bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label phase II study of lenvatinib plus pembrolizumab in patients with advanced gastric cancer (EPOC1706).
Authors: Kawazoe Akihito , Fukuoka Shota , Nakamura Yoshiaki , Kuboki Yasutoshi , Mikamoto Yuichi , Shima Hikari , Fujishiro Noriko , Higuchi Tsukiko , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Shitara Kohei 
Published: February 2020

374 Background: Pembrolizumab, anti–PD-1 antibody, provides response rates of around 15% in patients (pts) with PD-L1-positive advanced gastric cancer (AGC). Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. This phase 2 study has been conducted to evaluate efficacy and safety of the combination of lenvatinib plus pembrolizumab in pts with AGC. Methods: Eligible pts were with AGC having measurable lesions according to RECIST ver. 1.1. Pts could be enrolled regardless of PD-L1 status. Pts received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Primary endpoint was objective response rate (ORR). Planned sample size was 29 pts based on Simon’s optimal two-stage design with one-sided ɑ = 5% and power = 80%. The threshold and expected ORRs were 10% and 30%. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 22C3 antibody. Results: From October 2018 to March 2019, 29 pts (27 MSS and 2 MSI-H) were enrolled and assessed for anti-tumor response. Fourteen pts received the study treatment as first-line and 15 pts as second-line. ORR was 69% (95% CI 49 to 85). The disease control rate was 100%. ORR in MSS pts was 70%. ORR was numerically higher in pts with CPS≥1 (n=19, ORR 84%) than that of pts with CPS<1 (n = 10, ORR 40%). Median progression-free survival was 6.9 months (95% CI, 4.4-9.4 months) with 14 pts with ongoing treatment at the data cut off in August 2019. Grade ≥ 3 treatment related adverse events occurred in 13 pts (45%) including hypertension (34%), proteinuria (17%), and platelet count decreased (7%). Conclusions: Lenvatinib with pembrolizumab showed a promising antitumor activity with acceptable safety profiles for pts with AGC, which warrants further investigations in a larger cohort. Clinical trial information: NCT03609359 .
Surrogate indicators of survival in patients who received neoadjuvant chemotherapy for type 4 and large type 3 gastric cancer in JCOG0501.
Authors: Terashima Masanori , Mizusawa Junki , Katayama Hiroshi , Iwasaki Yoshiaki , Kawashima Yoshiyuki , Kinoshita Takahiro , Nunobe Souya , Nakatsuka Hideki , Omori Takeshi , Nakamori Mikihito , Akiyama Yuji , Tsujimoto Hironori , Ito Seiji , Kurokawa Yukinori , Yoshikawa Takaki , Boku Narikazu , Sano Takeshi , Sasako Mitsuru , Fujiya Tsuneaki ,   Stomach Cancer Study Group, Japan Clinical Oncology Group
Published: February 2020

381 Background: Pathological response rate (pRR) is a common endpoint for assessing the efficacy of neo-adjuvant chemotherapy (NAC) in patients with advanced gastric cancer (GC). We performed supplementary analysis to investigate if pRR can be a surrogate endpoint using data from JCOG0501. Methods: Patients with type 4 and large type 3 resectable GC were randomized either surgery plus adjuvant S-1 (arm A) or NAC (S-1 plus cisplatin) plus surgery plus S-1 (arm B) in JCOG0501. Histological type (sig vs non-sig) was evaluated using preoperative biopsy specimen. Cox proportional hazards model was utilized to assess the effects of covariates for overall survival (OS). Pathological response was defined as Grade1b-3 according to the Japanese Gastric Cancer Association grading. Results: Among 286 (147 in arm A and 139 in arm B) patients who underwent surgery, 132 patients with complete pathological data in arm B were evaluated. Macroscopic tumor response (PR) was observed in 47 patients (36%) and pathological response (Grade 0/1a/1b/2/3) was 15/40/30/44/3, respectively. As shown in the table, pathological response was significantly better OS after adjusting other factors (HR, 0.51 [95% CI 0.30-0.87], p = 0.014). Conclusions: pRR may be used as a surrogate endpoint for future clinical trials in type 4 and large type 3 GC. Clinical trial information: C000000279. [Table: see text]
A phase III study of nivolumab (Nivo) in previously treated advanced gastric or gastric esophageal junction (G/GEJ) cancer (ATTRACTION-2): Three-year update data.
Authors: Chen Li-Tzong , Kang Yoon-Koo , Satoh Taroh , Chao Yee , Kato Ken , Chung Hyun Cheol , Chen Jen-Shi , Muro Kei , Kang WonKi , Yoshikawa Takaki , Oh Sang Cheul , Tamura Takao , Lee Keun Wook , Boku Narikazu 
Published: February 2020

383 Background: Nivo is the first immune checkpoint inhibitor (ICI) to show efficacy and tolerability in G/GEJ cancer patients refractory to or intolerant of standard chemotherapy. Although Nivo has demonstrated durable efficacy in several cancer types, no long-term efficacy data in G/GEJ cancer has been reported to date. Here, we report the 3-year survival data of Nivo in G/GEJ cancer. Methods: A total of 493 patients with unresectable advanced or recurrent G/GEJ cancer after the failure of two or more chemotherapy regimens were randomized in a 2:1 ratio to receive 3 mg/kg Nivo (N = 330) or placebo (N = 163) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Updated results of the efficacy and safety were based on ≥ 3 years of follow-up after last patient enrollment. In subgroup analysis, we evaluated OS by BOR and incidence of select treatment-related adverse events (TRAEs). Results: As of data cut-off in February 2019, 3 years after last patient enrollment, the hazard ratios of OS and PFS in the Nivo group compared with the placebo group remained 0.62 and 0.60, respectively. The 36-month OS rates of Nivo and placebo were 5.6% and 1.2 % and the 36-month PFS rates were 2.4% and 0%, respectively. In the OS subgroup analysis by BOR, the median OS and 3-year OS rate in CR/PR patients with Nivo were 26.7 months and 35.5%, respectively. The incidence rate and severity of TRAEs were comparable with those of the 2-year cut-off. In the OS subgroup analysis based on the presence or absence of select TRAEs, the hazard ratio in patients with select TRAEs was 0.46 compared to those without select TRAEs. We are analyzing the baseline characteristics that are associated with long-term survival with Nivo. Conclusions: Nivo showed durable efficacy and a good safety profile on long-term follow-up in heavily pretreated G/GEJ cancer patients. Clinical trial information: NCT02267343.
LINE-1 hypo-methylation as a distinct phenotype in non-EBV/non-MSI-H esophagogastric junction adenocarcinoma.
Authors: Imamura Yu , Takamatsu Manabu , Tanaka Norio , Mori Seiichi , Oki Eiji , Morita Masaru , Baba Hideo , Sano Takeshi , Watanabe Masayuki 
Published: February 2020

411 Background: Most esophagogastric junction (EGJ) adenocarcinoma exhibits chromosomal instability (CIN) type with wide range of CpG site methylation. However, it is still uncertain if epigenetic alteration is clinically useful. LINE-1 methylation level is representative of genome-wide methylation status. The aim of this is to examine clinicopathological and molecular characteristics of LINE-1 methylation, and its prognostic role, in non-EBV/non-MSI-H EGJ adenocarcinoma. Methods: After removing EBV-associated or MSI-H tumors, which are the distinct molecular subtype with hyper methylation, a total 335 case of chemo-naïve non-EBV/non-MSI-H EGJ adenocarcinoma from four academic institutions in Japan, were eligible. LINE-1 methylation was examined by Pyrosequencing. Results: LINE-1 methylation level was successfully sequenced in 319 cases (92.5%). LINE-1 methylation level was associate with tumor differentiation. Intestinal type was frequently observed in the lowest quartile Q1 cases (P = 0.0006). Of note, TP53 mutation rate was significantly frequent in Q1-2 cases (P < 0.0001). Ki-67 index was also higher in Q1-2 cases. Tumor PD-L1 expression, or CD8+ cell infiltration was not associated with LINE-1 methylation level. In survival analysis, the patients with the lowest LINE-1 methylation level (Q1), experienced the worst outcome in disease-specific survival, relapse-free survival, and overall survival rates. Conclusions: Tumor with LINE-1 hypomethylation harbors significantly higher TP53 mutation and higher Ki-67 index, resulting in worse outcome in EGJ adenocarcinoma patients.
Gastric Immune Prognostic Index (GIPI) in metastatic (m) gastro-oesophageal junction (GOJ)/gastric cancer (GC) patients (pts) treated with PD-1/PD-L1 immune checkpoint inhibitors (ICIs).
Authors: Morelli Cristina , Formica Vincenzo , Patrikidou Anna , Murrias Carmen , Butt Sabeeh , Nardecchia Antonella , Lucchetti Jessica , Renzi Nicola , Iannantuono Giovanni Maria , Roselli Mario , Shiu Kai-Keen , Arkenau Tobias 
Published: February 2020

417 Background: ICIs demonstrated improved overall survival (OS) in heavily pre-treated mGOJ/GC pts. Pts selection exclusively based on PD-L1 tissue expression appears to be suboptimal, despite data from subgroup analyses of KEYNOTE trials. Strong rationale suggests a potential predictive role of inflammatory biomarkers in ICIs treated mGOJ/GC pts. Methods: 11 systemic inflammatory markers [platelets, monocytes, neutrophil/lymphocyte ratio (NLR), platelets-lymphocyte ratio, lymphocytes, sum of mononuclear cells, albumin, lactate dehydrogenase, alkaline phosphatase (ALP), c-reactive protein (CRP) and serum globulin] were retrospectively analyzed at baseline in 57 mGOJ/GC pts with unknown PD-L1 status treated in second-line with ICIs, and correlated with OS. Least Absolute Shrinkage and Selection Operator (LASSO) method was used to select variables (preliminarily subject to optimal coding using HR smoothed curves for OS) with the highest prognostic value.Selected variables were then analysed in a multivariate Cox Regression Model and used to build a GIPI nomogram. Results: NLR and CRP taken as continuous variables and ALP categorized as < vs > 150 IU/L were found as the most meaningful independent predictors of OS [(HR 1.30 (95%CI 1.02-1.65), 2.00 (95%CI 1.09-3.66), 2.82 (95%CI 1.29-6.20) and p values 0.04, 0.01, 0.02, respectively)] and used to build the GIPI nomogram. Nomogram-based lowest(l), mid and highest(h) risk tertiles were associated with median(m)OS of 14.5,10.6 and 2.4 months(mos), respectively [HR of l vs h 0.26 (95%CI 0.12-0.53), p 0.0002]. By optimally dichotomizing CRP and NLR, pts with one or more of the following risk factors: NLR > 6, CRP > 15 mg/L, ALP < 150 IU/L (n: 31) had a mOS of 3.9mos vs 14.5mos of pts with no risk factor (n: 26) (HR 2.72, p 0.0005). Conclusions: GIPI, combining NLR, CRP and ALP, is the first inflammatory index with a significant prognostic value in mOGJ/GC pts receiving second line ICIs. Its implementation with analysis of PD-L1 expression in the present cohort is ongoing. GIPI merits validation in external cohorts and prospective clinical trials.
The FGFR-inhibitor derazantinib (DZB) is active in PDX-models of GI-cancer with specific aberrations in FGFR.
Authors: McSheehy Paul , Bachmann Felix , Forster-Gross Nicole , El Shemerly Mahmoud , Roceri Mila , Kellenberger Laurenz , Lane Heidi A 
Published: February 2020

421 Background: DZB is an oral small-molecule Fibroblast Growth Factor Receptor 1/2/3 inhibitor (FGFRi) with clinical activity in FGFR2-fusion-positive cholangiocarcinoma. DZB was screened for activity in gastrointestinal cancer (GIC), by using a panel of GIC cell-lines, human tumor xenografts and 30 GIC patient-derived xenograft (PDX) models. Methods: DZB anti-proliferative potency was determined in 26 GIC cell lines to determine the GI50. The GIC cell-line, SNU-16 was grown s.c. in nude mice and treated daily for 3-weeks with DZB at the MTD of 75 mg/kg, p.o. Plasma and tumor were removed and analyzed for drug-levels and PD biomarkers to assess pathway inhibition. DZB (@MTD) was tested in the PDX-screen (15 biliary, 13 gastric and 2 colorectal cancer; n≥3/group) using models with FGFR-fusions, FGFR-mutations and/or differing FGFR copy-number (CN)/RNA-seq expression levels. Efficacy and tolerability were quantified as a dT/C (treated/control). Results: Cellular GI50s ranged from 0.02-20 μM; the most sensitive (GI50≤0.5 μM) had FGFR-fusions or high-expression. In mice, DZB induced stasis of SNU-16 tumors (dT/C∼0.0) and was well tolerated (dT/C > 1.0); the plasma PK was dose-dependent with a Cmax of 2 μM (4 hr), a Cmin of 0.5 μM. DZB induced dose- and time-dependent changes in the MAPK-pathway and expression of downstream genes, consistent with its mode of action. In PDX-models, efficacy varied from no-response to 100% regression. Known driver-mutations were associated with partial-responses (best dT/C = 0.42), but models with FGFR-fusions, especially FGFR2-fusions, were very sensitive leading to stasis or strong-regression, particularly in gastric cancer. High-expression of FGFR2 was also associated with strong responses. There was no direct correlation between CN and high RNA-seq values suggesting amplification was not always a predictor of high expression. Endpoint PD-analyses of the PDX-models is ongoing to identify other potential stratifiers and PD-markers of response. Conclusions: DZB showed convincing activity in GIC-models with FGFR-fusions and/or high expression. A clinical trial is planned in patients with gastric cancer to investigate DZB as mono- and combination-therapy.
DS-Screen: Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer population.
Authors: Hara Hiroki , Takeno Atsushi , Yasui Hisateru , Imamura Hiroshi , Akamatsu Hiroki , Fujitani Kazumasa , Nakane Minoru , Kondoh Chihiro , Yukisawa Seigo , Nasu Junichiro , Miyata Yoshinori , Makiyama Akitaka , Ishida Hiroyasu , Yoshida Norimasa , Matsumura Eiji , Ishigami Masato , Sugihara Masahiro , Ochiai Atsushi , Doi Toshihiko 
Published: February 2020

431 Background: FGFR2 and HER2 proteins are well-known molecular targets for cancer therapy, and there are emerging attractive protein-targeted agents such as second generation antibody-drug conjugates. However, there are still limited information about the expression status of FGFR2 and HER2 in gastrointestinal cancer and their relationship to patient background with cancer. In this study, expression status of FGFR2 and HER2 in advanced/metastatic gastric cancer (GC) and colorectal cancer (CRC) were prospectively analyzed in clinical setting. Moreover, eligible patients for the clinical trials of DS-1123 or DS-8201, which are FGFR2- or HER2-targeting anti-cancer agent respectively, were screened. Methods: Patients with advanced/metastatic GC, gastroesophageal junctional cancer (GEJ), and CRC were enrolled. Expression status of FGFR2 and HER2 were prospectively analyzed by IHC and/or FISH. Results: A total of 565 patients (GC; 160, GEJ; 16, CRC; 389) have been enrolled in this study from November 2016 to June 2018. FGFR2 expression (IHC 1+~3+) was observed in 24%, 44%, and 3% of GC, GEJ, and CRC respectively. HER2 expression (IHC 2+, 3+) was observed in 24%, 44%, and 17% of GC, GEJ, and CRC respectively. Expression levels of FGFR2 and HER2 seemed to be not correlated with each other in all 3 types of cancer. Distributions of expression level of FGFR2 or HER2 were slightly different among the histological types in GC. In CRC, distribution of HER2 expression level was also slightly different among the histological types and HER2 expression level was higher in KRAS/NRAS wild type compared to KRAS/NRAS mutant. There was no association between HER2 expression level and primary tumor sites in patients with CRC. Slight concordance of HER2 expression was observed between IHC and FISH in CRC. A total of 7 patients have been enrolled in clinical trials of DS-1123 or DS-8201 through this study based on the analysis findings. Conclusions: This study showed insights into the expression status of FGFR2 and HER2 in GC and CRC as a large-scale prospective analysis. Seven patients who had no standard therapy could access exploratory new drug based on targetable agents through this study. Clinical trial information: 163380.
Identification of cancer hallmarks associated with benefit in advanced gastroesophageal adenocarcinoma patients treated with checkpoint blockade.
Authors: Elboudwarej Emon , Brachmann Carrie , Catenacci Daniel V.T. , Cunningham David , Van Cutsem Eric , Kennedy Richard D. , Lambe Shauna , Logan Gemma E. , Metges Jean Philippe , Muro Kei , Satoh Taroh , Takashima Atsuo , Wainberg Zev A. , Walker Steven M. , Yamaguchi Kensei , Zavodovskaya Marianna , Patterson Scott D. , Bhargava Pankaj , Boku Narikazu , Shah Manish A. ,   ADX
Published: February 2020

439 Background: The benefit of checkpoint blockade in advanced gastric cancer is limited and biomarkers related to response are needed. Novel gene expression analysis software was used to identify Hallmarks of Cancer associated with clinical benefit following nivolumab treatment in >2nd line advanced gastroesophageal adenocarcinoma (GEA). Methods: RNA-sequencing data from baseline GEA patient diagnostic tumor samples (103 from NCT02862535; 5 from NCT02862535) were analyzed using the claraT platform (V2.0.0, Almac Diagnostic Services). 62 gene signatures were quantified representing 6 key Hallmarks of Cancer (Avoiding Immune Destruction, Activating Invasion and Metastases, Sustaining Proliferative Signaling, Inducing Angiogenesis, Resisting Cell Death and Genome Instability and Mutation). Clinical benefit (CB) was defined as tumor response or overall survival (OS) > 1 year. HER2 status was from medical records. Survival analyses used cox proportional hazards models. Results: Gene expression signatures (GES) identified 5 molecular subgroups (C1-C5). Rate of CB in each molecular subtype are outlined in Table. C3 and C4 had significantly improved OS compared to C2, (HR = 0.45; p= 0.02 and HR = 0.42; p= 0.02). Greater proportions of HER2+ subjects were present in C4 and C3 vs. C2, with C3 statistically significant (60% vs. 14%; p= 0.012). Gene expression characterized by chromosomal instability (CIN) and homologous recombination repair deficiency (HRD) were associated with HER2(+) (wilcox p= < 0.05). Patients selected by only using CIN & HRD had significant improvement in OS (HR = 0.63; p= 0.03). Conclusions: Interferon-based GES did not predict benefit from immune checkpoint blockade. GES representing HRD and activation of HER2, EGFR and MAPK (each enriched in CIN) were associated with improved survival upon checkpoint blockade in advanced GEA patients. Clinical trial information: NCT02862535 . [Table: see text]
The relevance of neuropilin-1 expression with prognosis according to the histology of gastric cancer.
Authors: Seo Ho Seok , Lee Han Hong 
Published: February 2020

442 Background: Neuropilin-1 (NRP-1) is known to be related with various types of cancer and considered as a novel tumor marker or a therapeutic target. The aim of the study is to identify the clinical implication of NRP-1 expression in terms of prognosis in gastric cancer. Methods: A total of 265 patients who underwent radical gastrectomy for the treatment of gastric cancer from 2008 to 2011 were included. NRP-1 expression of tumors was determined by immunohistochemistry. Patients’ clinicopathologic characteristics, operation details, and long-term outcomes were retrospectively analyzed. Results: 181 (68.3%) patients showed NRP-1 expression. There was no survival difference according to the NRP-1 expression in all patients. The patients were divided into gland formation (GF) type and no gland formation (nGF) type according to histologic type. NRP-1 expression rates were 65.6% (84/128) and 70.8% (97/137), respectively. In the group of GF, NRP-1 expression was not independent prognostic factor, although patients with NRP-1 expression had better survival outcome. In contrast, patients with NRP-1 expression had worse 5-year survival rate in the group of nGF (p = 0.027) and it was an independent prognostic factor multivariate analysis (HR, 1.923; 95% CI, 1.041 - 3.551). Conclusions: NRP-1 expression in the nGF type gastric cancer predicts a poor prognosis.
Patient-reported outcomes (PROs) from the Phase III IMbrave150 trial of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC).
Authors: Galle Peter R. , Finn Richard S. , Qin Shukui , Ikeda Masafumi , Zhu Andrew X. , Kim Tae-You , Kudo Masatoshi , Breder Valeriy Vladimirovich , Merle Philippe , Kaseb Ahmed Omar , Li Daneng , Mulla Sohail , Verret Wendy , Xu Derek-Zhen , Hernandez Sairy , Liu Juan , Huang Chen , Lim Ho Yeong , Cheng Ann-Lii , Ducreux Michel 
Published: February 2020

476 Background: Atezo + bev in pts with unresectable HCC who had not received prior systemic therapy has shown statistically significant and clinically meaningful improvement in OS and PFS per independent review facility-assessed RECIST 1.1 vs sor in the Phase III IMbrave150 study (Cheng ESMO Asia 2019). Here, we report PRO data from this trial to show pt perspectives on the overall clinical benefit of atezo + bev. Methods: Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg PO BID until loss of clinical benefit or unacceptable toxicity. Pts completed the EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires before tx, every 3 wk on tx, and every 3 mo after tx discontinuation or disease progression. A pre-specified secondary endpoint was time to deterioration (TTD; first ≥ 10-point decrease from baseline held for 2 consecutive assessments or 1 assessment followed by death within 3 wk) of pt-reported quality of life (QOL), physical functioning, and role functioning. Pre-specified exploratory analyses included TTD of and proportion of pts with a clinically meaningful change (≥ 10 points from baseline) in key pt-reported symptoms. Results: Questionnaire completion rates were ≥ 92% in both arms from baseline through most of the tx period. Compared with sor, atezo + bev delayed TTD of pt-reported QOL (median TTD, 11.2 vs 3.6 mo; HR, 0.63 [95% CI: 0.46, 0.85]), physical functioning (median TTD, 13.1 vs 4.9 mo; HR, 0.53 [95% CI: 0.39, 0.73]), and role functioning (median TTD, 9.1 vs 3.6 mo; HR, 0.62 [95% CI: 0.46, 0.84]). Atezo + bev also delayed TTD in pt-reported appetite loss, fatigue, pain, and diarrhea vs sor; a lower proportion of pts on atezo + bev experienced clinically meaningful deterioration in each of these symptoms vs sor. Conclusions: High-quality PRO results from IMbrave150 showed large and consistent benefits in key aspects of the pt experience with atezo + bev, further supporting its overall clinical benefit in pts with unresectable HCC who have not received prior systemic therapy. Clinical trial information: NCT03434379.