tbuckley/cabot-search huggingface dataset:
Systematic review and meta-analysis of definitions and reported incidences of anthracycline cardiotoxicity.
Authors: Sae Jang, Kathryn Jean Ruddy, Charles L. Loprinzi, Saro Armenian, Daniel John Lenihan, Joerg Herrmann
Journal: Journal of Clinical Oncology (2019)

e23081 Background: Anthracycline-induced cardiotoxicity (AIC) is a well-known phenomenon, but the true incidence is poorly defined, and definitions of AIC in the literature are variable. We performed a systematic review and meta-analysis to elucidate AIC definitions and the incidence of clinical heart failure (HF) and subclinical AIC reported in adult breast cancer and lymphoma patients after anthracycline (AC) therapy. Methods: 3,428 abstract and titles were identified via PubMed search. Inclusion criteria for full text review included minimum of 100 adult patients receiving ACs; median/mean follow up of at least 12 months; and specified evaluation of left ventricular ejection fraction. Outcomes were divided into clinical HF and subclinical AIC. Meta-analysis was performed with MedCalc software with random effects model. Results: 366 full text articles were reviewed. 24 studies, including a total of 11,065 patients, reported clinical HF findings; 21 studies, including a total of 8,098 patients, reported subclinical AIC findings. Meta-analysis showed an overall incidence of clinical HF of 3.1% (range 0 to 29%, CI 1.9 to 4.6%, I 2 = 93.9%); an incidence of 2.0% (CI 0.9 to 3.6%, I 2 = 91.6%) in breast cancer patients receiving AC; and 4.8% in lymphoma patients receiving AC (CI 2.1 to 8.6%, I 2 = 93.6%). Subclinical AIC was seen in 13.8% overall patients (range 2 to 45%, CI 10.4 to 17.7%, I 2 = 95.3%); 10.3% of breast cancer patients (CI 7.0 to 14.3%, I 2 = 95.0%); and 19.8% of lymphoma patients (CI 12.3 to 28.6%, I 2 = 94.4%). Incidence of HF correlated with increasing age (r = 0.51, p = 0.06) and cumulative dose (r = 0.51 , p = 0.19). There was notable heterogeneity of AIC definitions between studies (Table). Conclusions: Cardiotoxicity is not uncommon among patients who receive AC, particularly at doses given for the treatment of lymphoma. However, there was considerable heterogeneity in HF incidences. More uniform criteria and precise estimates are needed to inform clinical practice and trials. [Table: see text]
Multiplex genomic testing (MGT): Four-year real-world experience of two community oncology practices in central rural Nebraska.
Authors: Mehmet Sitki Copur, Pornchai Jonglertham, Thomas Zusag, Carlene R. Springer, Sally Molnar, Leslie Robbins, Tonya Peterson, Jessica Arbogast, Chandra Muske, Stacia Shipman, Emily Fakkema
Journal: Journal of Clinical Oncology (2019)

e14728 Background: MGT forms the basis of precision oncology. More and more community oncology practices are utilizing MGT to identify somatic Actionable Alterations (AA) in solid tumors. This information is increasingly being used to choose FDA and/or guideline approved treatment options, or clinical trials. Methods: From July 2014 to July 2018, MGT (Foundation Medicine) data of patients (pts) with solid tumors at two community hospital-based oncology practices in central rural Nebraska were retrospectively analyzed. Study population consisted of advanced solid tumor pts (ECOG 0-2) with an available MGT result who had progressed on standard treatment regimens. Treating community oncologists directed treatment choices based on MGT results. Results: 360 pts underwent MGT. Average (avg) turn-around time from order to reporting was 20.19 days. Reimbursements were through commercial insurance (27 %), Medicare (66%), Medicaid (3%), self-pay (2 %) and financial assistance by company (2%). Most common cancer types were non-small cell lung (27%), pancreas (9%), colon (8%), unknown primary (4%), sarcoma (4%), breast (4%), gastro-esophageal (2%) and kidney (1%). 79% of samples had at least one AA. In 69 (19%) pts these alterations were matched to one or more on/off label FDA and/or guideline approved targeted therapies. Only 26/69 pts (37%) in this group were able to have a therapy that was new. 43 (12%) of pts qualified and went on locally available clinical trials (MATCH, LUNG-MAP and TAPUR). Conclusions: Our analysis reflects a 4-year real-world MGT experience in two community oncology practices in central rural Nebraska. In addition to established barriers of cost, long turnaround time, adequate tissue, the low yield of new FDA and/or guideline approved treatments decreases the utility of MGT. Increased variety and availability of precision medicine clinical trials with improved patient access in the rural setting may improve this shortcoming.[Table: see text]
T cell trafficking within the peritoneal tumor environment and ovarian cancer progression.
Authors: Sharina Palencia Desai, Maryam Bahmani, Sarah Foster Adams
Journal: Journal of Clinical Oncology (2019)

5573 Background: Ovarian cancer is associated with high mortality due to detection at late stages with widespread peritoneal metastases at diagnosis in a majority of patients. Ovarian cancer recurrences are primarily found in the peritoneal cavity, and peritoneal disease is the primary cause of morbidity and mortality in this disease. This pattern of tumor engraftment and recurrence indicates that the peritoneal tumor environment is distinct from other niches. Our data indicate that selective peritoneal dissemination is immunologically mediated, based on functional differences in peritoneal and systemic T cells during ovarian cancer progression. This is consistent with data in other solid tumors demonstrating that tumor immunity is driven by regional lymphocyte populations. However, less is known about the mechanisms that establish a permissive immune environment in the peritoneal cavity. We hypothesize that pathways regulating T cell recruitment and retention in the peritoneal cavity (PC) are co-opted by ovarian cancer cells to enable intraperitoneal cancer dissemination and recurrence. Methods: We have developed a novel model that uses direct in vivo labeling of peritoneal cells in an established immune-competent high grade serous murine cancer model. This functional approach enables us to identify T cell subsets retained in the PC with tumor engraftment and progression. Results: We identified high expression of CD49d (a4 integrin) as the most prevalent cell surface marker on T cells retained in the peritoneal cavity, consistent with prior published data in healthy mice and people. We demonstrated a functional role for CD49d hi in T cell retention by showing preferential binding to VCAM. A role for tumor cells mediating this interaction was observed based on enhanced binding affinity in vitro with tumor monolayers. The importance of this mechanism is supported by high VCAM expression in multiple murine and human ovarian cancer cell lines, and T cell localization to VCAM rich areas within ovarian cancer tumors in vivo. Conclusions: CD49d not only defines a lymphocyte subset with a significant role in tumor immunity but presents itself as an important potential therapeutic target to modulate T cell trafficking.
Immune-related toxicities in non-small cell lung cancer: Real-life predictors of outcome to checkpoint inhibitors?
Authors: Emanuela Romano, Roberta Poli, Clement Dumont, Lisa Pietrogiovanna, Marie Vigan, Vincent Servois, Francois-Clement Bidard, Sophie Beaucaire-Danel, Catherine Daniel, Nicolas Girard, Segolene Hescot, Alexia Savignoni
Journal: Journal of Clinical Oncology (2019)

e14135 Background: Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC) and are associated with immune-related adverse events (irAEs). However, real-life data on type, occurrence and kinetics of irAEs, and their predictive value on treatment outcome are lacking. Here, we report on the relation between irAEs, including endocrine irAEs, and outcome to anti-PD-/L-1 (programmed cell death protein-/ligand-1) ICIs. Methods: A total of 147 patients (pts), with locally advanced/metastatic NSCLC, treated with anti-PD-1 (N 140; 95%) or anti-PD-L1 agents (N 7; 5%) as ≥ 2 line treatment were included in two independent, prospective, cohorts at the Institut Curie (ALCINA-NCT02866149) and at Biella Hospital (Italy). PD-L1 status was assessed by immunohistochemistry (clone 22C3, Dako). Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier curves. Results: Median follow-up of 147 pts was 10.2 (range: 0.7-42.8) months; median age, 66 (35-85) years; 100 men (68%). After treatment initiation, irAEs were observed in 72 pts (49%). Thirty one (43%) pts had only endocrine irAEs, mostly thyroid dysfunctions (N 44, 61%). Pre-existing thyroid disease was present in only 6 pts (4%). Dermatologic toxicity in 21 (29%) pts was the next most frequent irAE, 22 (30%) pts had other types of irAEs. Among patients with irAEs, 61 (85%) had ≤ 2 coexisting irAEs, and 13 (18%) pts had &gt; 2 irAEs. Most irAEs were G1 (63%) and G2 (18%). Onset and kinetics differed according to irAE type. There was no association between PD-L1 status and irAE occurrence. Median PFS was 7.2 and 4.2 months in irAEs vs no-irAEs group, respectively [HR 0.70 (95% CI 0.46;1.08), p 0.11]. Median OS in the irAEs group was 18.1 months vs 13.6 months no-irAEs group [HR 0.64 (95% CI 0.37;0.98), p 0.039]. Median OS in the endocrine-irAEs group was 23.5 vs 13.6 months in the no-irAEs group [HR 0.58 (0.74;3.92), p 0.2]. Conclusions: In this study, we show that irAEs – including endocrine type – are frequent in NSCLC pts treated with ICIs and that their occurrence is associated with a survival benefit.
Tumor mutational burden (TMB) and PD-L1 expression as predictors of response to immunotherapy (IO) in NSCLC.
Authors: Emily Castellanos, Jeremy Snider, Siraj Mahamed Ali, Daniel Backenroth, Lee A. Albacker, Karthikeyan Murugesan, Gerald Li, Garrett M. Frampton, Brian Michael Alexander, Kenneth Robert Carson
Journal: Journal of Clinical Oncology (2019)

2630 Background: PD-L1 expression and TMB, as a proxy for neoantigen burden, have been correlated with response to IO in advanced NSCLC (aNSCLC) clinical trials, but their combined utility is unclear. We assessed TMB and PD-L1 as predictors of response in aNSCLC patients (pts) after IO monotherapy in a real-world setting. Methods: Pts had a diagnosis of aNSCLC, comprehensive genomic profiling of 186-315 genes/1.1 megabase (Mb), PD-L1 testing of pre-IO specimens, and were treated in the Flatiron Health network (1/2011 - 6/2018). Clinical characteristics and real-world tumor response (rwTR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports, and linked to genomic data in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. A general additive model examined the predictive value of TMB (as continuous measure) and PD-L1 level on rwTR. A reduced PD-L1-only model was compared to the full model using Akaike Information Criterion (AIC). rwTR predictions at representative TMB and PD-L1 levels were calculated. Results: Of 426 pts, PD-L1 expression was high (≥50%) in 140, low (1-49%) in 123, and negative (&lt;1%) in 163. Median TMB was 9.6 mut/Mb (IQR 4.4 - 14.8) overall, 11.3 in responders and 8.7 in non-responders. TMB did not correlate with PD-L1 level (Kruskal-Wallis p=0.29). The TMB + PD-L1 model had superior prediction of rwTR than the PD-L1 model, as assessed by lower AIC score. In the combined model, higher TMB and PD-L1 levels were each associated with higher rwTR likelihood (Table). Predicted rwTR probability, % (95% CI), by TMB and PD-L1 in line 1. Conclusions: TMB and PD-L1 expression are independent markers that, when combined, have increased predictive power for response to IO. High TMB + low/neg PD-L1 behaved similarly to low TMB + high PD-L1, and high TMB + high PD-L1 predicted the highest rwTR. Investigation of these biomarkers as complementary predictors of progression and overall survival is ongoing.[Table: see text]
Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers.
Authors: Matthew H. Taylor, Justin F. Gainor, Mimi I-Nan Hu, Viola Weijia Zhu, Gilberto Lopes, Sophie Leboulleux, Marcia S. Brose, Martin H. Schuler, Daniel W. Bowles, Dong-Wan Kim, Christina S Baik, Elena Garralda, Chia-Chi Lin, Douglas Adkins, Debashis Sarker, Giuseppe Curigliano, Hui Zhang, Corinne Clifford, Christopher D. Turner, Vivek Subbiah
Journal: Journal of Clinical Oncology (2019)

6018 Background: RET alterations are targetable oncogenic drivers in ~90% of advanced medullary thyroid cancer (MTC) and 20% of papillary thyroid cancer (PTC), yet no selective RET inhibitors are approved. BLU-667 is an investigational highly potent and selective RET inhibitor targeting oncogenic RET alterations including those that confer resistance to multikinase inhibitors (MKIs). We provide an update on the expanded experience of BLU-667 in RET-altered thyroid cancer from the registration-enabling ARROW study (NCT03037385). Methods: ARROW is a global DE (30-600 mg daily [QD or BID]) and dose expansion (DX; 400 mg QD) study in pts with advanced solid tumors. Primary objectives are response rate (ORR; RECIST 1.1) and safety. Results: As of 19Dec2018, 60 pts with RET-mutated MTC (M918T [37], C634R/S/W [8], V804M [4], other/pending [11]) and 5 pts with RET-fusion+ PTC (NCOA4 [3], CCDC6 [2]) received BLU-667 (37 DE, 28 DX). 58% had prior MKI therapy. Among 49 response-evaluable MTC pts, ORR is 47% (95% CI: 33, 62; 2 complete and 21 partial responses (PR); 4 PR pending confirmation; 25 stable disease; 1 progressive disease). 96% (22/23) of responding pts continue treatment; 15 with response duration ≥ 6 months. 2/4 evaluable PTC pts had PR; all 5 enrolled PTC pts continue treatment at 8-11 months. Responses in MTC occur regardless of MKI resistance (prior cabozantinib/vandetanib: ORR 46% (12/26)) or RET genotype (PR in 2/3 evaluable pts with V804M). Disease control rate in MTC pts is 98%. Rapid plasma clearance of RET variants and marked reduction in CEA and calcitonin is observed. Treatment-related toxicity in MTC/PTC pts, generally low-grade and reversible (28% had grade 3 events, no grade 4/5 events, no events requiring discontinuation), includes decreased WBC (23%), increased AST (17%), increased ALT, blood creatinine, and phosphate, hypertension, and decreased neutrophils (all 15%). Conclusions: BLU-667 demonstrates potent, durable and broad antitumor activity and is well tolerated in MTC/PTC pts regardless of MKI resistance and may significantly improve outcomes for pts with RET-altered thyroid cancers. Enrollment of the expansion is ongoing with registrational intent. Clinical trial information: NCT03037385.
Minimum important difference of the incremental shuttle walk test distance in patients with COPD
Authors: Rachael A Evans, Sally J Singh
Journal: Thorax (2019)

We aimed to describe the minimum important difference (MID) of the incremental shuttle walk test (ISWT) in patients with COPD using both distribution and anchor-based methods. Two cohorts were used (n=613) with eligibility criteria of a clinical diagnosis of COPD, an FEV 1 /FVC &lt;70% and an ISWT (after familiarisation) before and after a 7-week course of pulmonary rehabilitation (PR). The MID of the ISWT using the distribution method was 36.1 m. The area under the curve to discriminate between perceived ‘improvement’ and ‘no improvement’ after PR for a change in ISWT of 35 m was 0.66 (0.58–0.73). The MID of the ISWT is therefore between 35.0 and 36.1 m.
Ramucirumab and irinotecan in patients with previously treated gastroesophageal adenocarcinoma.
Authors: Haeseong Park, Nikolaos Trikalinos, Aravind Sanjeevaiah, Katrina Pedersen, Nusayba Ali Bagegni, Andrew B. Nixon, Jesse Huffman, Benjamin R. Tan, Rama Suresh, Kian-Huat Lim, Manik A. Amin, Andrea Wang-Gillam, A. Craig Lockhart
Journal: Journal of Clinical Oncology (2019)

TPS4150 Background: Ramucirumab is used for treatment of metastatic gastroesophageal adenocarcinoma after disease progression on first-line chemotherapy. Superior survival outcome is expected when combined with paclitaxel. However, many patients suffer from neuropathy after oxaliplatin-containing first-line chemotherapy and are unable to tolerate paclitaxel. Irinotecan has shown survival benefit as a single agent or in combination with other agents, but has not been used in combination with ramucirumab for treatment with gastroesophageal cancer. We hypothesize that this combination regimen of irinotecan plus ramucirumab administered as second-line treatment will be well-tolerated with improved outcomes similar to paclitaxel plus ramucirumab in patients with advanced gastroesophageal cancer. Circulating levels of angiogenic factors are correlatives of particular interest in this study. Methods: This is a multi-institutional, single-arm phase II clinical trial of ramucirumab and irinotecan. Primary objective of the study is to determine the progression-free survival in patients treated with this combination after disease progression on first-line chemotherapy. Secondary objectives are to determine other indices of efficacy including overall survival, time to progression, objective response rate, and clinical benefit rate; and to evaluate toxicity and tolerability. Patients with confirmed diagnosis of gastroesophageal adenocarcinoma with measurable disease are included. Patients are required of have disease progression during or within 4 months of first line chemotherapy. Key exclusion criteria include squamous histology; prior irinotecan or ramucirumab use; active brain metastases; or other contraindications to ramucirumab including recent history of gastrointestinal bleeding or perforation, thromboembolic event, and uncontrolled hypertension. Patients receive ramucirumab 8mg/kg with irinotecan 180mg/m 2 IV every 14 days. We plan to enroll 40 patients which will provide 85% power at a 0.05 significance level to detect a median progression free survival time of 4 months compared to historic control of 2.5 months. 25% of patient accrual is complete as of February 2019. Clinical trial information: NCT03141034.
Real-world demographic and clinical characteristics of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) in the United States (US).
Authors: Xiaoqin Yang, François Laliberté, Guillaume Germain, Monika Kumar Raut, Mei Sheng Duh, Shuvayu Sen, Dominique Lejeune, Cristi Cavanaugh, Kaushal Desai, Phillippe Armand
Journal: Journal of Clinical Oncology (2019)

e18347 Background: DLBCL, the most common type of non-Hodgkin lymphoma in the US, is associated with significant morbidity and mortality. In October 2015, DLBCL was differentiated from other related lymphoma entities with the advent of ICD-10-CM DLBCL-specific codes. With limited real-world data on patients (pts) with DLBCL in the modern treatment era, this study was conducted to characterize these pts. Methods: A retrospective study was conducted using the Optum Clinformatics Data Mart database (01/2013–03/2018). Pts ≥ 18 years of age with ≥ 1 hospitalization or ≥ 2 outpatient visits with an ICD-10-CM diagnosis code for DLBCL (or an antecedent diagnosis of other lymphoma, which may have been assigned before confirmation of DLBCL) after October 1 st , 2015 (index date) and no prior ICD-9-CM code for unspecified DLBCL were identified as incident. Pts with an ICD-9-CM code for unspecified DLBCL before October 2015 (index date) were classified as prevalent. At least 12 months of continuous enrollment pre-index date (baseline period) was required. Pts with ICD-10-CM code for primary mediastinal B-cell lymphoma (PMBCL), baseline diagnoses of other malignancies such as Hodgkin lymphoma and multiple myeloma were excluded. Characteristics, including baseline comorbidities, healthcare resource utilization, and costs were assessed. Results: Among 4,074 DLBCL pts (3,201 incident; 873 prevalent), mean age ± standard deviation (SD) was 71 ± 12 years; 46% were female. Incident and prevalent pts had mean Charlson comorbidity index scores of 2.7 and 2.3, respectively. Most common baseline Elixhauser comorbidities were hypertension (68.4%), diabetes (31.1%), and cardiac arrhythmia (25.3%) in incident pts and hypertension (62.5%), diabetes (28.3%), and chronic pulmonary disease (20.6%) in prevalent pts. Mean ± SD number of baseline hospitalizations was 0.32 ± 0.83 and 0.21 ± 0.49 in incident and prevalent pts, respectively. Total mean ± SD baseline healthcare costs (before diagnosis) were $24,621 ± 45,628 for incident pts and $19,137 ± 29,307 for prevalent pts. Conclusions: This study documents substantial co-morbid and economic burden of incident as well as prevalent pts with DLBCL.
Clinical outcomes of patients with or without common AEs in anlotinib cohort: Subgroup analysis of the ALTER0303 trial.
Authors: Wang Zhe-Hai, Baohui Han, Kai Li, Ying Cheng, Jie Liu, Jun Guo, Liyan Liu, Chao Xie, Xiao Han, Haiyong WANG, Qiming Wang, Li Zhang, Jianhua Shi, Jianxing He, Yuankai Shi, Weiqiang Chen, Yi Luo, Lin Wu, Xiuwen Wang, Kejun Nan
Journal: Journal of Clinical Oncology (2019)

e20507 Background: In ALTER 0303, the common adverse reaction (AE) included hypertension (HTN) and hand foot syndrome (HFS). In this subgroup analysis, we aim to assess the relationship between common AEs and clinical benefit in anlotinib cohort. Methods: Eligible patients showed disease progression after second-line or further treatment were randomly assigned in a 2:1 ratio to receive 12 mg/day of anlotinib or placebo. The primary endpoint was overall survival (OS). This subgroup analysis was based on anlotinib cohort. Results: Patients with HTN had significantly improved median OS, median progress-free survival (PFS), objective response (ORR) and disease control rate (DCR) compared with patients without HFS in anlotinib cohort. Similarly, patients with HFS had better clinical outcomes in anlotinib cohort. Not surprisingly, patients occurred both HFS and HTN had more superior medium OS compared with only HFS, only HTN and neither HFS nor HTN. Conclusions: HTN or HFS is associated with better clinical outcomes in advanced NSCLC patients received anlotinib. Clinical trial information: NCT02388919. [Table: see text]