bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of poor outcome for transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC).
Authors: Prins Petra , Singh Bhavana P , Armstrong Samantha Ann , He Aiwu Ruth 
Published: May 2019

4100 Background: The use of TACE in select patients with BCLC stage B HCC has been shown to improve survival. Despite this, it remains unclear which patients will benefit from repeated TACE versus switching to systemic therapy upon disease progression. The purpose of this study is to identify prognostic factors that predict poor outcomes in patients who receive TACE. Methods: In this single-institutional retrospective analysis, patients with unresectable HCC were treated with TACE between 2007-2016. Relevant factors such as staging by BCLC stage B, Child-Pugh score, vascular invasion (VI), tumor thrombus (TT), AFP levels, and number of TACE treatments within six months from the initiation of TACE were analyzed using either Pearson’s chi-square test or the student's t-test. The Kaplan-Meier method was used for survival analysis. Results: Patients (n = 176) underwent TACE; 45% had stage I-II disease, 42% were BCLC stage B prior to TACE, 71% were Child-Pugh A, 21% had extrahepatic spread, 34.7% had VI, and 26% had TT. The median number of TACE treatments was 2 (range, 1- 6). The median overall survival (mOS) was 43 months (m) (95% CI 31.3-54.7) and mOS from start of TACE was 34m (95% CI 26.2-41.8). Elevated AFP (>400) correlated with decreased mOS (25m vs. 35m, p=0.041). Similarly, the presence of TT correlated with poor outcomes (25m vs. 37m, p=0.015). The mOS was also negatively impacted by having 3 or more TACE treatments within a 6 m period (25m vs. 38m, p = 0.09). AFP >400, TT, and interval between TACE were all independent factors in this multivariate analysis, resulting in a shorter mOS of approx. 2 years compared to 3 years in patients without these negative prognostic factors. There was a strong association with both elevated AFP and TT (Chi square p=0.009). Conclusions: Elevated AFP (>400), the presence of TT, and a need for 3 or more TACE treatments within 6 months appear to be independent predictors for shorter mOS in patients receiving TACE. Patients with these poor prognostic factors tend to have more aggressive HCC, and earlier initiation of systemic therapy might provide benefit to these patients. A larger study is needed for confirmation of these findings.
The SUNEVO (GETNE-1408) trial to evaluate the activity and safety of thecombination of sunitinib with evofosfamide (TH-302) in patients with G1/G2 metastatic pancreatic neuroendocrine tumours (pNETs) naïve forsystemic treatment: A phase II study of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumors (GETNE).
Authors: Grande Enrique , Lopez Carlos , Alonso-Gordoa Teresa , Benavent Marta , Capdevila Jaume , Teule Alex , Custodio Ana , Sevilla Isabel , Gajate Pablo , Molina-Cerrillo Javier , Hernando-Cubero Jorge , Garcia-Carbonero Rocio 
Published: May 2019

4105 Background: Angiogenesis plays an important role in tumorigenesis and progression of pNETs. Evofosfamide (EVO) is a DNA alkylator prodrug that selectively activates under hypoxia. Sunitinib as monotherapy shows a wide range of responses (9-24%) in similar populations. We hypothesized that sunitinib-induced hypoxia might increase the cytotoxic activity of EVO in patients with metastatic pNETS and naïve for systemic treatment other than somatostatin analogues (SSA). Methods: This is a phase-II, single-arm, and multicenter trial of EVO (340mg/m2 on days 8, 15 and 22 every 4 weeks) and sunitinib (37.5mg/day continuously). Primary endpoint was Objective Response Rate (ORR) by RECIST v1.1 assessed every 8 weeks. A Simon two-stage optimal design was used, considering a minimum of 3 responses in the first 18 pts in order to start with the second stage (power = 0.80, alpha = 0.05). Results: Between May/2015 and May/2018, 17 pts were included (median age was 62.4 y.o). Prior SSA was reported in 7 (41.2%) pts and 8 (47.1%) had a Ki-67 > 10%. There were 2 responders (11.8%; n = 1 complete and n = 1 partial response); stable disease was observed in 76.5%. Median (range) PFS and duration of response were 10.4 months (m) (2.9-17.9m) and, respectively 24.4m (13.7-35.2m), respectively. Grade 3 or 4 adverse events occurred in 11 (64.7%) pts, being neutropenia (33.3%), fatigue (16.7%), thrombocytopenia (11.1%), hand-foot syndrome (5.6%), and pancreatitis (5.6%) the most frequent. Toxicity led to treatment discontinuation in 5 (38.5%) pts. Dose reductions were reported in 20% (sunitinib) and 100 % (EVO) of pts. Conclusions: Combination of sunitinib and EVO failed to demonstrate activity in terms of tumor shrinkage as only two patients achieved response, therefore, second stage was not proceeded. While cross trial comparisons are difficult, response rate of 12% with the combination was disappointing. Concerns over toxicity arose; translational analysis are undergoing. Clinical trial information: NCT02402062.
Efficacy and safety of pembrolizumab in patients with advanced adrenocortical carcinoma.
Authors: Raj Nitya Prabhakar , Zheng Youyun , Kelly Virginia , Katz Seth , Chou Joanne F , Do Richard K. G. , Capanu Marinela , Zamarin Dmitriy , Ariyan Charlotte Eielson , Untch Brian R. , O'Reilly Eileen Mary , Gopalan Anuradha , Berger Michael F. , Olino Kelly , Segal Neil Howard , Reidy Diane Lauren 
Published: May 2019

4112 Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333.
Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.
Authors: Park Joon Oh , Feng Yin-Hsun , Chen Yen-Yang , Su Wu-Chou , Oh Do-Youn , Shen Lin , Kim Kyu-Pyo , Liu Xiufeng , Bai Yuxian , Liao Huimin , Nie Jing , Qing Min , Ji Qinmei , Li Jiongyan , Zhao Mianzhi , De Porre Peter , Monga Manish 
Published: May 2019

4117 Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( > 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.
H3B-6527 clinical biomarker assay development and characterization of HCC patient samples.
Authors: Kumar Pavan , Rimkunas Vicki , Yu Kun , Zhang Zhaojie , MacKenzie Crystal , Schindler Joanne , Smith Peter , Zhu Ping , Selvaraj Anand , Yu Lihua , Das Subhasree , Joshi Jaya Julie 
Published: May 2019

4121 Background: FGFR4/FGF19 signaling axis is a novel therapeutic target in HCC. Multiple covalent FGFR4 inhibitors, including H3B-6527, are under clinical development. Preclinical efficacy studies in mice (including PDX) have shown that FGF19 expression (FGF19+) is a predictive biomarker for FGFR4 inhibitor response. The mechanisms driving FGF19 expression in HCC is largely unknown however, in some cases, focal amplification of ch11q13.3 containing FGF19 gene is thought to drive the FGF19 expression. Consistent with the preclinical observations, clinical studies have also shown that FGF19+is a predictive biomarker for FGFR4 inhibitor response. However, these trials have also reported a large number of FGF19+patients failing to respond to FGFR4 inhibitors necessitating refinement of patient selection strategies. In an attempt to obtain deeper insights into the role of FGF19+as a predictive biomarker and potentially uncover additional biomarkers that will enable improvement in patient selection strategies, we have characterized a set of 258 HCC patient samples Methods: Samples were acquired from biobanks and utilized to qualify clinical assays including FGF19 copy number (FISH), mRNA expression (qRT-PCR), FGF19 protein (IHC), and a focused NGS panel for assessing both mutations and copy number. A multiplexed protein and mRNA platform enabled assessment of p-ERK and Ki67 (protein) and Cyp7A1 (mRNA) amongst other exploratory PD biomarkers from two FFPE slides. Results: FGF19 positivity rates for IHC and qRT-PCR were 18% (41/225) and 42% (87/209), respectively. The overall correlation was 60%, with 63% (22/235) IHC positive cases also being positive by qRT-PCR. For IHC+/qRT-PCR (-) cases, RNA quality may have impacted assay sensitivity. 4% (9/244) of samples were positive for FGF19 copy number. Among samples with FGF19 copy number gains, 22% (2/9) did not show positive FGF19 expression. Conclusions: Based on our data, FGF19 mRNA is a more inclusive selection strategy and offers an approach to further refine thresholds for efficacy as determined in the clinic. Multiplexed protein-mRNA assays were also validated and implemented to enable a more comprehensive clinical biomarker program.
Metformin use and pancreatic cancer survival in U.S. veterans with diabetes mellitus: Are there racial differences?
Authors: Toriola Adetunji T. , Luo Suhong , Thomas Theodore Seth , Drake Bettina F. , Chang Su-Hsin , Sanfilippo Kristen Marie , Carson Kenneth Robert 
Published: May 2019

4129 Background: Experimental and observational studies suggest that metformin holds promise in improving survival among pancreatic cancer patients. However, findings from prior observational studies have been questioned because most did not control for immortal time bias, which can overestimate the survival benefit of a drug. In addition, previous studies did not present data on African American patients. Thus, it is unknown if any survival advantage from metformin extends to African Americans. To address these limitations, we analyzed data from the U.S. Veterans Health Administration (VHA). Methods: A population-based retrospective cohort study of 3,811 (N = 773 are African Americans) pancreatic cancer patients with pre-existing diabetes mellitus diagnosed within the VHA between October 1, 1998 and December 30, 2010, and followed until December 2014. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using both the time-varying Cox proportional hazards regression model, which controls for immortal time bias, and conventional Cox model. Analyses were adjusted for confounders. We also stratified analyses by race. Further, we performed analyses among patients who were metformin naïve (N = 1158) at the time of pancreatic cancer diagnosis (most representative of patients enrolled in clinical trials). Results: Median survival was 4.5 months among metformin users versus 3.7 months among non-users. Metformin use was not associated with pancreatic cancer survival in analysis using the time-varying Cox model: HR = 1.05 (95% CI 0.92-1.14, P-value = 0.28). Results were identical among non-Hispanic Whites and African Americans. In analysis using conventional Cox model, metformin use was associated with an artificial survival benefit: HR = 0.89 (95% CI 0.83-0.98, P-value = 0.01). Among patients who were metformin naïve at the time of pancreatic cancer diagnosis, metformin use was associated with improved survival in analysis using the time-varying Cox model: HR = 0.77 (95% CI 0.61-0.98, P-value = 0.03). The HRs were 0.78 (95% CI 0.61-0.99, P-value = 0.04) among non-Hispanic Whites and 1.20 (95% CI 0.75-1.93, P-value = 0.45) among African American patients. Conclusions: We observed no associations between metformin use and pancreatic cancer survival. Nevertheless, we noted improved survival (limited to non-Hispanic White patients) among patients who were metformin naïve at the time of pancreatic cancer diagnosis, which requires conformation in other studies.
SWOG S1505: Initial findings on eligibility and neoadjuvant chemotherapy experience with mFOLFIRINOX versus gemcitabine/nab-paclitaxel for resectable pancreatic adenocarcinoma.
Authors: Sohal Davendra , Lew Danika L. , Ahmad Syed A. , Gandhi Namita , Beg Muhammad Shaalan , Wang-Gillam Andrea , Wade James Lloyd , Guthrie Katherine A , Lowy Andrew M. , Philip Philip Agop , Hochster Howard S. 
Published: May 2019

4137 Background: Clinical outcomes after curative therapy of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. For early control of systemic disease with aggressive perioperative chemotherapy (CTx), we conducted a prospective trial in the National Clinical Trials Network (NCTN) setting. Methods: S1505 was a randomized phase II trial of periop (12 weeks pre-, 12 weeks post-op) CTx with either mFOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin – without bolus 5-FU and leucovorin; Arm 1), or gemcitabine/nab-paclitaxel (Arm 2). Eligibility required adult patients with ECOG PS 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease: no involvement of the celiac, common hepatic, or superior mesenteric arteries (and, if present, variants); < 180° interface between tumor and vessel wall, of the portal or superior mesenteric veins; patent portal vein/splenic vein confluence; no metastases. Primary outcome is 2-year overall survival (OS), using a “pick the winner” design; for 100 eligible patients, accrual up to 150 patients was planned, to account for cases deemed ineligible at central radiology review. Results: From 2015 to 2018, 147 patients were enrolled; 74 to Arm 1; 73 to Arm 2. At central radiology review, 42/147 (29%) were ineligible; of these, 15 (36%) had venous involvement ≥180°, 22 (52%) had arterial involvement, 28 (67%) had distant disease. One patient had distal cholangiocarcinoma (ineligible); one withdrew consent after randomization. Eligible patients (n = 103) had median age 64 years; males 58%; whites 89%; PS 0 64%. Of 103, 99 (96%) started and 86 (83%) completed preop CTx. There was one death due to sepsis and 61 additional patients experienced grade 3/4 toxicities. To date, 76 of 99 (77%) patients went to surgery and 72 (73%) underwent resection. Conclusions: This is the first-ever NCTN study of periop CTx for resectable PDA. Accrual was brisk, establishing feasibility. Ineligible cases after central radiology review highlight quality control and physician education imperatives for neoadjuvant PDA trials. Preop CTx safety and resection rates are encouraging. Follow up for OS is ongoing. Clinical trial information: NCT02562716.
BIONADEGE: Genomic profiling of small bowel adenocarcinoma from the NADEGE prospective cohort.
Authors: Aparicio Thomas , Svrcek Magali , Henriques Julie , Afchain Pauline , Lièvre Astrid , Tougeron David , Gagniere Johan , Terrebonne Eric , Piessen Guillaume , Legoux Jean-Louis , Lecaille Cedric , Pocard Marc , Gornet Jean-Marc , Zaanan Aziz , Lavau-Denès Sandrine , Lecomte Thierry , Benallaoua Mourad , Helfen Sabine , Vernerey Dewi , Laurent-Puig Pierre 
Published: May 2019

4140 Background: Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. Methods: BIONADEGE is an ancillary study of the NADEGE cohort that enrolled 347 patients (pts) with SBA from 2009 to 2012. Next generation sequencing investigates the presence of 740 hot spot somatic mutations in 46 genes involved in carcinogenesis. The MSI (MicroSatellite Instable) status was assessed using 5 microsatellites. The MMR (MisMatch Repair) status was assessed by immunochemistry (4 antibodies). Results: A total of 196 tumour samples were collected and 125 pts had conclusive results for mutation analysis. The clinical and tumours characteristics were comparable in the NADEGE and BIONADEGE cohort except for metastatic stage at diagnostic underrepresented in the BIONADEGE cohort (17.7%) due to missing tumour sample. A predisposing disease was reported in 25 (20.0%) cases (among them 14 Lynch syndromes and 7 Crohn diseases). The number of mutation observed was 0 in 9.6% pts, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. The most frequent genomic alteration were KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%). Altogether, a genomic alteration was observed in 90.3% of tumour. KRAS mutation were more frequent in synchronous metastatic tumour than in localized tumour (72.7% vs 38.2%, p = 0.003). There was no significant difference of mutation rate according to primary location for the most frequently altered gene. With caution to small sample, IDH1 mutation is more frequent and APC mutation never seen in Crohn disease. The rate of dMMR tumor was 38.6% in localized tumour and 0% in synchronous metastatic tumour. After a median follow-up of 55 months (95%CI [44-63]), M0 stage, pN0, pT1-2 were associate with better survival in univariate analysis. No significant prognostic value of genomic alteration was associated with OS. dMMR status was associate with a better prognosis for OS in pts with MMR status determined by immunohistochemistry (HR = 0.55 [0.29-1.01], p = 0.055). Conclusions: A high frequency of targetable alteration is observed in SBA. There is several specificities according to predisposing disease. No association between genomic alteration and prognostic was observed except a trend for a better prognosis associate with dMMR.
Randomized, double-blind phase III study of pazopanib versus placebo in patients with metastatic renal cell carcinoma who have no evidence of disease following metastasectomy: A trial of the ECOG-ACRIN cancer research group (E2810).
Authors: Appleman Leonard Joseph , Puligandla Maneka , Pal Sumanta K. , Harris Wayne , Agarwal Neeraj , Costello Brian Addis , Ryan Christopher W. , Pins Michael , Kolesar Jill , Vaena Daniel A. , Parikh Rahul Atul , Hashmi Mehmood , Dutcher Janice P. , DiPaola Robert S. , Haas Naomi B. , Carducci Michael Anthony 
Published: May 2019

4502 Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. > 1 site of resected disease, and by disease-free interval ≤ vs. > 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.