tbuckley/cabot-search huggingface dataset:
Comparison of time to failure of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy: A consecutive analysis of NSCLC patients with high PD-L1 expression.
Authors: Hiroshi Takumida, Hidehito Horinouchi, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Yasushi Goto, Noboru Yamamoto, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2021)

9061 Background: There are two types of pembrolizumab-containing strategies for patients with non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥50%): the early combination of pembrolizumab plus chemotherapy, and chemotherapy after pembrolizumab failure. Which strategy is superior, however, remains unclear. Comparing progression-free survival (PFS) or progression after the next therapy line (PFS2) in previous clinical trials has not allowed any conclusions regarding superiority to be made. Instead, the time to failure of strategy (TFS), which represents the time until disease exacerbation when the same number of drugs has been used, should be used to compare the two strategies. Methods: We consecutively reviewed the efficacy and safety of first-line, pembrolizumab-containing regimens administered between December 2017 and November 2020. We divided the patients who received pembrolizumab as a first-line treatment into two groups according to whether they received chemotherapy: a pembrolizumab plus chemotherapy group (combo group), and a pembrolizumab monotherapy group (mono group). TFS was defined as the PFS in the combo group and the PFS2 in the mono group. We used the propensity score matching (PSM) method to reduce the bias. Results: Of the 964 patients with advanced NSCLC who underwent first-line treatment, 126 with a PD-L1 TPS ≥50% were eligible for inclusion in this analysis (89 in mono group, 37 in combo group). PSM matched 36 people from each of the two groups. The median follow-up period was 16.2 months (range, 0.1-34.3 months). The patient backgrounds were similar. The overall response rate (ORR) of the combo group was higher than that of the mono group (69.4% vs. 50.0%). The median PFS (mPFS) in the combo group was longer (11.4 months vs. 6.0 months). However, the median TFS (mTFS) of the two groups was almost the same (11.4 months vs. 11.7 months). At the time of the analysis, the median overall survival had not been reached. The frequency of all immune-related serious adverse events (irSAE) was similar, however, that of all SAE and AE leading to treatment discontinuation were larger in the combo group. Conclusions: The ORR of the combo group was higher than that of the mono group; however, the TFS was similar. We suggest that pembrolizumab plus chemotherapy, which can increase toxicity, might be of value in patients, producing a clinically meaningful increase in the ORR.[Table: see text]
Anlotinib combined with pemetrexed and carboplatin as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): ALTER L012.
Authors: Qiming Wang, Xiuli Yang, Tianjiang Ma, Qiumin Yang, Chenghui Zhang, Yunfang Chen
Journal: Journal of Clinical Oncology (2021)

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m 2 , iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.
OMIC-01. THE LANDSCAPE OF EXTRACHROMOSOMAL CIRCULAR DNA IN MEDULLOBLASTOMA SUBGROUPS
Authors: Owen Chapman, Jens Luebeck, Shanqing Wang, Alexandra Garancher, Jon Larson, Joshua Lange, Ivy Tsz Lo Wong, John Crawford, Scott Pomeroy, Paul Mischel, Ernest Fraenkel, Robert Wechsler-Reya, Vineet Bafna, Jill Mesirov, Lukas Chavez
Journal: Neuro-Oncology (2021)

Abstract Extrachromosomal circular DNA (ecDNA) is an important driver of particularly aggressive human cancers. However, the prevalence of ecDNA, and its role in tumor development and progression in the different molecular subgroups of medulloblastoma (MB), remain unknown. To answer these questions, we have assembled a multi-institutional retrospective cohort of 472 MB patients with available whole genome sequencing (WGS) data, drawing from three cancer genomic data repositories and covering all MB subgroups (WNT, SHH, Group 3 and Group 4). Using recent computational methods to detect and reconstruct ecDNA, we find ecDNA in 66 patients (14%) and observe that the presence of ecDNA is associated with significantly poorer outcomes. By subgroup, ecDNA was found in 0/24 WNT (0%), 22/109 SHH (20%), 15/107 Group 3 (14%) and 20/181 Group 4 (11%) patients. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. We further analyzed 24 patient-derived xenograft (PDX) and four cell line models of MB tumors. ecDNA was substantially more frequent in patient-derived models (17 of 29, 59%) than in our patient cohort. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identify regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we are currently conducting in-vitro CRISPRi screens targeting regulatory regions on the ecDNA of a MB cell line to determine whether these enhancers promote proliferation. In summary, our study analyzes the frequency, diversity and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.
CaCO<sub>3</sub>‐Encapuslated Microspheres for Enhanced Transhepatic Arterial Embolization Treatment of Hepatocellular Carcinoma
Authors: Aimi Zhang, Zhisheng Xiao, Qiufang Liu, Panli Li, Fei Xu, Jianjun Liu, Huiquan Tao, Liangzhu Feng, Shaoli Song, Zhuang Liu, Gang Huang
Journal: Advanced Healthcare Materials (2021)

Abstract Transcatheter arterial embolization (TAE) is an extensively applied treatment method for hepatocellular carcinoma (HCC). However, the worsened tumor microenvironment (TME, e.g., reduced pH post‐TAE) may result in unsatisfactory therapeutic outcome. Herein, a new kind of embolic agent, calcium carbonate encapsulated alginate microspheres (CaCO 3 ‐ALG MSs) are synthesized. Such CaCO 3 ‐ALG MSs are able to neutralize the tumor pH owing to the reaction of CaCO 3 with protons, which would not affect the overall morphology of microspheres after decomposition of CaCO 3 . TAE treatment with CaCO 3 ‐ALG MSs is then conducted in an orthotopic rat liver cancer model. 18 F‐Fluorodeoxyglucose micropositron emission tomography/computed tomography imaging is conducted post‐TAE and discovered that intra‐arterial injection of CaCO 3 ‐ALG MSs shows obvious enhanced therapeutic outcome compared to the same treatment with bare ALG MSs or the clinically used lipiodol. Further studies including analysis of immune cells in tumors, cytokine assays, and bioinformatics analysis all verify the reverse of immunosuppressive TME toward a more immunosupportive one after TAE with CaCO 3 ‐ALG MSs. The research not only presents a new CaCO 3 ‐containing embolic agent for enhanced TAE treatment of HCC but also highlights a clinically meaningful approach to improve cancer treatment via tumor pH neutralization.
Molecular testing in advanced lung adenocarcinoma: A single-center experience.
Authors: Mahir Khan, Ryan Huu-Tuan Nguyen, Mary Pasquinelli, Lawrence Eric Feldman
Journal: Journal of Clinical Oncology (2021)

e21157 Background: Standard of care testing prior to first-line therapy for advanced lung non-small cell lung cancer (NSCLC) includes EGFR mutations, ALK rearrangements, and PD-L1 expression. There is limited real-world evidence on NSCLC molecular testing patterns in underrepresented racial and ethnic populations. Methods: We identified adult patients newly diagnosed with stage IV lung adenocarcinoma at the University of Illinois Hospital &amp; Health Sciences System between January 1, 2015 and October 1, 2019. Rates of biomarker testing for EGFR, ALK, and PD-L1 were determined, as well as the median time from tissue biopsy to each result. Data were stratified by race and ethnicity. Timelines of molecular testing were studied in relation to cancer therapy initiation. Results: Among 80 patients diagnosed with advanced NSCLC, 70 (87.5%) received EGFR testing, 69 (86.3%) received ALK testing, and 40 (50%) received PD-L1 testing from 2015-2019. Thirty-one (81.6%) patients diagnosed from 2017-2019 had PD-L1 testing. Median time from biopsy to molecular test result in the overall population was 3.0 weeks for EGFR, 3.0 weeks for ALK, and 2.0 weeks for PD-L1. There was no significant difference in EGFR and ALK testing rates between Black and non-Black patients. PD-L1 testing was decreased in Black patients compared to non-Black patients ( p = 0.02) from 2015-2019, but there was no significant difference from 2017-2019. All three biomarkers had similar testing rates between White and non-White patients and between Hispanic and non-Hispanic patients. Median time from biopsy to PD-L1 result decreased from over 12 weeks in 2015 and 2016 to 2 weeks in 2018 and 2019. Six (7.5%) patients received first-line treatment before results were available. Two (2.5%) required treatment changes based on results. Conclusions: In an urban, academic center we found similar EGFR and ALK testing rates among race and ethnicity subgroups. PD-L1 testing was lower in Black patients from 2015-2019 but not after national guidelines recommended PD-L1 testing in 2017. Treatment was initiated without full biomarker data in multiple cases, sometimes leading to changes in therapy after results were obtained. Further studies are indicated to determine strategies for comprehensive, timely, and equitable biomarker testing in advanced NSCLC.[Table: see text]
Disparities in ovarian cancer treatment and overall survival according to race: An update.
Authors: Deanna Huffman, Thejus Thayyil Jayakrishnan, Karthik Shankar, Chelsea Peterson, Rodney E. Wegner
Journal: Journal of Clinical Oncology (2021)

5552 Background: It has long been identified that black women with ovarian cancer have worse overall survival when compared to white women. Disparities in the adherence to NCCN guideline-directed treatment and socioeconomic characteristics may be responsible for the differences in these outcomes. Methods: A retrospective review of National Cancer Database (NCDB) was performed to identify patients diagnosed with ovarian cancer from 2012-2016. We defined adherence to NCCN (National Comprehensive Cancer Network) guidelines as having stage and year-appropriate chemotherapy and surgery. Differences in guideline adherence, socioeconomic characteristics and survival outcomes were assessed. Results: In total, 32,163 were identified meeting the study criteria; 27,744 identified their race as “white” and 2,204 identified their race as “black”. Characteristics associated with higher likelihood of black race were advanced stage of disease- stage III (OR = 1.1869, CI = 1.03-1.37) or stage IV disease (OR = 1.4495, CI = 1.23-1.70) and treatment in a comprehensive (OR = 1.5757, CI = 1.16-2.15) or academic (OR = 2.3023, CI = 1.70-3.12) treatment facility. Variables associated with a lower likelihood of black race were higher education level (OR for high school degree &lt; 6.5 % = 0.2501, CI = 0.21-0.30) and higher median household income (OR for income &gt; $63,333 = 0.4218, CI = 0.36-0.49). Whether the care received was adherent to NCCN guidelines did not seem to be associated with black race (OR for adherence = 1.0021, CI = 0.89-1.13). 5-year overall survival for patients who received adherent care was 58% for white patients vs. 49% for black patients. Among those who didn’t receive adherent care, the outcomes were 49% among white patients vs. 38% among black patients. Conclusions: Overall survival remains worse for black patients, regardless of whether their care adhered to NCCN guidelines as defined by our study. This suggests that while receipt of care that is not adherent to NCCN guidelines seems to be negatively associated with overall survival, we must consider and evaluate other socioeconomic, environmental and system factors that are contributing to this continued survival discrepancy in women being treated for ovarian cancer.
Cell-free circulating tumor DNA (cfDNA) analysis of advanced thymic epithelial tumors (TETs).
Authors: Hiba I. Dada, Leylah Drusbosky, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2021)

8577 Background: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelial cells of the thymus. Thymomas tend to be slowly growing, whereas thymic carcinomas are more aggressive and often metastasize wildly. TETs have a very low tumor mutational burden (TMB). cfDNA has been used in several tumor types to describe the molecular characteristics and select treatment options, especially in absence of tissue availability. There is no information on the cfDNA detected in TETs. The purpose of this study was to identify common genomic alterations occurring in circulating tumor DNA (ctDNA) in patients with advanced TETs, detected using a cfDNA assay. Methods: We retrospectively evaluated 157 TET samples from the Guardant Health database between November 2017 – November 2020. The cfDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes using a commercially available liquid biopsy assay (Guardant360; Guardant Health, Redwood City, CA) . We evaluated the frequency of genomic alterations based on diagnosis, age, and sex. Results: In this cohort, 66% of the patients had thymic carcinoma and 34% had thymoma. The median age was 60 years, and 59% of patients were male. 126 patients (80%) of this cohort had ≥1 somatic alteration detected. The most prevalent mutations detected are TP53 (55%), KIT (13%), EGFR (12%), BRCA2 (11%), PIK3CA (10%), ARID1A (10%), ATM (10%), KRAS (9%), APC (9%), and BRAF (9%). Mutations were more commonly observed in thymic carcinomas than thymomas, but statistical significance was not reached due to the small sample size. Frequencies of the observed genomic alterations are shown in the table below. Conclusions: This study confirms that advanced stage TETs shed tumor DNA into the circulation that can be picked up in the majority of patients, using a solid tumor platform, despite the low TMB typically observed in these tumors. This assay can potentially be used to monitor response to therapy. A more targeted gene panel, enriched for genes commonly mutated in TETs (e.g. GTF2I, BAP1, CYLD) might provide further insights in the future in the management of TETs.[Table: see text]
Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab (P+T) in the APHINITY trial.
Authors: Evandro de Azambuja, Daniel Eiger, Marion Jennifer Procter, Noam Falbel Ponde, Sebastien Guillaume, Damien Parlier, Matteo Lambertini, Antoine Desmet, Carmela Aves Caballero, Christian Aguila, Guy Heinrich Maria Jerusalem, Janice Maria Walshe, Elizabeth S. Frank, Jose Bines, Sibylle Loibl, Martine J. Piccart-Gebhart, Michael S. Ewer, Susan Faye Dent, Chris Plummer, Thomas M Suter
Journal: Journal of Clinical Oncology (2021)

510 Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to &lt;50%, or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF or CEs confirmed by the cardiac advisory board. Results: The safety analysis population consists of 4,769 pts. With 74 mos median follow-up (FU), CEs were observed in 159 pts (3.3%): 83 (3.5%) in the P+T and 76 (3.2%) in Pla+T arms, respectively. Most CEs occurred during anti-HER2 therapy: 123/159 (77.4%) and were asymptomatic or mildly symptomatic LVEF decrease (133/159; 83.6%) (Table 1). There were 2 cardiac deaths in each arm (0.1%). More CEs occurred in pts receiving an anthracycline-based CT compared to those receiving non-anthracycline CT (139 vs. 20 CEs, respectively). Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 pts (81.9%). Conclusions: Dual blockade with P+T does not increase the risk of CE compared to Pla+T alone. The use of anthracycline-based CT increases the risk of a CE; hence non-anthracycline CT may be considered particularly in pts with other cardiovascular risk factors. Clinical trial information: NCT01358877. [Table: see text]
Consensus disease definitions for the spectrum of neurologic immune related adverse events.
Authors: Amanda C Guidon, Leeann B Burton, Bart K Chwalisz, James M Hillis, Teilo Schaller, Kerry Lynn Reynolds
Journal: Journal of Clinical Oncology (2021)

2647 Background: Expanding FDA-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in both therapeutic success and immune related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes evidence-based treatments and research progress. The objectives of this study were to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. Methods: A working group of 4 neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the Neuro irAE Disease Definition Panel, consisting of neurologists, oncologists, neuro-oncologists and irAE subspecialists. A modified Delphi consensus process was used, with 2 rounds of anonymous ratings by panelists and 2 virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. The working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions. Results: Twenty-seven panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for 7 core disorders: irMeningitis, irEncephalitis/Encephalomyelitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, 6 sub-classifications are described: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation and present or absent concurrent irAE. Conclusions: These disease definitions standardize irAE-N classification. They are being incorporated into a multi-institutional registry that our group has initiated to study irAEs. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.