tbuckley/cabot-search huggingface dataset:
Interim analysis of the data of non-interventional study to determine the prevalence of EGFR mutations in advanced NSCLC Russian patients (ORTUS).
Authors: Konstantin K. Laktionov, Irina Demidova, Aleksandr Ageev, Valeriy Vladimirovich Breder, Pavel Grigoriev, Marat Gordiev, Liudmila Gurina, Evgenia Ivanova, Evgenii Imianitov, Tatiana Kekeeva, Vadim Kozlov, Viktor Prikhod'ko, Yury Ragulin, Dina Sakaeva, Galina Statsenko, Aleksandr Filippov, Maxim Filipenko, Viktor Khaylenko, Sergei Andreev, Vera Karaseva
Journal: Journal of Clinical Oncology (2019)

e13109 Background: There is a little information of correlation between EGFRm rate in cytology and plasma samples in Russian NSCLC population. The interim analysis of the study aimed to evaluate the prevalence and types of EGFR mutations in paired cytology and plasma samples in treatment-naive patients with advanced NSCLC. Methods: ORTUS is a multicenter, non-interventional, prospective study to determine EGFR mutations rate in treatmentnaive Russian patients with advanced NSCLC. ClinicalTrials.gov identifier: NCT02321046. The study enrolled 426 patients in stage IIIB / IV of NSCLC. Interim analysis covered the data of 214 cytology verified patients (mean age - 62.6 (range 32-86) years, 58,4% of men) with EGFRm test results in paired cytology and ctDNA samples. 99.5% cases were adenocarcinoma. The proportion of non-smokers/smokers/exsmokers was 46.3%/36%/17.8% respectively. Stage IV disease was in 81% of cases; 84.1% of patients had symptoms. DNA isolation performed using QIAamp DNA FFPE Tissue Kit for cytology and Qiagen Circulating Nucleic Acid Kit for ctDNA according to the manufacturer’s instructions. EGFR gene mutations were analyzed using THerascreen RGQ EGFR PCR Kit in cytology samples and RGQ Plasma EGFR PCR kit in plasma (Qiagen). Results: EGFRm was identified in 17,8% cytology samples (38/214) that is close to 20,2% (1759/8716) in Russian tissue EGFRm study (Imyanitov et al., 2016). 10,3% of paired ctDNA samples were EGFRm positive. Sensitivity and specificity for ctDNA were 42.1%, and 97.1% respectively. The EGFRm rate was 3,9% and 2,6% in smokers, 5,3% and 0% in ex-smokers and 33,3% and 21,2% in nonsmokers in cytology and plasma samples respectively. EGFRm rate and concordance between cytology and ctDNA are presented in a table. EGFRm in ctDNA were detected more frequently in M1a/b groups (p = 0,028). Conclusions: Cytology samples are appropriate for EGFRm testing in NSCLC patients in comparison with tumor tissue ones. High tumor burden (positive metastatic status) is an important factor for successful mutation analysis in ctDNA. [Table: see text]
Validation of neoadjuvant rectal cancer(NAR) score as a surrogate endpoint for disease free survival in Chinese FOWARC study.
Authors: Yanhong Deng, Yue Cai, Jianwei Zhang, Huabin Hu, Jiayu Ling, Zehua Wu, Jianping Wang
Journal: Journal of Clinical Oncology (2019)

e15162 Background: NAR score is considered as a surrogate endpoint for survival in patients with locally advanced rectal cancer who received neoadjuvant treatment. Here we validate it in Chinese FOWARC study, especially in the chemotherapy alone arm. Methods: NAR score is calculated based on cT, ypT, ypN as reported for patients who received surgery in FOWARC study. NAR score is correlated to DFS with COX regression and Kaplan-Meier analysis. Results: 451 patients had surgery, 147 in FU-RT group, 152 in FOLFOX-RT arm and 152 in FOLFOX arm. NAR score is a significant prognostic factor in COX regression (P=0.000, HR 1.034, 95% CI 1.024-1.045) and in FOLFOX alone group (p=0.001, HR 1.030, 95% CI 1.013-1.047). When NAR score is quartile to &lt;5, 5-10, 10-15,&gt;15, the survival of patients is listed below, and similar to pathological staging. Conclusions: NAR score can be used as a surrogate endpoint for disease free survival Chinese patients. But it is not superior to pathological stage, especially in patients who received chemotherapy alone. [Table: see text]
The heterogeneity of genomic biomarkers for immune checkpoint inhibitor in therapy-naïve primary hepatocellular carcinoma and their metachronous metastases.
Authors: Yun-Fan Sun, Jian Zhou, Fan Jia
Journal: Journal of Clinical Oncology (2019)

e15665 Background: Immune checkpoint blockade (ICB) has delivered unprecedented success in treating patients with metastatic cancers to extend overall survival, yet only a small percentage of patients respond. Immune-relevant genomic biomarkers, such as tumor mutation burden (TMB), neoantigen, and human leukocyte antigen class I (HLA-I) are emerging as potential predictors for immunotherapy response. However, little is known about their heterogeneity in metastatic cancer patients. In this study, we aim to characterize these immune-relevant genomic biomarkers in primary and matched metastatic hepatocellular carcinoma (HCC). Methods: Two cohorts of samples were included in this study. Cohort 1: a total of 24 pairs of surgical resected primary and matched metastatic HCC tissue. Cohort 2: 29 surgical resected primary HCC tissue from patients with long-term relapse-free survival. All samples were characterized using whole exome sequencing and RNA sequencing. We compared TMB, neoantigen and HLA-I genotype between primary and matched metastatic tumors, as well as between primary tumors with or without postoperative metastatic relapse. Results: The TMB of primary HCC with metastatic relapse was significantly higher than that with long-term relapse-free survival (Mean, 32 vs 17 mutations/Mb, P&lt; 0.05), while neoantigen and HLA-I genotype failed to show statistical difference. Paired comparison between primary and matched metastatic tumors indicated that both TMB and neoantigen were significantly decreased in metastases ( P&lt; 0.05). We further categorized metastases into two subgroups based on their HLA-I genotype. HLA-I homozygosity in at least one locus (homozygous) occurred in 9 metastases, while the rest metastases showed maximal heterozygosity at HLA-loci (heterozygous). HLA-I heterozygous metastases were associated with significantly higher neoantigen load compared with HLA-I homozygous metastases ( P&lt; 0.05). Conclusions: High TMB might be a poor prognostic factor in patients with resected HCC and a potential predictor for postoperative adjuvant therapy with ICB. Metastatic HCC showed lower antigenicity than the corresponding primary tumors. Therefore, they might not show the same responsiveness to immunotherapy as primary tumor did. However, our HLA-I genotype analysis provides evidence that HLA-I heterozygosity has potential implication for predicting response of metastatic HCC to ICB.
Modeling an oncology outcomes-based contract using a blockchain database approach: Cost and technology considerations.
Authors: Jennifer M. Hinkel, Arka Ray, Sirtaj Brar, Rahul Lalmalani
Journal: Journal of Clinical Oncology (2019)

e18360 Background: Cost of care is an ongoing concern for all oncology stakeholders. Outcomes Based or Risk Sharing contracts are increasingly discussed, but difficult and costly to implement. The literature notes barriers of outcomes definition, reliable data sources, and technology enablement. The authors sought to design and test software that could enable faster, lower-cost, and auditable administration of such contracts. Methods: The authors developed software using blockchain databases and transactional proof of work to simulate such a contract and to compare the financial result to usual fee-for-service reimbursement (FFSR). The software processed a synthesized Medicare claims dataset and Average Sales Price (ASP) data from 2008-2010, looking for use of the Bevacizumab(BV)/Carboplatin/Paclitaxel(CP) regimen in non-small cell lung cancer (NSCLC). The contract hypothesized a scenario that offered payers a discount for “underperforming” BV doses (defined as doses given to a patient with &lt; 9 mo. BV duration) and required a bonus payment for “overperforming” BV doses (defined as doses given to a patient with &gt; 14 mo. BV duration). These parameters were selected based on survival data supporting the 2007 FDA approval of BV/CP in 1L tx of advanced nonsquamous NSCLC. Results: The software successfully processed the claims dataset and projected financial results (additional/saved cost) to the payer in this hypothetical contract compared to FFSR. The software also enabled comparison of different hypothetical contracts, inclusion/exclusion rules for claims, and discount structures. The software accurately categorized doses according to the defined logic. Conclusions: Outcomes based contracts have potential for better aligning oncology reimbursement with meaningful results, particularly for costly therapeutics and where patient response or outcome is difficult to predict. While such agreements are recognized as difficult to implement, a software platform that facilitates efficient and scalable design, simulation, and implementation of such agreements, under constraints of real world data availability and sharing, may advance their adoption.
External validation of the COMPASS-Cancer Associated Thrombosis Study: A predictive score to identify patients with solid tumors on treatment who are at risk for venous thromboembolism.
Authors: Lalitha N Anand, Alex C Spyropoulos, Joanna B Eldredge, Soheila Nourabadi, Meng Zhang, Michael Qiu, David Rosenberg
Journal: Journal of Clinical Oncology (2019)

e18005 Background: A predictive model to identify patients on active treatment for solid tumors at risk for venous thromboembolism (VTE) remains an important clinical need. The COMPASS-CAT Risk Assessment Model (RAM) for VTE in a Eurasian patient population with solid tumors undergoing active treatment displayed good discrimination to identify patients into low/intermediate versus high VTE risk groups. We sought to externally validate this RAM in a North American cancer population. Methods: Patients age &gt; 17 years who presented to the Monter Cancer Center between 1/12014 to 12/31/2016 with breast, ovarian, lung, or colorectal cancers were included. The COMPASS CAT RAM included 8 scored variables that were identified by ICD-9 and -10 codes and chart review. The primary endpoint at 6-month study follow-up was symptomatic VTE. Area under the ROC Curve (AUC) was calculated. We calculated a binary cut off to define VTE risk groups into low/intermediate and high VTE risk categories and calculated sensitivity, specificity, and negative and positive predictive values (NPV, PPV). Results: 3814 patients were included with a mean age of 64, of whom 49%, 5%, 29%, and 17% had breast, ovarian, lung, and colorectal cancer, and 52% had localized and 48% had advanced stage disease. In 94% of patients, cancer was diagnosed within the last 6 months prior to inclusion and 46% of patients were on active therapy when evaluated. Symptomatic VTE at 6-month follow-up occurred in 5.85% of patients. The AUC was 0.62. Using model cut-offs of 0-6 or &gt; 7 points, patients stratified into low/intermediate and high-risk groups had VTE rates of 2.27% and 6.31%, respectively. The sensitivity, specificity, NPV, and PPV of the RAM were 95%,12%, 97.73%, and 6.31%, respectively. Conclusions: In this large retrospective external validation study of the COMPASS-CAT RAM for VTE in cancer patients undergoing active treatment, model discrimination and calibration was fair. Further prospective validation studies are needed before the model can be implemented into routine clinical practice for primary thromboprophylaxis of high VTE risk cancer patients with solid tumors.
Efficacy and safety of FOLFIRINOX in advanced biliary tract cancer after failure of gemcitabine plus cisplatin: A phase II trial.
Authors: Ali Belkouz, Judith de Vos-Geelen, Ferry Eskens, Ron A.A. Mathot, Thomas van Gulik, Martijn G.H. van Oijen, Cornelis J. A. Punt, Johanna Wilmink, Heinz-Josef Kluempen
Journal: Journal of Clinical Oncology (2019)

4086 Background: Currently there is no established standard treatment after failure of gemcitabine plus cisplatin (GemCis) for advanced biliary tract cancer (BTC). Based on the efficacy of FOLFIRINOX in advanced pancreatic cancer, which has histological and prognostic similarities with BTC, a Phase 2 study was conducted to determine whether FOLFIRINOX is effective and safe in BTC. Methods: Patients with BTC and an ECOG PS of 0/1 who had disease progression or unacceptable adverse events (AEs) after at least 3 cycles of GemCis were included. Patients received oxaliplatin 85 ml/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil bolus at 400 mg/m2, followed by fluorouracil continuous infusion of 2400 mg/m 2 over 46-hour every 2 weeks. This phase 2 study was conducted according to the two-stage Simon’s Design. Stage 2 was activated if at least 1 objective response rate (ORR) or 2 stable diseases were observed among 10 patients in stage 1 and a maximum of 3 patients had severe AEs within the first 6 weeks of treatment. If more than 4 patients required a dose reduction in stage 1, stage 2 was initiated with a standard dose reduction (fluorouracil bolus was omitted and irinotecan reduced to 140 mg/m 2 ). Primary outcome was ORR per RECIST 1.1 and secondary outcomes were overall (OS), progression free survival (PFS), and safety profile. Results: Forty patients were screened and 30 patients were included between May 2016 and July 2018. Median age was 60 years and 63% of patients were males. In stage 1, 5 patients required a dose reduction within the first 6 weeks due to AEs, leading to initiation of stage 2 with modified FOLFIRINOX after inclusion of 10 patients. The partial response rate was 10% (3/30), disease control rate 67% and median OS and, PFS were 10.7 and 6.2 months, respectively. Most common grade 3/4 adverse events include neutropenia (50%), anemia (17%), diarrhea (13%), thrombocytopenia (10%), and deviated liver function tests (10%). Conclusions: This is the first Phase 2 study with modified FOLFIRINOX in BTC showing promising disease control rate, OS, and PFS, with an acceptable safety profile. Modified FOLFIRINOX is currently tested as a first-line treatment for patients with BTC in the ongoing randomized prospective Phase 2/3 AMEBICA trial (NCT02591030). Clinical trial information: NCT02456714.
Development of a patient-oriented navigation model for lung cancer patients.
Authors: Christine Holmberg, Kathrin Gödde, Hella Fuegemann, Jacqueline Mueller-Nordhorn, Nina Rieckmann, Ute Goerling
Journal: Journal of Clinical Oncology (2019)

e18033 Background: Patient navigation is seen to support and enable patient-oriented, optimal care both in palliative and in screening settings. However, the evidence remains inconclusive on what patient groups are best targeted by navigation and what may be improved by such a care model. Lung cancer patients are at particular risk for sub-optimal care because they face complex care trajectories due to severe and rapid disease progression and accompanying comorbidity. Methods: To develop a navigation model for lung cancer, we conducted a mixed-methods study to investigate who may be at risk of receiving sub-optimal care in the German health care setting. To capture the patient perspective a longitudinal qualitative component was included with patients (N = 20) assessed at three dtime points. In addition, a secondary data analysis of cancer registry data of a comprehensive cancer center was conducted and a repository of patient support offers gathered. Results of the study components were integrated to develop a patient-oriented navigation model. Results: Secondary data analysis showed that medical care functioned according to tumor board recommendations. Patient data revealed institutional barriers that conflict with individual needs and preferences. A lack of contact persons, information provision as well as bureaucratic difficulties were identified. Patients without a social network seem particularly in need for support. Identification of regional support offers shows that there are resources available to meet some of these needs. However, knowledge on such offers was not common among patients and caregivers. Navigators should provide practical support, give advice on social care issues and refer to existing support offers. Conclusions: Social networks crucial. Patients lack knowledge to use available resources. Navigation needs to be implemented within existing care structures to reach patients.
Real-world evidence evaluating continuation of CDK4/6 inhibitors beyond first progression in hormone receptor-positive (HR+) metastatic breast cancer.
Authors: Akaolisa Samuel Eziokwu, Leticia Varella, Megan Lynn Kruse, Xuefei Jia, Halle C. F. Moore, George Thomas Budd, Jame Abraham, Alberto J. Montero
Journal: Journal of Clinical Oncology (2019)

e12538 Background: CDK inhibitors (CDKi), in combination with aromatase inhibitors (AI), are approved for the treatment of hormone receptor positive (HR+) Her2 negative metastatic breast cancer (MBC). The effectiveness of continuing CDKi beyond first disease progression is not known. This study evaluated real world evidence and assessed the impact of continuation of CDKi beyond first disease progression in combination with endocrine therapy. Methods: This is a retrospective, single institution review of HR+ MBC patients treated with CDKi from 2015-2018 who continued CDKi after initial progression. The primary outcome was progression-free survival (PFS) beyond first disease progression, as assessed by the clinician based on radiological and/or clinical criteria. Overall survival (OS) – defined as date of initial CDKi treatment to date of death or last follow up – was a secondary outcome. Results: 30 women with HR+/HER2- MBC, median age 47.5 years (range: 31 – 81), sequentially continued on CDKi beyond first progression were identified from a database of patients treated with Palbociclib. Median and average follow up times on CDKi were 27.18 and 24.53 months, respectively. Initial endocrine/CDKi regimen received included: palbociclib (PA)/letrozole (LTZ) [67%], PA/fulvestrant (FULV) [23%], and PA/other AI [10%]. Prescribed combinations beyond 1 st progression were: PA/FULV [56.7%], PA/LTZ [16.7%], and PA/other AI [20%], abemaciclib plus LTZ or FULV [6%]. As of 1/31/2019, 25 patients (83.3%) were still alive, and 19 (63%) had undergone a second progression on CDKi. The estimated median PFS for the entire duration while on CDKi was 23.5 months (95% CI 12.8 – 27.8), of which 11.8 months (95% CI 5.34 – 13.13) was the median PFS beyond first progression. The estimated median OS was 45.4 months. Conclusions: Among a small cohort of HR+ MBC patients, in a non-clinical trial setting, continuation of palbociclib plus endocrine therapy beyond first progression was associated with a median PFS of approximately 11 months. Formal clinical evaluation of continuation of CDK inhibitor plus endocrine therapy beyond first progression is warranted.
First-in-human phase I trial of anti-hepatocyte growth factor (HGF) antibody (YYB101) in refractory solid tumor patients: Integrative pathologic-genomic analysis and the final results.
Authors: Jeeyun Lee, Seung Kim, Do-Hyun Nam, Su Jin Lee, Se Hoon Park, Joon Oh Park, Jeong-Won Lee, Kyoung-Mee Kim, Hukeun Lee, Neunggyu Park, Hoon-Kyo Kim, Song-Jae Lee, Seong-Won Song, Jung Ju Kim, Young Suk Park, Ho Yeong Lim, Won Ki Kang
Journal: Journal of Clinical Oncology (2019)

3104 Background: It has been demonstrated in vivo that HGF-MET signaling axis is a key molecular determinant in tumor invasion and there is a significant association in HGF expression and mesenchymal phenotype in addition to immune cell recruitment. We have developed a HGF neutralizing humanized monoclonal antibody antibody, YYB-101. The aim of this study was to determine the maximum tolerate dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of YYB101, in patients with refractory solid tumors. Methods: YYB101 was administered intravenously at once every 2 weeks doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Enrolled patients were planned to receive YYB101 until disease progression or intolerable toxicity. The escalation and expansion cohorts (20mg/kg) were completed. Pre-planned biomarker analysis was performed in parallel. Results: 39 heavily pre-treated refractory cancer patients were enrolled and received YYB101. No DLT was observed. YYB101 demonstrated dose proportional PK up to the dose of 30 mg/kg. No patients discontinued treatment because of adverse events. Based on PK analysis and toxicity data, the recommended dose was determined as 20 mg/kg. Of 39 evaluation patients, there was 1 confirmed partial response for &gt; +14months (2.5%, N = 1; 1 (of 2) sebaceous carcinoma) and 17 stable disease as best response (43.5%, N = 17; 7 (of 13) CRC, 3 (of 4) melanoma, 1 (of 2) sebaceous carcinoma, 1 (of 3) gastric, 1 (of 1) basal cell carcinoma, 2 (of 10) ovarian cancer, 1 (of 1) HCC, 1 (of 1) lung cancer). Of note, 1 sebaceous carcinoma patient who have failed to ≥2+ lines of chemotherapy, have been responding to YYB for 14 months. The MET and HGF expressions by immunohistochemistry (IHC) were evaluated in 19 and 17 tumor specimens, respectively. Neither protein expressions were significant predictors for treatment response to anti-HGF antibody. However, we have observed significant reduction in HGF in responders to YYB. Two long-term responders had mesenchymal signature in RNA sequencing. Conclusions: YYB101 has a favorable safety profile in patients with refractory solid tumors and a dose-proportional PK. Efficacy data are encouraging and phase II combination therapy with YYB101 is planned to be open in metastatic CRC patients as salvage treatment. The predictive power of mesenchymal signature in YYB responders will be defined prospectively. Clinical trial information: 02499224.