tbuckley/cabot-search huggingface dataset:
Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: A trend over five decades.
Authors: Takefumi Komiya, Gerard Chaaya, Leigh Deshotels, Emily Powell
Journal: Journal of Clinical Oncology (2019)

e18048 Background: ASCO and Friends of Cancer Research have proposed that cancer clinical trials must ease eligibility criteria to make the trials more generalizable in “real-world” patient populations. The specific items in exclusion criteria included presence of brain metastasis (BM), which is commonly seen in small cell lung cancer patients. Frequency and trend of BM as exclusion criteria in extensive-stage (ES) SCLC trials is unknown. Methods: We conducted a comprehensive search to identify prospective clinical trials in patients with ES-SCLC. Pubmed search was conducted with key words “small cell lung cancer” and “extensive” in title. Websites of 20 oncology journals were also searched by their online archives. Recent review articles in ES-SCLC were also investigated for additional articles. Eligible studies must have enrolled primarily ES-SCLC and been published in English. Studies involving brain/chest radiation and brain metastasis specific trials were excluded. Studies were categorized into allowed/undefined, conditional, or complete exclusion of BM. Chi-squire test was used for categorial group comparison. Results: A total of 491 published studies were identified by Pubmed (240), journal websites (198), and review articles (53). Early publication year (1970-1999) and first-line/maintenance setting were associated with higher incidence of complete exclusion of cases with BM (p &lt; 0.0001, 0.0233, respectively). Studies in the 1990s had the highest incidence (27%) of exclusion. In 2010, only 12% allowed or undefined BM. There is no correlation between complete exclusion of BMs and other clinical characteristics including journal impact factor, region, trial phase, randomization, sample size, patient performance status, and age limit. Conclusions: A significant number of ES-SCLC trials continue to exclude patients with BM. Future studies need to ease eligibility regarding BM according to ASCO/Friends recommendations.[Table: see text]
TACTICAL: A phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma.
Authors: Alice Davies, Beth Sage, Krishna Kolluri, Doraid Alrifai, Rebecca Graham, Ben Weil, Rita Rego, Owen Bain, P. Stephen Patrick, Kim Champion, Alex Day, Bilyana Popova, Graham Wheeler, Dan Fullen, Tammy Kalbur, Martin Forster, Mark Lowdell, Sam Janes
Journal: Journal of Clinical Oncology (2019)

TPS9116 Background: Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has its limited therapeutic efficacy. We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression. Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1]. Methods: TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment naïve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study, patients receive SOC on day 1 and 4x10 8 MSCTRAIL cells on day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL. 46 patients will then be randomised into a multi-centre phase II double blind, placebo-controlled trial to receive SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12 weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC therapy in cancer. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42. Clinical trial information: NCT03298763.
Genome-wide chromosomal instability by cell-free DNA sequencing to predict patient survival in metastatic breast cancer.
Authors: Hongnan Mo, Xiaobing Wang, Fei Ma, Ziliang Qian, Xiaoying Sun, Zongbi Yi, Xiuwen Guan, Lixi Li, Binliang Liu, Binghe Xu
Journal: Journal of Clinical Oncology (2019)

e12591 Background: Cell-free DNA (cfDNA) could well recapitulate the genomic features of tumor with minimal invasion. For metastatic breast cancer (MBC), prior applications of cfDNA have focused on tracking specific gene locus. We aimed to evaluate the prognostic value of genome-wide chromosomal instability derived from cfDNA in patients with MBC. Methods: We retrospectively identified 65 patients with MBC who were intended to change line of therapy and had blood draw for cfDNA. We performed low-coverage whole-genome sequencing of cfDNA from plasma, and chromosomal instability was analyzed and represented by chromosomal instability (CIN) score. Results: 32 (53.3%) samples resulted to have high CIN score, with similar clinicopathologic characteristics relative to patients with low CIN. None of patient’s age (P = 0.073), receptor status (P = 0.136), disease stage at primary diagnosis (P = 0.353), or previous lines of therapy (P = 0.067) was correlated with genome-wide chromosomal instability. Different subtypes of MBC exhibit remarkably diverse copy number profiles. High CIN score was associated with significantly shorter overall survival after blood draw, median 21.2 months (95% CI 14.1-28.3) versus not reached (P = 0.006). Besides, patients with high CIN had worse progression free survival compared with the low CIN group (median 7.3 vs 11.0 months, P = 0.034). CIN score remained an independent prognostic factor in multivariate analysis (hazard ratio, 3.563; 95%CI, 1.481 to 8.572; P = 0.005). Conclusions: Here we present a framework for minimally invasive genomic characterization of different subtypes of MBC, and subsequent integration with clinicopathologic data and patient outcomes. Genome-wide chromosomal instability tracking by cfDNA is reliable and predicts survival in patients with MBC.
Patient-reported outcomes (PROs) in patients (pts) with <i>PIK3CA</i>-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) from SOLAR-1.
Authors: Ingrid A. Mayer, Hope S. Rugo, Sibylle Loibl, Tamar Safra, Yeon Hee Park, Petr Krivorotko, Hiroji Iwata, Fabrice Andre, Pier Franco Conte, Eva Ciruelos, Dejan Juric, Jinhee Park, Celine Wilke, David Mills, Agnes Lteif, Mario Campone
Journal: Journal of Clinical Oncology (2019)

1039 Background: Approximately 40% of pts with HR+, HER2– ABC have tumors with a PIK3CA mutation, resulting in phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation. Use of the oral α-specific PI3K inhibitor alpelisib (ALP) + fulvestrant (FUL) in SOLAR-1 significantly improved (vs placebo [PBO] + FUL) both progression-free survival (PFS) (median 11.0 vs 5.7 mo, respectively; HR 0.65; 95% CI, 0.50-0.85; P&lt; 0.001) and objective response rate (ORR) (measurable disease: 36% vs 16%; P&lt; 0.001) in the PIK3CA mutant cohort. In addition to primary efficacy and safety measures, PROs offer valuable insight into therapeutic benefit by measuring whether quality of life (QoL) is maintained during treatment. Methods: Postmenopausal women or men with HR+, HER2– ABC whose disease progressed on/after an aromatase inhibitor were randomized to receive ALP 300 mg once daily or PBO, + FUL 500 mg every 28 days + Cycle 1, Day 15. Secondary objectives included PROs using the EORTC QLQ-C30, EQ-5D-5L, and BPI-SF scales. PROs were collected at screening, every 8 wk for 18 mo then every 12 wk thereafter, at end of treatment, and during follow-up for efficacy. Linear mixed effects models were used to assess score changes from baseline. Time to 10% deterioration (TTD), an established measure of clinically meaningful change in QoL, was compared between the treatment arms’ survival distribution using Kaplan-Meier methodology. Results: At baseline, 93% of pts in the PIK3CA mutant cohort (n = 341) completed questionnaires; ≥75% completed them post-baseline. Adjusted mean changes from baseline in EORTC global health status/QoL scores were &lt; 10% for all visits through wk 96 for both arms, with a mean difference between arms of &lt; 3% for all visits. There was no difference between arms in TTD in global health/QoL status (HR 1.03; 95% CI, 0.72-1.48). Analysis of TTD in EORTC physical, social, and emotional functioning scores revealed no meaningful differences between arms. Conclusions: In addition to significantly improving PFS and ORR, overall QoL was maintained in pts treated with ALP + FUL. Clinical trial information: NCT02437318.
Durability of complete response (CR) with atezolizumab (atezo) in locally advanced/metastatic urothelial carcinoma (mUC).
Authors: Yohann Loriot, Arjun Vasant Balar, Robert Dreicer, Jean H. Hoffman-Censits, Jose Luis Perez-Gracia, Daniel Peter Petrylak, Michiel Simon Van Der Heijden, Xiaodong Shen, Qian (Cindy) Zhu, Beiying Ding, Constanze Kaiser, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2019)

4527 Background: Atezo (anti–PD-L1) has been shown to elicit CRs in a number of mUC patients (pts) in clinical trials. We sought to describe the kinetics, durability and outcomes associated with these CRs in Ph I (PCD) and II (IMvigor210) atezo studies, each with long-term follow-up. Methods: In PCD (pre-treated mUC) and IMvigor210 (Cohort 1, cisplatin-ineligible untreated mUC; Cohort 2, platinum-treated mUC), pts received atezo per protocol (Petrylak JAMA Oncol 2018; Balar Lancet 2017; Rosenberg Lancet 2016). This post hoc analysis descriptively assessed pt disposition, time to and duration of RECIST 1.1 response and overall survival in pts with CR. Results: CR rates were 13%, 8% and 7% in PCD, IMvigor210 Cohort 1 and Cohort 2, respectively. First response was PR in most pts with CR. Median CR duration was &gt; 3 y in PCD, not estimable (NE) in IMvigor210 Cohort 1 and &gt; 2 y in Cohort 2 (Table). At data cutoff, all but 2, 0 and 1 pts were alive, respectively; across studies, ≥ 40% of pts with CR were on treatment. CR pts had a first response (PR/CR) by a median of 3.5 cycles. Further pt characteristics and survival outcomes will be reported. Conclusions: Across Ph I/II atezo mUC studies, CRs appeared durable (median duration &gt; 2 y) despite small pt numbers. Most pts with CR were alive, with responses ongoing after long-term follow-up (median follow-up &gt; 30 mo). Clinical trial information: NCT01375842, NCT02951767, NCT02108652. [Table: see text]
ARQ 197, a highly selective small molecule inhibitor of c-Met, with selective antitumor properties in a broad spectrum of human cancer cells
Authors: Sebastien Jeay, Neru Munshi, Jason Hill, Magdi Moussa, Mark Ashwell, David Leggett, Chiang Li
Journal: Cancer Research (2007)

2369  The expression of the receptor tyrosine kinase c-Met in most cancers, and its role in controlling multiple signal transduction pathways involved in tumor growth and proliferation render this enzyme a highly compelling therapeutic target for a broad spectrum of human cancer. The lack of a highly selective c-Met inhibitor has made it difficult to validate c-Met as a cancer target twenty years after its discovery. It remains to be demonstrated whether c-Met inhibition can target cancer cells selectively. We have discovered ARQ 197, a highly selective small molecule c-Met inhibitor, which has allowed us to investigate the potential of c-Met as a target against cancer. We present herein pre-clinical investigation of ARQ 197 which is currently in phase I clinical trial. ARQ 197 potently inhibits c-Met via a mechanism that is not ATP-competitive. When ARQ 197 was profiled biochemically against 230 kinases, only c-Met was inhibited to any appreciable extent demonstrating a high selectivity for c-Met. In cell-based assays, ARQ 197 potently inhibited HGF-stimulated and constitutive c-Met phosphorylation in multiple human cancer cell lines and decreased phosphorylation of several c-Met downstream effectors including Akt, Erk-1/2, and STAT-3. ARQ 197 showed broad-spectrum in vitro anti-cancer activity against multiple human tumor cell lines expressing detectable c-Met, with cells expressing constitutively active c-Met being the most sensitive; a context in which apoptosis is the major response to c-Met inhibition. Importantly, while ARQ 197 potently inhibited cell growth in cancer cells, it was found to be relatively non-toxic to c-Met expressing primary CD34+ bone marrow mononuclear cells. In studies conducted in vivo, oral administration of ARQ 197 inhibited the activity of c-Met as well as tumor growth in human tumors xenografted in nude mice. Taken together, these data strongly support ARQ 197 as a promising selective oral c-Met inhibitor to target a broad spectrum of tumor types.
Clinical assessment of tumor angiogenesis and its predictive value for chemotherapy responses of colorectal metastatic hepatic tumors.
Authors: Hirotaka Okamoto, Hiroshi Iino, Shugo Shiba, Makoto Sudoh, Suguru Maruyama, Hiroyuki Wakana, Daisuke Ichikawa, Hideki Fujii
Journal: Journal of Clinical Oncology (2019)

e14505 Background: The treatment of colorectal cancer (CRC) with metastasis is now widely accepted to be systemic chemotherapy of 5-FU base chemotherapy (FOLFOX or FOLFILI) in combination with molecular antibody. The objective of this study was to determine the significance of tumor angiogenesis in metastatic hepatic tumors in relation to the response of systemic chemotherapy. Methods: A total of 48 consecutive CRC patients with hepatic metastasis who had been treated with or without hepatic resection were retrospectively reviewed, and factors, such as metastatic tumor angiogenesis and chemotherapy response, were analyzed. Tumor angiogenesis in association with ring-enhancement (RE) on computed tomography (CT) was also microscopically evaluated by microvessel counting (MVD) in sections stained immunochemically with CD34. Results: The overall response rate after 6 courses of first-line chemotherapy for the liver metastasis with RE on CT was 64% (23/36), whereas the response rate without RE was 25% (3/12), which was significantly different. The survival rate of patients with or without liver resection of all RE-positive tumors was not different, but the survival rate of patients with liver resection was longer than that of patients without liver resection for all RE-negative tumors. Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. Conclusions: The peripheral RE on CT of the metastatic hepatic tumor was associated with tumor angiogenesis and may predict chemotherapy response. A combination of liver resection with chemotherapy improves the survival of patients who have multiple hepatic metastasis.
Abstract 12140: Risk of Death as a Function of the PR-Interval: Results From the Duke Databank for Cardiovascular Disease
Authors: Fredrik Holmqvist, Kevin L Thomas, Samuel Broderick, Mads Ersboll, Devinder Singh, Karen Chiswell, Linda K Shaw, Donald D Hegland, Eric J Velazquez, James P Daubert
Journal: Circulation (2013)

Objective: Recently, a U-shaped association between PR-interval and the risk of atrial fibrillation was described, with a higher risk observed both in patients with extremely long and short PR-inte...
Patterns of healthcare utilization in patients with newly diagnosed advanced lung cancer.
Authors: Emily Miller Ray, Sharon Peacock Hinton, Katherine Elizabeth Reeder-Hayes
Journal: Journal of Clinical Oncology (2019)

e18386 Background: Advanced lung cancer (ALC) is a symptomatic disease that is often diagnosed in the context of hospitalization. The index hospitalization may be a window of opportunity to improve cancer care delivery. We aimed to define the frequency of ALC diagnosis associated with hospitalization and the relationship to subsequent cancer care and readmissions. Methods: We identified patients in the SEER-Medicare database with: ALC (stage IIIB-IV non-small cell or small cell), diagnosed 2007 to 2013; with continuous enrollment in Medicare from 6 months prior to lung cancer diagnosis through death or 12/2014; and an index hospitalization within 7 days of their ALC diagnosis. Our primary outcomes of interest were 30-day re-hospitalization and emergency department (ED) use. We examined: utilization of services during index hospitalization, including intensive care and oncology or palliative care consultation; discharge destination; receipt of systemic therapy; and hospice enrollment. Results: Fifty-four percent (n = 28,976) of ALC patients had an index hospitalization, with 90% of those having their cancer diagnosed while hospitalized. During their index hospitalization, 16% had oncology consultation, and 6% had palliative care (PC) consultation. Thirty-three percent were in the intensive care unit. At discharge, 59% returned home, 8% died, and 11% went to hospice. Of those who survived to discharge, 69% later returned to the ED or were re-hospitalized, with 49% of re-hospitalizations and 35% of ED visits occurring within 30 days of the index hospitalization. Thirty-five percent of these patients eventually received systemic treatment for their cancer. By 180 days post-discharge, 77% had enrolled in hospice with a median of 10 days on hospice care. Conclusions: Newly diagnosed ALC patients are high risk for acute care utilization, and many patients experience a return to the hospital early in their cancer trajectory. These patients may benefit from additional health system support prior to hospital discharge to help prevent high-cost, low-value healthcare utilization.
Identifying a potential biomarker for anti-PD-1 immunotherapy in patients with advanced stage, surgically-resectable endometrial cancer.
Authors: Katherine Cynthia Fuh, Elena Lomonosova, Lei Guo, Wendy Fantl, Russell Kent Pachynski, Olga Malkova, Stephen T. Oh, Andrea R. Hagemann, Carolyn K. McCourt, Matthew A. Powell, Premal H. Thaker
Journal: Journal of Clinical Oncology (2019)

5590 Background: The FDA approval of pembrolizumab for patients with MSI-H or dMMR tumors has led to the treatment of a select cohort of endometrial cancer (EC) patients. We sought to ascertain tumor immune modulatory effects in the front-line setting for advanced stage III/IV EC patients regardless of MSI-H or dMMR. The primary objective was to determine the safety of preoperative and maintenance pembrolizumab. The secondary objective was to examine pembrolizumab-induced changes in peripheral immune effector phenotype in order to identify potential biomarkers of clinical response. Methods: In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by chemotherapy and 4 doses of pembrolizumab IV. As an initial study, pre- and post-treatment (on the day of surgery) peripheral blood was collected from 3 patients as well as a healthy control and processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized antibody panel. Results: Six of 8 patients completed the treatment. One patient had rapid cancer progression and another had an exacerbation of comorbidities. Peripheral blood from 3 patients with pathological response were then immunoprofiled using CyTOF. Data analysis revealed that the frequencies of CD8 + T cells, B cells and CD56 hi CD16 - NK cells were lower, whereas the frequency of CD14 + CD16 - HLA-DR hi classical monocytes was higher in the cancer patients compared to controls. Cancer patients had lower frequencies of circulating CD4 + and CD8 + naïve T cells but higher frequencies of effector CD8 + and CD4 + T cells. Notably, the median expression of Granzyme B in CD8 + and CD4 + T cells was higher and median expression of signal regulatory protein (SIRP), CD172a-b on monocytes was lower for cancer patients compared to control. The frequencies of NK and myeloid cells expressing CD137(4-1BB), PD-1 + NK cells, and PD-L1+DCs were greater in post-compared to pre-pembrolizumab. Conclusions: This is the first trial to evaluate the use of neoadjuvant pembrolizumab in advanced stage EC patients. Here, we present peripheral immune correlative data and show an increase in markers of activation in patients with pathologic responses to pembrolizumab. Additional data from this ongoing study will help us to identify candidate predictive biomarkers. Clinical trial information: NCT02630823.
Predictors and rates of adverse events (AEs) among non-metastatic prostate cancer (nmPC) patients (pts) treated with bicalutamide, abiraterone, or enzalutamide following surgical/medical castration.
Authors: Anuj Shah, Arif Hussain, Ruchit Shah, Shelly Ikeme, Ateesha F. Mohamed, Marc Botteman, Reg Waldeck
Journal: Journal of Clinical Oncology (2019)

e16556 Background: The castration-resistant nmPC treatment landscape has evolved following the recent approval of enzalutamide and abiraterone. Skin rash, fractures, and central nervous system (CNS) AEs have been reported among pts treated with these drugs as well as other antiandrogens (eg. bicalutamide). We assessed the rate and predictors of AEs among nmPC pts treated with abiraterone, enzalutamide, or bicalutamide (“study drugs”) in a real-world setting. Methods: nmPC pts initiating one of the study drugs ≥1 year after medical/surgical castration were identified in the MarketScan Commercial database (2012-17). We included pts who had all the following: a claim for a prostate-specific antigen test or an oncologist visit ≤6 months (mos) before study drug initiation (baseline period), no claim for hormonal therapies (except castration) nor metastasis before study drug, and ≥3-mos metastasis-free follow-up while on study drug. Kaplan Meier analyses were used to describe the rates and median time to onset for 18 CNS AEs (including, but not limited to, fatigue, cognitive impairment, or falls) or any AE (i.e., CNS AE, skin rash, or fracture). Baseline period AE predictors were identified using multivariate Cox-proportional hazards models. Results: 532 pts were included (bicalutamide: 89.7%, enzalutamide: 4.3%, abiraterone: 6.0%). The percentages of pts experiencing CNS AEs/any AE were 19%/22% at 3 mos, 28%/35% at 6 mos, and 43%/52% at 12 mos. Median time to AE onset since study drug initiation was 17.9 mos (CNS AE) and 11.0 mos (any AE) respectively. Significant predictors of having any AEs included baseline period AEs (hazard ratio [HR]: 3.07 [2.35-4.02]), Charlson comorbidity index (1 vs 0) (HR: 1.51 [1.04-1.19]), surgical castration (HR: 1.50 [1.07-2.08]), and older age (HR: 1.021 [1.002-1.040]). Similar predictors were found for CNS AE. Conclusions: nmPC pts treated with bicalutamide, enzalutamide or abiraterone experience high AE rates. Balancing the risks/benefits of treatment in this largely asymptomatic population is paramount to maintaining their quality of survival while optimizing survival outcomes.