tbuckley/cabot-search huggingface dataset:
Phase I study of KN035, the first subcutaneously administered, novel fusion anti-PD-L1 antibody in patients with advanced solid tumors in China.
Authors: Jian-Ming Xu, Shukui Qin, Yun Zhang, Yaoyue Zhang, Ru Jia, Rongrui Liu, Gairong Zhang, Chuanhua Zhao, Ni Lu, Huilong Liu, Wenlian Xu, Meng Fu, Walt Cao, Haolan Lu, David Liu, Ruiping Dong, Xiaoxiao Wang, Pilin Wang, Ting Xu, John Gong
Journal: Journal of Clinical Oncology (2019)

2608 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc fragment, formulated for subcutaneous (SC) injection. Methods: The escalation phase followed a modified 3+3 design with a 28-day DLT evaluation period and 8 dose levels were planned at 0.1, 0.3, 1.0, 2.5, 5 and 10 mg/kg SC weekly. One patient each was enrolled at 0.1 and 0.3 mg/kg dose levels. Additional dose levels followed traditional 3+3 design. Response was assessed per RECIST 1.1 every 12 weeks. Results: As of 11/2/2018, 17 patients were enrolled in the escalation phase (urothelial carcinoma (n=2), hepatic cell carcinoma (n=2), intrahepatic cholangiocarcinoma (n=2), thymic carcinoma (n=2), colorectal cancer£¨n=2£©£¬renal cell carcinoma (RCC, n=3), Squamous-cell lung carcinoma (n=1) and ovarian cancer (n=1)). The majority of subjects had advanced disease stage, stage IV (15/17) and stage III (2/17). A total of 7 subjects received radiotherapy, 16 subjects received surgery, and 13 subjects received systematic anti-cancer therapies from previous treatment. None had received prior checkpoint inhibitor treatment. Planned maximum dose of 10 mg/kg was reached (n=3) without DLT occurred. There was only one Grade 3 drug related Treatment Emergent Adverse Event (TEAE) occurred at 0.3 mg/kg dose level, which was immune related dermatitis and resolved later. All other drug related TEAEs were either Grade 1 or 2, with the most common events as elevated ALT (5/17) and elevated AST (4/17). Among all enrolled subjects, three subjects had confirmed PR, including one RCC subject at 2.5 mg/kg and one Intrahepatic cholangiocarcinoma subject at 5 mg/kg, and one cholangiocarcinoma subject at 10 mg/kg. Conclusions: KN035 exhibits a favorable safety profile and promising preliminary anti-tumor activity in patients with advanced malignancies. Clinical trial information: NCT03101488.
Association of an inflammatory gene signature with CD8 expression by immunohistochemistry (IHC) in multiple tumor types.
Authors: Peter M Szabo, Zhenhao Qi, Kim Zerba, Scott Ely, Robin Edwards, James Lu, James Cooley, Marian Navratil, Gillian L Dalgliesh, Neeraj Adya
Journal: Journal of Clinical Oncology (2019)

2593 Background: A multiparameter tumor inflammation assay based on gene expression profiling (TIA-GEP) can extend the utility of IHC to interrogate the tumor microenvironment (TME). Using CD8 expression assessed by IHC (CD8-IHC) as a surrogate for inflammation, statistical modelling was used to develop a specific gene signature on the TIA-GEP panel to predict CD8-IHC. The correlation between TIA-GEP and CD8-IHC and the prevalence of inflammation were explored across multiple tumor types. Methods: Levels of inflammation were measured by CD8-IHC and TIA-GEP on 1778 procured samples across 12 tumor types. Quality control metrics involved sample input quality, technical errors, and inter-run variability. Generalized linear models were used to identify an inflammation score that predicts the CD8-IHC score in melanoma and SCCHN tissue. The predictive accuracy of this signature was also examined in 10 additional tumor types. Results: Assessment of TME inflammation by CD8-IHC was consistent with that observed by TIA-GEP in multiple tumor types. The range of inflammation varied across different tumor types, with relatively lower inflammation range and scores in SCLC, ovarian, and prostate cancers, and higher values in NSCLC, melanoma, SCCHN, and gastric cancers. R 2 x 100 values reflecting percent variation in CD8-IHC associated with TIA-GEP ranged from 62.4% to 79.2% ( P &lt; 0.0001) for all tumor types except prostate cancer (32.5%). Low correlation in prostate cancer may be a result of low prevalence of inflammation by CD8-IHC. Estimated linear regression slopes between CD8-IHC and TIA-GEP ranged from 0.74 in SCLC to 1.27 in gastric cancer. Conclusions: The results suggest that the inflammation signature is a robust potential diagnostic tool predicting inflammation in the TME. The inflammation signature not only correlates with CD8-IHC for multiple tumor types, but also leverages the alternative benefits associated with TIA-GEP, which include information related to tumor inflammation-associated biomarkers and flexibility in exploring the value of other genomic signatures.
Effect of estrogen and progesterone receptor expression on progression-free and overall survival outcomes in low-grade serous ovarian cancer.
Authors: Marta Llaurado Fernandez, Amy Dawson, Hannah Kim, Nicole Lam, Maegan Bruce, Holly Russell, Joshua Hoenisch, Diane M. Provencher, Melica Nourmoussavi, Cyril Blake Gilks, Cheng-Han Lee, Martin Kobel, Nelson Wong, Stephanie Scott, Gabriel Dimattia, Anne-Marie Mes-Masson, Mark Stafford Carey
Journal: Journal of Clinical Oncology (2019)

5560 Background: Research on ER/PR receptor function in low-grade serous ovarian cancer (LGSC) and the determinants of response to treatment are lacking. A recent study (Sehouli et al.,2018) described ER/PR immunohistochemistry (IHC) cut-points that distinguished PFS. Thus, we report on a group of patients with ER/PR expression by IHC in tumor samples of patients with LGSC and used this information to evaluate survival outcomes. Methods: Clinical information and FFPE sections were obtained from the Canadian Ovarian Experimental Unified Resource (COEUR). Tissue microarray (TMA) sections were stained for ER/PR using standard IHC techniques (MK). 50 stage 3 and 5 stage 4 patients were analyzed. ER/PR expression was scored using a simple scoring system ( &lt; 1% cells staining, 1-50%, and ≥ 50%) and Allred scoring. We compared Kaplan-Meier (KM) survival (PFS and OS) curves using Log rank testing and Cox regression was used to model predictive/prognostic factors. A p-value of 0.05 was considered significant. Results: The mean age of the population was 49.5 years (SD;13.7). Ninety percent of patients were treated by surgery followed by platinum-based chemotherapy (PBC). Simple scoring did not discriminate outcomes as well for ER levels. PR Allred score ( &lt; 2, vs 2- &lt; 6 vs ≥6) clearly discriminated KM curves for PFS (p = 0.036) and OS (p = 0.01). For Allred ER score ( &lt; 7 vs.7- &lt; 8 vs 8) did not distinguish PFS (p = 0.4) but notably most patients received PBC after surgery. ER Allred score significantly distinguished OS (p = 0.008). Significant factors on Cox regression for PFS were residuum (p = 0.008;95%CI:1.2-3.1) and PR (p = 0.05;95%CI:0.39-0.99), whereas for OS ER(p = 0.01:95%CI:0.2-0.8) and residuum (p = 0.04;95%CI:1-2.8). Conclusions: ER/PR expression by Allred scoring was associated with PFS and OS. Patients will benefit from much needed research on ER/PR prediction/prognosis in LGSC. This work can inform clinical trials selection/stratification and patient selection for endocrine treatment.
Patient-reported outcomes (PROs) in IMmotion150: Atezolizumab (atezo) alone or with bevacizumab (bev) versus sunitinib (sun) in first-line metastatic renal cell carcinoma (mRCC).
Authors: Sumanta K. Pal, David F. McDermott, Michael B. Atkins, Bernard Escudier, Brian I. Rini, Robert J. Motzer, Lawrence Fong, Richard Wayne Joseph, Stephane Oudard, Alain Ravaud, Sergio Bracarda, Cristina Suarez Rodriguez, Elaine Tat Lam, Toni K. Choueiri, Beiying Ding, Caroleen Quach, Kenji Hashimoto, Christina Schiff, Elisabeth Piault, Thomas Powles
Journal: Journal of Clinical Oncology (2019)

4515 Background: The phase 2 IMmotion150 study showed improved PFS with atezo + bev vs sun in patients (pts) whose tumors were PD-L1+ and corroborated the activity of atezo monotherapy in previously untreated mRCC. This study offers an opportunity to evaluate PROs with immunotherapy and VEGF-directed therapy alone and in combination. Methods: Pts randomized to atezo 1200 mg IV q3w alone or with bev 15 mg/kg IV q3w, or sun 50 mg po qd for 4 wk on/2 wk off completed the MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) q3w of each 6-wk cycle until progression (RECIST 1.1). Time to deterioration (TTD; first ≥ 2-point score increase over baseline [BL]) and change from BL (effect size [ES] ≥ 0.2 suggests a clinically important difference vs sun) in MDASI symptom severity and interference and BFI fatigue severity and interference scores are reported for all-comers. Results: Completion rates were &gt; 90% at BL and ≥ 80% at most visits across arms. BL PRO scores indicating mild symptoms and interference were similar across arms. Delayed TTD of symptom severity and interference with daily life was seen with atezo vs sun and atezo + bev vs sun and was longest with atezo alone (Table). Pts reported milder symptoms and less interference during the first 6 cycles with atezo vs sun: ES mean (range) was 0.36 (0.07-0.68) for core symptom severity and 0.36 (0.04-0.83) for symptom interference. The 5 worst pt-reported symptoms during tx (dry mouth, fatigue, rash, drowsiness, lack of appetite) were all in the sun arm; all 16 symptoms measured were milder with atezo vs sun. Conclusions: PROs suggest that atezo alone or with bev maintained daily function with minimal symptom interference vs sun. Clinical activity, safety and PRO data for atezo support its investigation in adjuvant tx of high-risk RCC pts (IMmotion010; NCT03024996). Clinical trial information: NCT01984242. [Table: see text]
A phase I study of LOXO-292, a highly selective RET inhibitor, in pediatric patients with <i>RET</i>-altered cancers.
Authors: Steven G. DuBois, Catherine Michelle Albert, Leo Mascarenhas, Theodore Willis Laetsch, Cornelis Martinus van Tilburg, Samara L Potter, Brian Turpin, Julia Lynne Glade Bender, Sheri L. Spunt, Raquel Hladun, Michela Casanova, David Simon Ziegler, Daniel A. Morgenstern, Todd Eary, Shannon Ibabekci, Hope Qamoos, Stephen M. Rothenberg, Michael Craig Cox, Frank M. Balis, Alberto S. Pappo
Journal: Journal of Clinical Oncology (2019)

TPS10066 Background: Genomic alterations in the RET kinase, including gene fusions and activating point mutations, are implicated in the pathogenesis of lung, thyroid, sarcoma and other cancers in both chidren and adults. Currently available multikinase inhibitors with anti-RET activity are non-selective and may be associated with less favorable toxicity profile. LOXO-292 is a novel, highly selective, ATP-competitive small molecule RET inhibitor. LOXO-292 has preclinical nanomolar potency against diverse RET alterations (e.g. fusions, activating mutations and anticipated acquired resistance mutations) and anti-tumor activity in the brain. LOXO-292 has demonstrated clinical activity in adult patients with RET-alterated solid tumors. Methods: LIBRETTO-121 (EudraCT 2019-000212-28) is an ongoing multicenter phase 1/2 dose escalation multicenter trial in patients 6 months-21 years of age with advanced, RET-altered solid and CNS tumors. Dose escalation follows a rolling 6 design starting at the equivalent of the adult recommended phase 2 dose. Enrollment began on 12 Feb 2019 and is ongoing. Key eligibility criteria include: solid or CNS tumor with a documented RET gene alteration refractory to standard therapy; age 6 months to 21 years of age; and adequate bone marrow, liver and kidney function. LOXO-292 is administered orally BID for continuous 28-day cycles. Both capsule and liquid suspension dosage forms are available. The primary objective of the phase 1 portion of the study is to determine safety and dose limiting toxicities. Key secondary objectives include characterization of pharmacokinetic properties, identification of the MTD and initial characterization of the anti-tumor activity of LOXO-292. Archival tissue will be used to further characterize molecular abnormalities. Clinical trial information: 2019-000212-28.
Abstract 17970: Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Pressure-Overload Induced Heart Failure
Authors: Yang Liu, Mohamed Abdalla, David Kidwell, Colby Souders, Kevin Duong, David M Weber, Adam Willms, Troy Baudino, Richard L Moss, Carl W Tong
Journal: Circulation (2013)

Cardiac myosin binding protein-C (MYBPC3) is a muscle thick filament protein that inhibits actin-myosin cross-bridge interaction. Phosphorylation can release MYBPC3 inhibition to improve cardiac co...
A phase I/II study of GSK3145095 alone and in combination with anticancer agents including pembrolizumab in adults with selected solid tumors.
Authors: Deirdre Jill Cohen, Shubham Pant, Bert O'Neil, Jill Marinis, James Winnberg, Christoph Matthias Ahlers, Justin Callaway, Chetan Rathi, Andre Acusta, Adeline Verticelli, John Bertin, James F . Smothers
Journal: Journal of Clinical Oncology (2019)

TPS4165 Background: The immunosuppressive myeloid infiltrate characteristic of the tumor microenvironment in pancreatic cancer represents a major therapeutic barrier in this disease. Modulation of this infiltrate may increase sensitivity to immune checkpoint blockade in this and other tumors with a similar phenotype. The receptor interacting protein 1 (RIP1) is a serine/threonine kinase that becomes active upon homeostatic disruptions. Bound to RIP3 and mixed lineage kinase domain-like protein (MLKL), RIP1 kinase activity drives necroptosis. However, RIP1 also signals in response to inflammatory stimuli independently of its association with RIP3. A correlation between increased RIP1 protein expression and a worse prognosis has been reported in a variety of solid tumors. Furthermore, in an unbiased screen RIP1 was identified as a top gene contributing to resistance to immunotherapy (Manguso 2017). In murine models, RIP1 kinase activity has been reported to drive pancreatic oncogenesis. Inhibition of RIP1 in the pancreatic TME leads to the replacement of tumor-permissive myeloid infiltrates with innate cells promoting an anti-tumor response by the adaptive immune system (Seifert 2016; Wang 2018) and synergized with anti-PD-1 treatment. These data suggest that the small molecule RIP1 inhibitor GSK3145095 may have therapeutic potential in multiple tumor types. Methods: This is a four-part phase 1/2 study designed to evaluate the safety, PK, PD, and preliminary activity of GSK3145095 given orally to participants with selected advanced or recurrent solid tumors. Part 1 will be conducted in approximately 30 adults with pancreatic cancer with escalating doses of GSK3145095. Part 2 will combine escalating doses of GSK3145095 with 200 mg pembrolizumab and may be conducted in a broader population of selected solid tumors. Part 3 represents a cohort expansion of Part 2. Part 4 may investigate the combination of additional anticancer agent(s) with one or more doses of GSK3145095 identified as safe in Part 1. References: Manguso RT. Nature. 2017;547(7664):413-418. Seifert L. Nature. 2016;532(7598):245-249. Wang W. Cancer Cell 2018; 34: 757-774. Clinical trial information: NCT03681951.
Hyaluronidase Treatment of Scleroderma-Induced Microstomia
Authors: Olivia G. Melvin, Katherine M. Hunt, Elizabeth S. Jacobson
Journal: JAMA Dermatology (2019)

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Safety and outcomes of a cancer patient urgent care clinic.
Authors: Jack S Bevins, Hannah Fullington, Thomas W. Froehlich, Stephanie Hobbs, Ethan Halm, Simon Craddock Lee, Arthur Hong
Journal: Journal of Clinical Oncology (2019)

6542 Background: Several cancer centers describe cancer-patient dedicated urgent care clinic (UCC) that address commonly anticipated complaints of adults with cancer. UCC may be capable of preventing some ED visits, but little is known of the safety and outcomes for patients after a UCC visit. Methods: We identified UCC visits made by adults at our comprehensive cancer center between 2013-2016 and compared the cohort to patients who did not visit the UCC. We linked patients to tumor registry data and their electronic health record from the UCC visit, then tracked ED visits, inpatient and intensive care unit (ICU) admissions occurring within 24 hours of the UCC visit. Results: Between 2013-2016, 551 patients generated 772 UCC visits, compared to 17,496 who did not visit. UCC users had significantly (p&lt;0.001) more advanced-stage cancer than non-UCC users (37.3% vs 18.9%), but there were no significant differences in mean age, race/ethnicity, or death within 180 days of diagnosis. The most common chief complaints accounted for nearly half of all UCC visits: (17.4%), URI symptoms/fever (12.6%), nausea/vomiting/diarrhea (7.8%), and fatigue/weakness (7.6%). After 10.0% of UCC visits, patients had an ED visit, while 12.3% were admitted to the hospital; only 5 UCC visits (0.7%) had an associated ICU stay. Most patients (75.7%) only had a single UCC visit, but patients who visited the UCC more often tended to have higher rates of ED visits and hospitalizations within 24 hours (Table). The mean time from UCC arrival to ED arrival was 3.0 hours, and 6.5 hours from UCC arrival to inpatient arrival. Conclusions: The majority of patients seen in UCC did not require ED or inpatient hospitalization. Patients with subsequent ED or inpatient visits had minimal delays in care. Findings suggest that triaging cancer patients for commonly anticipated complaints to a UCC does not result in high rates of mis-triaging or major delays in care. Patients with ED, Inpatient, or ICU visit after UCC, stratified by UCC visits per patient (2013-2016). [Table: see text]
PD-L1 expression on circulating tumor cells and prognosis of breast cancer patients.
Authors: Xuefei Wang, Guochao Zhang, Qiang Sun
Journal: Journal of Clinical Oncology (2019)

e14028 Background: Nowadays programmed cell death (ligand) 1 (PD1/PD-L1) inhibitors in the clinic show benefit for appropriate patient. There are clinical trials for specific breast cancer patients. We all know that the prognosis of breast cancer is associated with CTC. However, PD-L1 expression on circulating tumor cells (CTC) is lack of research. It is crucial for the prediction and supervision of molecular-targeted therapy, while the predictive biomarker response to PD(-L)1 checkpoint inhibitors is lacking. So we tried to explore the relationship between overexpression of PD-L1 on CTCs and prognosis and clinicopathological features of breast cancer patients. Methods: We analyzed CTC and PD-L1 mRNA expression on CTC in 20 primary breast cancer patients, through mRNA probe hybridization. The relationship between clinicopathological features and PD-L1 expression on CTC was analyzed by chi square test. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with low PD-L1 expression. Results: The median follow-up time was 40 months (range, 36-43 months). Of the 20 patients, 15 had more than 1 CTC in 7.5ml peripheral blood. Among the 15 patients, each one has at least 1 CTC showing PD-L1. The expression of PD-L1 on CTC was divided into low expression, medium expression and high expression, then we gave 1 score for low expression, 2 score for medium expression and 3 score for high expression. PD-L1 high expression was total score≥3, while PD-L1 low expression was total score ＜ 3. We found PD-L1 expression on CTC is related to the tumor size(P = 0.012) lymph node status (P = 0.001) and PR status (P = 0.037). There was significant difference between T2 and T3 in large tumor group(P = 0.003), while in node status group statistical difference can be found in N1 vs N3(P = 0.000) and N2 vs N3(P = 0.015). Our data indicated that patients with high PD-L1 expression on CTC had poor overall survival(P = 0.004) compared to low PD-L1 expression on CTC (Table). Univariate Cox proportional hazards model analysis showed that high PD-L1 expression on CTC was an independent prognostic factor. Conclusions: PD-L1 on CTC is indeed associated with some poor clinicopathological features. High expression of PD-L1 on CTC is an independent prognostic factor for shorter survival. [Table: see text]
Quality of care and survival of women with uterine cancer by Hispanic origin: An NCDB analysis.
Authors: Charlotte Gamble, Yongmei Huang, Ana Isabel Tergas, Maria Paula Ruiz, June YiJuan Hou, Fady Collado, Caryn St. Clair, Jason Dennis Wright
Journal: Journal of Clinical Oncology (2019)

e17120 Background: In cancer research in the US, Hispanic patients are often analyzed as a homogeneous group despite significant diversity within this ethnic classification. Our objective was to assess the impact of place of origin on quality of care and overall survival for Hispanic women with uterine cancer living in the US. Methods: The National Cancer Database (NCDB) was used to identify all patients with uterine cancer from 2004-2015. Hispanic origin was classified based on NCDB subgroups: Mexican, Puerto Rican, Cuban, South or Central American, and Dominican Republic. Multivariable models were used to assess the adjusted relative risk (aRR) of receiving quality of care indicators. Thirty-day mortality and overall 5-year survival were calculated using multivariable log-Poisson and Cox proportional Hazard models. Results: A total of 5,411 Hispanic women and 288,111 non-Hispanic women were identified. Of Hispanic women, Mexican patients comprised the largest subgroup (n = 2,512), and increased from 34.5% to 49.7% over the study period. South or Central American (n = 1,217) and Dominican (n = 218) patients also increased modestly, while the volume of Puerto Rican patients remained unchanged (n = 877), and Cuban patients decreased from 23.3% to 5.6% (n = 587). Compared to non-Hispanic women, there were no significant differences in the rates of use of minimally invasive surgery, chemotherapy in early stage high risk disease, lymph node dissection, or 30-day readmission among the Hispanic subpopulations. Rates of chemotherapy for advanced stage disease were modestly increased for Dominican (aRR 1.37, 95%CI (1.23-1.54)) and South or Central American (aRR 1.16, 95%CI (1.05,1.29)) groups. Dominican patients had a statistically significant reduction in overall mortality at five years for stage III and IV disease with aHR 0.38, 95%CI (0.16-0.90) and aHR 0.28, 95%CI (0.09, 0.87), respectively. For all other Hispanic subgroups, there were no differences in stage-specific survival. Conclusions: The diversity within the Hispanic cohort of women with uterine cancer in NCDB is changing. Overall quality indicators and survival outcomes are comparable between each Hispanic origin group, with the exception of advanced stage Dominican women who are more likely to receive chemotherapy, and have superior survival outcomes.