trial (NCT05450562). Methods: This ongoing Phase 1/2 trial evaluated open label, intravenously administered SAR444200 (every week with lead-in doses) at DL1 (3 mg), DL1A (1 mg), DL2A (2.5 mg), DL3A (4.5 mg), DL4A (18 mg), and DL5A (36 mg) in adult patients with GPC3+ solid tumors. On study imaging was performed every 9 weeks after the date of first infusion of SAR444200. Whole blood samples were collected to assess the plasma concentrations of SAR444200 and for biomarker analysis. PK analysis was performed with electrochemiluminescence-based total PK assay using Meso Scale Discovery platform. Anti-drug antibody (ADA) monitoring was performed using a PandA assay. Results: As of 19 January 2024, a total of 24 patients with GPC3+ solid tumors received SAR444200, 4 patients per DL (DL1, DL1A, DL2A, DL3A, DL4A, DL5A). Most of the patients (17 patients, 71%) had hepatocellular carcinoma. No dose-limiting toxicities were observed. Twenty-two patients (92%) reported treatment-related adverse events (TRAEs) of any grade, including three patients with a serious TRAE (2 events with hospitalization prolongation for a Grade 1 and 2 cytokine release syndrome [CRS] that recovered completely without and with Tocilizumab, respectively, 1 event with pneumonitis Grade 3). All CRS (19 patients, 79%) and infusion-related reaction (7 patients, 29%) were Grade 1 or 2. C max was observed at the end or shortly after completion of infusion. The maximum ADA titer, though high, stabilized despite the target dose increased from Cycle 2. Biomarker analysis showed an increase of interleukin-6 and interferon gamma during lead-in doses, supporting CRS. Cytokines declined after Cycle 1. Among 14 HCC patients with baseline alpha-fatal protein (AFP) higher than 20 ng/ml, 4 (29%) had at least a 20% AFP decrease on treatment. Two patients (both with HCC) have been on study drug for more than 6 months. Conclusions: These results suggest that SAR444200 is tolerable at the tested dose levels in patients with GPC3+ advanced solid tumors. Dose escalation continues at this time. Clinical trial information: NCT05450562 .
Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study
Authors: Yu Hu, Xiaofan Liu, Hu Zhou, Shujie Wang, Ruibin Huang, Yi Wang, Xin Du, Jing Sun, Zeping Zhou, Zhenyu Yan, Wenming Chen, Wei Wang, Qingchi Liu, Qingshu Zeng, Yuping Gong, Jie Yin, Xuliang Shen, Baodong Ye, Yun Chen, Yajing Xu, Huiping Sun, Yunfeng Cheng, Zhuogang Liu, Chunling Wang, Guolin Yuan, Xiaohui Zhang, Xin Li, Peng Cheng, Xinhong Guo, Zhongxing Jiang, Feng'e Yang, Linhua Yang, Chengwei Luo, Taiwu Xiao, Sisi Fu, Hongyan Yin, Xiaojun Guo, Qian Xu, Songhua Fan, Michael M Shi, Weiguo Su, Heng Mei, Renchi Yang
Journal: The Lancet Haematology (2024)
Nivolumab With or Without Ipilimumab Combined with Stereotactic Body Radiotherapy in patients with Metastatic Biliary Tract Cancer: A Randomized Phase 2 Study
Authors: Alice Markussen, Julia S. Johansen, Finn O. Larsen, Susann Theile, Jane P. Hasselby, Gro L. Willemoe, Torben Lorentzen, Kasper Madsen, Estrid Høgdall, Tim S. Poulsen, Eva E. Wilken, Poul Geertsen, Claus P. Behrens, Inge M. Svane, Dorte Nielsen, Inna M. Chen
Journal: Clinical Cancer Research (2024)

The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC).