tbuckley/cabot-search huggingface dataset:
Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with <i>BRAF</i> V600-mutant melanoma.
Authors: Helen Gogas, Paolo Antonio Ascierto, Keith Flaherty, Ana Arance, Mario Mandalà, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsova, Ralf Gutzmer, Jan Willem de Groot, Caroline Dutriaux, Carmen Loquai, Ashwin Gollerkeri, Michael D Pickard, Caroline Robert, Reinhard Dummer
Journal: Journal of Clinical Oncology (2020)

10012 Background: Treatment of patients with BRAF V600–mutant melanoma includes BRAF/MEK-inhibitor combinations based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). To better understand the proportion of patients who derive long-lived benefit and their characteristics, we performed an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), and safety was conducted after an additional 24 months’ follow-up from the initial analysis. The study is ongoing. Results: At data cutoff (November 2019, as-is data), events had occurred in 65%, 59%, and 75% of patients in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 60.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 38% (HR, 0.62 [95% CI, 0.49–0.79]). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67]). A landmark analysis showed a higher rate of OS for COMBO450 at each year analyzed, with OS rates at 4 years of 39%, 37%, and 26% COMBO450, ENCO300, and VEM, respectively. Updated safety analysis confirmed the beneficial long-term tolerability of COMBO450. Conclusions: In the COLUMBUS trial, results for updated PFS and OS with COMBO450 continue to demonstrate long-term benefits in patients with BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.
Real-world characterization of advanced/metastatic non-small cell lung cancer (aNSCLC) patients (pts) with rapid disease progression (RDP).
Authors: Martin Gutierrez, Cliff Molife, Andrew J. Belli, Eric Hansen, Victoria Jennifer Stefaniak, Katherine B. Winfree, Zhanglin Lin Cui, Marta Batus, Jeffrey Melson Clarke, Viraj Narayanan, Chelsea Manion, Andrew David Norden, Philip D. Bonomi
Journal: Journal of Clinical Oncology (2019)

e20706 Background: Despite advances in therapy, recent observational data shows that aNSCLC pts with RDP continue to have a poor prognosis. This retrospective, observational study characterizes the demographic, molecular, &amp; treatment profile of pts with RDP. Methods: Adult aNSCLC pts receiving first-line (1L) platinum-based (Pt) therapy between 01/2014 - 12/2018 were identified in the COTA Real-World Evidence database and assigned to RDP (n = 280) &amp; non-RDP (n = 1,212) cohorts based on time to progression during 1L Pt therapy (≤ 12 and &gt; 12 weeks, respectively). Results: Of 1,492 eligible pts, the incidence of RDP was 19%. Mean age (±SD) was 64.6 (10.9) and 66.1 (10.2) in the RDP and non-RDP group, respectively (p = 0.04). Data showed RDP patients had higher percentage of stage IV disease at diagnosis (77 v 72, p &lt; 0.01), higher histologic grade G3/G4 (37 v 29, p = 0.01), and PD-L1 negative (&lt; 1% expression) status (p = 0.01). Table shows molecular profiling across cohorts. No notable difference in treatment patterns across 1L and 2L was observed. Conclusions: This study identifies stage IV disease at diagnosis, higher grade, &amp; PD-L1 negative ( &lt; 1% expression) as potential risk factors for RDP. A better understanding of this poor prognosis cohort may offer an opportunity to better optimize therapies &amp; outcomes. [Table: see text]
Novel genomic prognostic factors for nonsurgical esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy.
Authors: Honghai Dai, Yang Shao, Xiaoling Tong, Xue Wu, Jiaohui Pang, Alei Feng, Zhe Yang
Journal: Journal of Clinical Oncology (2019)

e15589 Background: Definitive concurrent chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients demonstrated great variations in responses and post-treatment progression inevitably. Methods: To identify prognostic factors that could assist in clinical judgment and make predictions ahead of disease relapse, we performed a targeted next generation sequencing of 416 cancer-related genes on primary tumor biopsies from 47 ESCC patients with locally advanced or metastatic nonsurgical diseases. Patients were subjected to dCRT treatment and local recurrence free survival (LRFS), progression free survival (PFS) and overall survival (OS) times were analyzed. Results: TP53 (78%), NOTCH1 (32%), ARID1A (13%), FAT1 (13%) and CDKN2A (13%) are the most commonly mutated genes in ESCC, while copy number gains are frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%) and YAP1 (11%). Multivariate analysis including clinical variables (age, gender and disease stage) and individual genetic alterations suggested that gender is an independent prognostic factor and male tend to have longer LRFS, PFS and OS after dCRT treatment. In addition, YAP1 amplification likely increased the risk of disease progression and death. To remove the impact of gender on prognosis, gender stratified survival analysis was performed and found that male patients with YAP1 amplification had significantly shorter LRFS (p = 0.002) and OS (p = 0.03), and also demonstrated a certain trend toward a shorter PFS (p = 0.06) than male patients without YAP1 amplification. Conclusions: YAP1 amplification might be a potentially useful biomarker in predicting treatment outcomes and selecting patients with high relapse risk for closely monitoring.
Metastatic presentations of previously treated early stage breast cancer patients.
Authors: Najla Itani, Sneha Deepak Phadke, Nicole Grogan, Sarah L Mott
Journal: Journal of Clinical Oncology (2019)

e23065 Background: Breast cancer (BC) patients on surveillance often suffer from a fear of recurrence. Given that routine surveillance imaging is not recommended, the ability to recognize metastatic disease early on requires a knowledge of recurrence patterns. The aim of this study was to analyze the most common presentations of metastatic disease. Methods: A retrospective review was conducted of all adult patients at the Holden Comprehensive Cancer Center that were initially diagnosed with early stage BC and later developed metastatic disease, from 2000-2017. Chi-squared tests, and logistic and Cox regression models were used. Results: Of the 2,033 patient charts reviewed, 372 were deemed adequate for analysis. While most metastatic diagnoses were made as a result of reported symptoms (77.6%), 3.2% were made with clinical exam findings and 7.8% incidentally on imaging. Among those with symptoms, musculoskeletal pain was the most common (33.7%) and more frequently noted at scheduled (48.9%) compared to unscheduled visits (26%, p &lt; 0.01). Receptor status was associated with nervous system (NS) symptoms at metastatic diagnosis (p = 0.01), with higher odds of NS symptoms in triple negative (TN) (OR = 3.0) and HER2+ cases compared to ER/PR+ HER2- cases (OR for ER/PR+ HER2+ = 3.5, OR for ER/PR- HER2+ = 3.8). Bone pain was not associated with any specific receptor subtype (p = 0.12). Initial stage and receptor status were associated with time to recurrence (TTR) (both p &lt; 0.01), with stage III disease (versus stage I, HR = 1.60) and TNBC (versus [ER/PR+ HER2-, HR = 2.52) having the shortest TTR. On multivariable analysis, initial stage (p = 0.03), receptor status (p &lt; 0.01), age (p &lt; 0.01), and TTR (p &lt; 0.01) were significantly associated with 10-year survival after metastatic diagnosis whereas the presence of symptoms at metastatic diagnosis was not (p = 0.27). Conclusions: Providers of patients on surveillance for a history of early stage breast cancer should modify their threshold of suspicion for recurrence depending on the characteristics of the initial diagnosis and symptoms subsequently reported. Although most metastatic recurrences were diagnosed by symptoms, patients did not necessarily have a shorter survival as a result of presenting with symptoms.
A landscape analysis of immunotherapy-related biomarkers across solid tumors.
Authors: Lara Ann Kujtan, Scott Morris, Ashiq Masood, Janakiraman Subramanian
Journal: Journal of Clinical Oncology (2019)

e14268 Background: Checkpoint inhibitor-based immunotherapy has varying success among tumor types and patients. Predictive biomarkers are in high demand to assist with patient selection. Responses to these agents are correlated with programmed cell death ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB). Here we evaluated PD-L1 expression, MSI status and TMB in a variety of solid tumors to determine their relationships. Methods: A total of 109 specimens were identified in patients diagnosed with solid tumors that underwent a Paradigm Diagnostic Cancer Test. MSI scores were determined by the number of indels present in runs of 6 homopolymer bases per megabase, with a cut-off of 6 to distinguish between MSI-high (MSI-H) and MSI-stable (MSI-S). TMB scores greater than or equal to 10 muts/Mb were designated as high (TMB-H). Results: Of all tumors, 19.3% were MSI-high. PD-L1 testing was performed in 71.5% of all samples; of these, 21.8% were PD-L1 positive. TMB scores of PD-L1 positive tumors (mean = 10.3 muts/Mb) and PD-L1 negative tumors (mean = 8.6 muts/Mb) did not differ significantly (p = 0.57). All MSI-H tumors were TMB-H, and MSI-H tumors had higher mean TMB scores than MSI-S tumors (57 muts/Mb versus 7.6 muts/Mb; p = 0.06). Among TMB-H tumors, MSI-H status was associated with higher TMB scores compared to MSI-S tumors (55.2 muts/Mb versus 22.1 muts/Mb, p = 0.18). Of the both MSI-S and TMB-H tumors, 68.8% were lung cancers and 18.8% were breast cancers. Tumors both MSI-H and TMB-H were 47.6% gastrointestinal carcinomas and 33.3% endometrial carcinomas. Conclusions: In our analysis, TMB was independent of PD-L1 status. All MSI-H tumors were also TMB-H; these were primarily gastrointestinal and endometrial carcinomas whereas TMB-H tumors that were MSI-S consisted predominantly of lung cancers. This difference may be due to the different mechanisms of acquiring mutations during carcinogenesis in these two tumor types. These data also highlight the need for integrated PD-L1, MSI and TMB testing to identify potential responders to immunotherapy.
Transcriptomic characterization of endometrial cancer in order to find new therapeutic targets.
Authors: Monica Parra-Grande, Martin Ore-Arce, Cristina Llorca, Andres Poveda
Journal: Journal of Clinical Oncology (2019)

e17113 Background: There are unmet needs for targeted therapy in Endometrial Cancer (EC). The integrated genomic characterization of EC provided insights into disease biology. Our primary objective is to identify potential actionable pathways to target therapeutically in EC according to the microsatellite status (microsatellite instability high = MSI-H, and microsatellite stable/microsatellite instability low = MSS/MSI-L). Methods: 375 RNAs from the genomic profile of EC within the TCGA database were used to perform RNA-seq analysis. We analyzed RNA-sequencing data with edgeR package to filter and normalize the data, followed by the limma package with its Voom method, linear modeling and empirical Bayes moderation to asses differential expression. Reactome FI Cytoscape app was used to perform pathway and network-based data analysis. Results: According to the microsatellite status, two groups were identified: Group 1 = MSI-H (127 patients) and Group 2 = MSS/MSI-L (248 patients). Significant expression differences were found in 2141 genes. In the Group 1 we identified 1194 genes overexpressed and 947 genes overexpressed in the Group 2. Group 1 includes genes associated with cell proliferation. Group 2 includes genes associated with genomic instability and apoptosis evasion (table 1). Conclusions: In EC patients, Cyclin-dependent kinase (CDK) pathways could be a potential therapeutic target, especially in patients with MSI-H tumors. Further studies are necessary in order to evaluate the activity of CDKs inhibitors in this population.[Table: see text]
Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC) after checkpoint inhibitor treatment failure.
Authors: Daniel Morgensztern, Rachel E. Sanborn, Lyudmila Bazhenova, Saiama Naheed Waqar, Lori McDermott, Jeff Hutchins, David L. Rimm, Luis E. Raez, Corey J. Langer, Roger B. Cohen
Journal: Journal of Clinical Oncology (2019)

9109 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with the gp96-Ig fusion protein that functions as an antigen chaperone for cross presentation and dendritic cell activation. DURGA is a multi-cohort study evaluating the combination of HS-110 and anti-PD-1 monoclonal antibodies in patients with advanced NSCLC. We report on Cohort B, consisting of patients with progressive disease (PD) after receiving a minimum of 4 months of treatment (tx) with a checkpoint inhibitor (CPI) at any time prior to study entry. Methods: Patients (pts) with previously treated NSCLC received weekly HS0110 (1 X 10 7 cells) intradermally for 18 consecutive weeks and nivolumab IV 240 mg every 2 weeks until intolerable toxicity or PD. Tissue was tested at baseline for PD-L1 expression (≥ 1% or &lt; 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined as &gt; 10% CD8+ lymphocytes in the tumor stroma. The primary endpoint was objective response rate by RECIST 1.1. Results: As of the September 2018 data cut-off, 20 pts were enrolled. 18 pts (90%) had PD after both chemotherapy and CPI, and 14 (70%) had CPI as their most recent line of tx. The median number prior tx lines was 2 [range 1 to 6]. 3 pts (15%) achieved partial response and 8 pts (40%) had stable disease. Disease control rate was 55%. Progression-free survival (PFS) was 2.7 months (95% CI, 1.8 – 4.0 months) with a median follow up of 6 months. Pts experiencing injection site reactions (ISR) had improved PFS (median NR vs 2.2 months; HR 0.23, p = 0.063) compared to those without ISR. Of 3 patients with confirmed response, 2 were TIL low/PD-L1 positive, and one was TIL high/PD-L1 negative. All pts experienced at least one adverse event (AE), 80% of which were grade 1 or 2. The most common AEs were fatigue (42%), cough and dyspnea (22.6% each) and anemia (16.1%). There were no grade 5 AEs. Conclusions: The combination of HS-110 and nivolumab is well tolerated. Pts continue to be enrolled in this cohort and early data suggest that the addition of HS-110 to nivolumab may restore responsiveness after tumor progression on prior CPI therapy. Clinical trial information: NCT02439450.
The functions and applications of A7R in anti-angiogenic therapy, imaging and drug delivery systems
Authors: Lu Lu, Hongyuan Chen, Dake Hao, Xinke Zhang, Fengshan Wang
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent antiangiogenic targets. They are highly expressed on vascular endothelial cells and some tumor cells. Therefore, targeting VEGFR-2 and NRP-1 may be a potential antiangiogenic and antitumor strategy. A7R, a peptide with sequence of Ala-Thr-Trp-Leu-Pro-Pro-Arg that was found by phage display of peptide libraries, can preferentially target VEGFR-2 and NRP-1 and destroy the binding between vascular endothelial growth factor 165 (VEGF165) and VEGFR-2 or NRP-1. This peptide is a new potent inhibitor of tumor angiogenesis and a targeting ligand for cancer therapy. This review describes the discovery, function and mechanism of the action of A7R, and further introduces the applications of A7R in antitumor angiogenic treatments, tumor angiogenesis imaging and targeted drug delivery systems. In this review, strategies to deliver different drugs by A7R-modified liposomes and nanoparticles are highlighted. A7R, a new dual targeting ligand of VEGFR-2 and NRP-1, is expected to have efficient therapeutic or targeting roles in tumor drug delivery.
Breast cancer patients’ quality of life: Real-world data.
Authors: Paris A. Kosmidis, Barbara Athanasakou, Thanos Kosmidis
Journal: Journal of Clinical Oncology (2019)

e23115 Background: CareAcross is a digital platform dedicated to support, inform and engage with cancer patients. It also collects medical and other data, and generates real world evidence. Methods: In an effort to collect and analyze information from breast cancer patients regarding side effects in relation to their treatments and supplements intake, we contacted 4837 patients in the UK, Germany, France, Spain and Italy. 474 had triple negative breast cancer (TNBC) and the remaining 4363 other breast cancer subtypes (non-TNBC). All data was collected anonymously, with strong privacy and security controls. Results: Different regimens were given either as adjuvant or as systemic treatments. AC treatment was given to 9% of TNBC vs 4% of non-TNBC patients; FEC-T to 20% vs 13%, FEC to 10% vs 8%, taxanes to 37% vs 20% and platinum-based chemotherapy to 12% vs 2%, respectively. Among non-TNBC patients, 12% received Trastuzumab and 53% received hormonal treatment. Eighty four TNBC and 696 non-TNBC patients were asked regarding side effects as well as vitamins and supplements intake. Among them, 76 TNBC patients reported an average of 2.8 side effects (95% CI 1.0-8.0) vs 577 non-TNBC patients reporting an average of 2.8 side effects (95% CI 1.0-13.0); p &lt; 0.92. Similarly, an average of 5.0 vitamins and supplements was reported by 64 TNBC patients (95% CI 10.0-17.0) and an average of 3.8 was reported by 555 non-TNBC patients (95% CI 1.0-29.0); p &lt; 0.023. Toxicity and supplements are tabulated below. Conclusions: The real world evidence obtained through an international analysis shows that TNBC patients receive more toxic treatments due to the aggressive disease, as expected. However, TNBC patients experience similar toxicities with non-TNBC patients, but their consumption of vitamins and supplements is much higher. [Table: see text]
Recurrent bacteraemia following variceal haemorrhage
Authors: Rooshi Nathwani, Benjamin H Mullish, David Kockerling, Nikil Rajani, Ameet Dhar
Journal: Gut (2019)

A 43-year-old man presented to the hospital with septic shock. Eight weeks prior, he had experienced recurrent gastric variceal bleeding (figure 1), treated initially with cyanoacrylate glue injection. Abdominal CT scan suggested features of chronic liver disease, with non-alcoholic fatty liver disease being the presumed aetiology. Despite endoscopic therapy, he had further variceal haemorrhage, and was treated successfully with insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS) (covered stent). Other past medical history included ulcerative colitis, antiphospholipid syndrome (treated with warfarin) and splenectomy.



Figure 1 
Gastroscopy demonstrating gastric varices.



On physical examination, there was no obvious source of infection. Laboratory investigations demonstrated a white blood cell count of 18.4×109/l, haemoglobin of 106 g/L, C-reactive protein of 195 mg/L and international …
A randomized trial of laryngeal organ preservation evaluating two cycles of induction chemotherapy with platinum, docetaxel, and a novel Bcl-xL inhibitor.
Authors: Paul Swiecicki, Emily Bellile, Keith Casper, Kelly M Malloy, Robbi Kupfer, Matthew E Spector, Andrew Shuman, Steven Bennett Chinn, Chaz Stucken, Ashok Srinivasan, Dawn Owen, Aleksandar Filip Dragovic, Michelle Mierzwa, Shruti Jolly, Carol Rossier Bradford, Avraham Eisbruch, Thomas E. Carey, Mark E Prince, Gregory T. Wolf, Francis P. Worden
Journal: Journal of Clinical Oncology (2019)

6066 Background: Laryngeal bio-selection with induction chemotherapy (platinum + 5-FU infusion: PF) has been demonstrated to result in impressive rates of survival and organ preservation with moderate toxicities. We sought to reduce the toxicity of PF by substituting docetaxel (T) for 5-FU and improve the tumor response rate with the addition of the Bcl-xL inhibitor AT-101. Methods: Pts with advanced stage laryngeal cancer were treated with 1 cycle of T 75 mg/m2 + platinum (P) (cisplatin 100 mg/m2 or carboplatin AUC 6) and were randomized 2:1 to the addition of AT-101. Patients with a CR proceeded to chemoradiation (CRT) with concurrent weekly P. All pts with PR or NR underwent a second cycle of induction with TP + AT-101. Pts with a &gt; 50% response (CR or PR) after the second cycle of induction chemotherapy underwent CRT. Pts with a ≤ 50% response (NR) underwent laryngectomy. PET-CT was performed 12 weeks after CRT. Pts with residual disease underwent salvage laryngectomy (SL). Results: 54 eligible pts were enrolled; 46 M, 8 F; median age 59; 26 T4; stage III 16, stage IV 38; site: 2 hypopharyngeal, 39 supraglottic, 11 glottic, 2 subglottic. After cycle 1 of induction, 2/54 (4%) died prior to assessment by DL and 2 were removed from protocol due to adverse events (AEs). 29/50 pts (58%) had ≥ 50% response, 3 of which had CR; 2 proceeded to CRT &amp; 1 received a 2 nd cycle of IC. 21/50 pts (42%) had &lt; 50% response. A total of 48 pts received cycle 2 of IC. After the 2 nd cycle, a total of 39/50 pts (78%) had ≥ 50% response &amp; received CRT. No difference in response was seen with addition of AT-101. 11/50 pts (22%) had &lt; 50% response- 8 had laryngectomy &amp; 3 refused. Following CRT, 10 pts underwent SL, 2 for residual disease &amp; 8 late SL. The organ preservation rate was 31/50 (62%). The most common grade 3/4 toxicities associated with IC were nausea 9%, neutropenia 9%, &amp; infection 7%. 1 pt died of CNS hemorrhage unrelated to therapy &amp; 1 from sepsis. The median follow-up time is 28 months. The 2 yr laryngectomy-free survival is 54% (95% CI:38-68) &amp; 2 yr overall survival is 81% (95% CI: 64-90). Conclusions: AT-101 did not improve responses to P. Treatment with 2 cycles of IC with PT produced similar response rates to our institutional controls, but organ preservation was somewhat less following treatment with weekly P + RT. Toxicities were overall improved with this treatment strategy. Clinical trial information: NCT01633541.
Abstract 16660: Prevalence and In-Hospital Outcomes of Cardiac Sarcoidosis in the United States From 2003-2011
Authors: Amitoj Singh, Sahil Agrawal, Sajeev Saluja, Avinainder Singh, Munveer Thind, Kartik Kalra, Aman Rajpal, Akshat Kumar, Nabil Ghani, Sudip Nanda, Jamshid Shirani, Ron Blankstein
Journal: Circulation (2017)

Background: Sarcoidosis is a multisystem granulomatous disease. Cardiac involvement confers an elevated risk of adverse events. We aimed to examine trends of hospital admissions and cardiovascular ...