bluuebunny/crossref_metadata_2025 huggingface dataset:
Health-related quality-of-life results from JCOG0912: A phase III noninferiority trial comparing open and laparoscopy-assisted distal gastrectomy for stage I gastric cancer.
Authors: Yoshikawa Takaki , Ando Masahiko , Mizusawa Junki , Katai Hitoshi , Yamada Takanobu , Ito Seiji , Fukagawa Takeo , Bando Etsuro , Misawa Kazunari , Katayama Hiroshi , Terashima Masanori , Sasako Mitsuru ,   JCOG Stomach Cancer Study Group
Published: February 2020

293

Background: Laparoscopy-assisted distal gastrectomy (LADG) was non-inferior to open (ODG) in patients with stage I gastric cancer in randomized phase 3 non-inferiority trial (JCOG0912). Here, we present the results of health-related quality of life (HRQoL) which was a secondary endpoint in JCOG0912. Methods: Among 33 institutions participated in JCOG0912, 4 major cancer centers were selected for HRQOL assessment. HRQoL was assessed using EORTC QLQ-C30 and the EORTC-STO22 before (baseline) and at 1, 3, 12, and 36 months after surgery. The primary HRQOL scale was QLQ-C30 global health status. We defined clinically meaningful decrease of HRQoL as decrease in 10 points or more from the baseline. Missing data were regarded as decrease. Assuming that expected %decrease of global health status at 3 months was 61% in ODG and 45% in LADG with 80% power and two-sided alpha of 0.05, sample size for HRQOL assessment was calculated to be 304. When this hypothesis at 3 months was confirmed, statistical comparison was tested in turn at 12 and 36 months. Results: Among 921 enrolled patients in JCOG0912 from Mar 2010 to Nov 2013, 592 were enrolled from the 4 centers in this HRQoL study. The %decrease of global health status at 3 months was different between ODG and LADG (37.2% (109/293) in ODG vs 29.2% (86/295) in LADG, odds ratio [OR] 0.65 (95% CI: 0.45-0.93, p = 0.020)), but was not different in 1 month (56.0% (164/293) vs 55.3% (163/295), OR 0.92 (0.61-1.32)), 12 months (26.3% (77/293) vs 27.8% (82/295) (OR 1.07 (0.73-1.56))and 36 months (31.4% (91/293)vs 30.8% (91/295) (odds ratio, 0.96 (0.67-1.37))). Among the other subscales, LADG had significantly better symptom scores for pain at 1 and 3 months, constipation at 3 and 12 months, and eating restrictions at 3 months. Conclusions: Decrease of HRQoL was less frequently observed in LADG than ODG especially in the early phase after surgery. Considering non-inferiority and better HRQoL of LADG, LADG is strongly recommended for stage I gastric cancer. However, we have to be careful to expand the indication of LADG for advanced gastric cancer until a solid evidence is obtained. Clinical trial information: UMIN000003319.
Improved efficacy to cytotoxic agents chemotherapy after immune checkpoint inhibitors exposure in metastatic gastric cancer.
Authors: Sagawa Tamotsu , Sato Yasushi , Hamaguchi Kyoko , Hirakawa Masahiro , Nagashima Hiroyuki , Waga Eriko , Fujikawa Koshi , Takahashi Yasuo
Published: February 2020

297

Background: An association between improved responses to chemotherapy after exposure to vaccine-based immunotherapy has been previously reported in other cancers. However, it is unclear whether the chemotherapy response improves after exposure to immunotherapy, such as immune checkpoint inhibitors (ICIs). The objective of this retrospective study was to evaluate whether chemotherapy (4th-line) would yield improved efficacy when given after exposure to anti-PD-1 antibody in metastatic gastric cancer (mGC). Methods: We investigated retrospectively clinical characteristics at baseline of mGC patients who received chemotherapy after progression of anti-PD-1 antibody (Nivolumab) between February 2018 and July 2019. Anti-PD-1 antibody was adapted as third-line therapy. Inclusion criteria for the analysis reported herein: histologically proven adenocarcinoma; ECOG PS 0-2; adequate organ functions; and received chemotherapy including 5-fluoropyrimidines (5-FU), platinum, and taxane or irinotecan. We evaluated efficacy outcomes, including ORR, DCR by RECIST version 1.1, PFS, and OS. Results: Out of 27 treated with anti-PD-1 antibody, 10 patients were evaluable for responses and eligible to be included in this analysis. Patient characteristics were as follows: median age (range), 72 (50-88) years; male/female, 8/2; ECOG PS (0/1/2), 4/5/1; HER2 (+/-), 5/5; histology (differentiated/undifferentiated), 5/5; metastatic lesions (LN/peritoneum/liver/lung), 5/3/1/3; number of metastatic sites (1/≥2), 5/5; number of prior CTx regimens (3/4/5), 10/0/0; median period (range) from first line CTx, 18.8 (7.9-47.1) months; and CTx regimens (CPT-11/PTX/S-1+Oxaliplatin), 7/2/1; Among the 10 patients, 1 achieved a partial response, giving an ORR of 10.0%. Six patients had stable disease and three had progressive disease. The DCR was 70%. Median PFS and OS were 5.5M and 8.5M, respectively. These were no new irAEs appeared during CTx. Conclusions: In mGC patients, our study demonstrated that increased efficacy to cytotoxic agents chemotherapy given after exposure to ICI was higher as compared to our historical data from the pre-anti-PD1 era. Updated results will be presented.
Impact of gastric cancer treatment pathways on patient outcomes in a community oncology practice setting.
Authors: Paulson Andrew Scott , Hess Lisa M. , Baidoo Bismark , Waycaster Curtis , Chatterjee Anindya , Liepa Astra M.
Published: February 2020

299

Background: Gastric cancer (GC, including gastroesophageal junction adenocarcinoma) pathways have been implemented and refined since 2010 in the US Oncology Network (USON), a community-practice-based network. This study was designed to evaluate the impact of 4 pathway periods (PP): pre-pathway: pre-Aug ‘10; Level 1: Sept ‘10-Nov ‘14; Clear Value, Dec ‘14-Feb ‘17; Value: After Mar ‘17, on treatment heterogeneity, treatment duration, and overall survival (OS). Methods: Adult patients were eligible if they were treated at a participating USON site and were diagnosed with and treated for GC; follow up was through Mar 2019. Heterogeneity was measured by the Herfindahl-Hirschman Index (HHI), which is evaluated from 0.0 to 1.0 (complete to no heterogeneity). Time to treatment failure (TTF) was defined as initiation of the line of therapy until start of the subsequent line of therapy or death. OS was estimated from start of first-line (1L) therapy. Time-to-event outcomes were estimated using Kaplan-Meier. Results: Of 3191 eligible patients, 2297 received treatment for advanced/metastatic disease. Of these, patient median age was 65.3 years, 60% were male, 70% were initially diagnosed with stage IV disease. Pre-pathway, common 1L regimens were single-agent fluorouracil (15%) and docetaxel-cisplatin-fluorouracil (14%); FOLFOX (45%) was most frequent during the value PP, 941 (41%) received second-line (2L) therapy. During Level 1 PP, single-agent irinotecan (11%) was most common during 2L, whereas in Value PP, ramucirumab+paclitaxel (43%) was most common. HHI and TTF are presented in the table. Median OS was 12.6 months (95% confidence interval, CI: 11.9, 13.5), which did not change significantly over PPs. Conclusions: 1L and 2L heterogeneity was initially high, and was reduced over time; TTF showed modest increase. OS data are limited by high levels of censoring in the latter PPs, which reduces the ability to evaluate changes in more recent years.

[Table: see text]
SOURCE: Prediction models for overall survival in patients with metastatic and potentially curable esophageal and gastric cancer.
Authors: van den Boorn Héctor G. , Abu-Hanna Ameen , Haj Mohammad Nadia , Hulshof Maarten C.C.M. , Gisbertz Suzanne S. , Klarenbeek Bastiaan R. , Slingerland Marije , Beerepoot Laurens Victor , Rozema Tom , Sprangers Mirjam A.G. , Verhoeven Rob H. A. , Zwinderman Aeilko H. , van Oijen Martijn G.H. , Van Laarhoven Hanneke W.M.
Published: February 2020

301

Background: Prediction models in cancer care can provide personalized prediction outcomes and can aid in shared decision making. Existing prediction models for esophageal and gastric cancer (EGC), however, are mostly aimed at predicting survival after a curative treatment has already been completed. The aim of this study is to develop prediction models, called SOURCE, to predict overall survival at diagnosis in potentially curable and metastatic EGC patients. Methods: The data from 12,756 EGC patients diagnosed between 2014-2017 were retrieved from the prospective Netherlands Cancer Registry. Four Cox regression models were created for potentially curable and metastatic cancers of the esophagus and stomach. Predictors, including treatment type, were selected using the Akaike Information Criterion. The models were validated with temporal cross-validation on their concordance-index (c-index) and calibration. Results: The validated model’s c-index is 0.76 for potentially curable cancer. For the metastatic models, the c-indices are 0.71 and 0.70 for esophageal and gastric cancer, respectively. The calibration intercepts and slopes lie in the 95% confidence interval of 0 and 1, respectively. The included model variables are given in Table. Conclusions: The SOURCE prediction models show fair c-indices and an overall good calibration. The models are the first in EGC to include treatment as a predictor. The models predict survival at diagnosis for a variety of treatments and therefore could have a high clinical applicability. Future research is needed to demonstrate the effect on shared decision making in clinical practice.

[Table: see text]
Induction oxaliplatin capecitabine followed by switch to carboplatin-paclitaxel based RT versus continuing oxaliplatin capecitabine RT in operable esophageal adenocarcinoma: Survival analysis of the randomized phase II neoscope trial.
Authors: Mukherjee Somnath , Hurt Chris , Cox Catrin , Radhakrishna Ganesh , Gwynne Sarah , Bateman Andrew Rea , Gollins Simon , Hawkins Maria A. , Canham Jo , Grabsch Heike I. , Falk Stephen , Sharma Ricky A. , Ray Ruby , Roy Rajarshi , Wade Wendy , Maggs Rhydian , sebag-Montefiore David joseph , Maughan Tim , Griffiths Gareth Owen , Crosby Tom David Lewis
Published: February 2020

373

Background: Initial results of the NEOSCOPE trial comparing pre-operative CarPac vs OxCap based chemoradiotherapy (CRT) in patients with adenocarcinoma of the oesophagus or oesophagogastric junction showed comparable toxicity and improvement in pathological complete response (pCR) in favour of the CarPacRT. Here we report survival after a median follow-up of 40.7 months (95% CI: 45.1-53.6). Methods: NEOSCOPE was an open, randomised, ‘pick a winner’ phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of RT) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). RT dose was 45 Gy/25 fractions/5 weeks. Induction OxCap (2 cycles) was given prior to CRT. Surgery was performed 6–8 weeks after CRT.The primary endpoint was pCR, secondary endpoints were toxicity, PFS and OS. Results: Between Oct 2013 and Feb 2015, 85 patients were recruited from 17 UK centres. Median OS was not reached in the CarPacRT group and was 41.72 months (95% CI 19.58-.)in the OxCap group (HR 0.56[95% CI 0.29-1.07]; p=0.079). 3-year and 5-year OS rates were 74% (95% CI 58%-85%) and 54% (95% CI 34%-71%) (CarPacRT), and 52% (95% CI 35%-67%) and 39% (95% CI 21%-56%) (OxCapRT). Median PFS (not reached vs 35.3 months, HR=0.61 [95% CI 0.33-1.12]; p=0.111) and metastatic PFS (not reached vs 39.0 months, HR=0.61 [95% CI 0.32-1.14], p=0.118) both favoured the CarPacRT arm. Local recurrence rate was low (OxCapRT= 10%; CarPacRT= 7%). The OS benefit for CarPacRT was consistent across subgroups but not statistically significant. Conclusions: In this longer term analysis there was some evidence that induction OxCap followed by switch to CarPacRT was superior to continuing OxCapRT, with efficacy similar to that seen in other published studies such as ‘CROSS’ and ‘FLOT’. Taken together with the previously published pCR results CarPacRT rather than OxCapRT warrants inclusion in future trials. Funding: Cancer Research UK (C44694/A14614). Clinical trial information: NCT01843829.
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.
Early nutritional risk assessment by NRS 2002 to predict survival in patients with advanced biliary tract cancer.
Authors: Oh Se Eung , Jeung Hei-Cheul
Published: February 2020

505

Background: Biliary tract cancer (BTC) has heterogenous disease with dismal prognosis. We investigated the predictors of overall survival (OS) among Korean patients with advanced BTC according to their baseline nutritional risks estimated by Nutritional Risk Screening (NRS) 2002 score. Methods: From September 2006 to July 2017, we retrospectively reviewed the data of 601 patients with BTC. Data on demographic and clinical parameters were collected from electronic medical records, and overall survival (OS) and progression-free survival (PFS) was estimated using the Kaplan–Meier method. Stepwise Cox regression analysis was used to determine the factors associated with survival. Patients with a NRS 2002 score ≤2 were classified as “no-risk; ” those with a score of 3 were classified as “moderate-risk; ” and those with a score of ≥4 were classified as “high-risk.” Results: Following nutritional screening at baseline, 333 patients (55%) were classified as the “no risk” group; 109 patients (18%), as the “moderate risk” group; and 159 patients (27%) as the “high risk” group. Survival analysis showed significant differences in the median OS according to the NRS 2002 groups: “no risk” group: 12.6 months (95% CI: 11.5–13.7); “moderate risk” group: 6.1 months (95% CI: 4.3–8.0); and “high risk” group: 3.9 months (95% CI: 3.2 – 4.6) (p<0.001). On the Cox’s regression analysis, NRS 2002 score came out as the most independent factor for OS (for “moderate-risk” HR 1.610, 95% CI 1.288-2.027, p<0.001; for “high-risk”, HR 2.121, 95% CI 1.728-2.612, p<0.001), compared with other prognostic factors including liver metastasis, peritoneal seeding, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, cholesterol, CEA, and CA19-9. Conclusions: Our study demonstrated OS of advanced BTC was strongly related to their baseline nutritional status assessed by NRS 2002. Constitutional nutritional assessment can help to improve patient prognosis through proactive and individualized nutritional intervention. Baseline nutritional status should be integrated for implementing prognostic scoring system, which can provide more sophisticated risk stratification of patients with metastatic BTC.
Updated efficacy and safety of KEYNOTE-224: A phase II study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Kudo Masatoshi , Finn Richard S. , Edeline Julien , Cattan Stéphane , Ogasawara Sadahisa , Palmer Daniel H. , Verslype Chris , Zagonel Vittorina , Fartoux Laetitia , Vogel Arndt , Sarker Debashis , Verset Gontran , Chan Stephen Lam , Knox Jennifer J. , Daniele Bruno , Gurary Ellen B , Siegel Abby B. , Jain Lokesh , Cheng Ann-Lii , Zhu Andrew X. ,   for the KEYNOTE-224 Investigators
Published: February 2020

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Background: Pembro received accelerated approval in pts with advanced HCC in the second-line setting based on results of the KEYNOTE-224 trial. Results of a 2 y follow-up analysis of the efficacy and safety in this trial are presented here. Methods: Eligible pts had histologically confirmed HCC, radiographic progression on/intolerance to sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for 2 y or until disease progression, unacceptable toxicity, consent withdrawal or investigator decision. Response was assessed every 9 wk. Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints were DOR, DCR, PFS, OS and safety. Results: Efficacy and safety were assessed in 104 pts. The median time from randomization to data cutoff (Jun 05, 2019) was 31.2 mo (27.5-35.5 mo). Pt characteristics were: median age 68 y (43-87), 21.2% HBV+, 25% HCV+, 94.2% Child Pugh A, 79.8% had PD on sorafenib, 17.3% had MVI and 64.4% had extrahepatic disease. ORR was 18.3% (95% CI 11.4-27.1) and was similar across subgroups. Median DOR was 21.0 mo (3.1-28+ mo); 77% had responses lasting ≥12 mo (Kaplan Meier). Best overall responses were 4 (3.8%) CRs, 15 (14.4%) PRs, 45 (43.3%) SDs and 34 (32.7%) PDs; DCR was 61.5%. The median PFS (95% CI) was 4.9 mo (3.5-6.7) and OS was 13.2 mo (9.7-15.3). PFS 24 mo rate was 11.3% and OS 24 mo rate was 30.8%. ORR was shown to be a predictor of longer OS by landmark analysis. Treatment-related AEs occurred in 76 (73.1%) pts; the most common AEs were fatigue, increased aspartate aminotransferase, pruritus and diarrhea observed in ≥10% pts. Grade ≥3 treatment related AEs occurred in 27 (26.0%) pts. Immune-mediated hepatitis occurred in 3 (2.9%) pts; no cases of HBV/HCV flare were identified. Conclusions: At 2 y follow-up, pembro continued to provide durable anti-tumor activity and prolonged survival (30.8% OS, 24 mo rate), further supporting its use in previously treated pts with advanced HCC. With longer follow-up, increases in ORR (18.3% vs 17.0%), DOR ≥12 mo (77.0% vs 61.4%) and CR rates (3.8% vs 1%) were seen. The safety profile was similar to the primary analysis. Clinical trial information: NCT02702414.
Baseline liver function and outcomes in the phase III REFLECT study in patients with unresectable hepatocellular carcinoma (uHCC).
Authors: Vogel Arndt , Frenette Catherine , Sung Max W. , Daniele Bruno , Baron Ari David , Chan Stephen Lam , Blanc Jean-Frédéric , Tamai Toshiyuki , Ren Min , Lim Howard John , Palmer Daniel H. , Takami Yuko , Kudo Masatoshi
Published: February 2020

524

Background: Lenvatinib (LEN) is approved for first-line treatment of uHCC. Baseline (BL) liver function (Child-Pugh score [CPS] and albumin-bilirubin grade [ALBI]) was prognostic in uHCC patients (pts) who received sorafenib (SOR) but has not been assessed with LEN in uHCC. Here, we report post hoc analysis of BL liver function and efficacy/safety outcomes from the phase 3 REFLECT study. Methods: Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were stratified by BL ALBI or CPS. OS and PFS were estimated by Kaplan–Meier method. Independent radiologic review utilized mRECIST criteria for ORR. Safety was assessed using NCI-CTCAE, version 4.0. Results: Liver function measured by ALBI and CPS seemed to be prognostic for OS and ORR. Median OS was longer in ALBI grade 1 (ALBI-1) vs grade 2 (ALBI-2) pts or for CPS-5 vs CPS-6 on either treatment arm and was longer for LEN vs SOR. ORR was higher in pts with better ALBI or CPS and for LEN vs SOR. Rates of treatment-emergent adverse events grade ≥3 were lower with better BL liver function (ALBI-1 vs ALBI-2: 70% vs 86%; CPS-5 vs CPS-6: 72% vs 86%). Study-drug withdrawal, dose reduction, and dose interruption occurred more often in pts with worse BL liver function. Conclusions: This post hoc analysis suggests ALBI (by OS, PFS and ORR) and CPS (by ORR) may be prognostic in uHCC pts and that BL liver function may be linked with efficacy/safety outcomes. This analysis also found that LEN provided benefit vs SOR for uHCC, regardless of BL liver function. The benefit of LEN may be underestimated, as more ALBI-2 pts and fewer ALBI-1 pts received LEN vs SOR. Clinical trial information: NCT01761266.

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Postoperative adjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of hepatocellular carcinoma patients with microvascular invasion: A preliminary report of a phase III, randomized, controlled clinical trial.
Authors: Li Shaohua , Wei Wei , Wang Qiaoxuan , Guo Zhixing , Mei Jie , Lu Lianghe , Ling Yihong , Xu Li , Chen Minshan , Lin Wenping , Zou Jingwen , Wen Yuhua , Guo Rongping
Published: February 2020

527

Background: Microvascular invasion (MVI) is a risk factor for recurrence after hepatectomy for hepatocellular carcinoma (HCC) patients. This study aimed to investigate to efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with FOLFOX regimen for HCC patients with MVI. Methods: In this prospective, phase III, randomized, open-labeled, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either 1-2 cycles adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), the secondary endpoints are overall survival (OS) and safety. Results: Between June, 2016 and April 2019, 127 patients were randomly assigned to AT group (n=63) or FU group (n=64). Clinicopathological characteristics were balanced between the two groups. The 6-, 12-, and 18-month OS rates for AT group were 100.0%, 97.7%, and 97.7%, and were 94.5%, 89.6%, and 78.5% for FU group, respectively. The 6-, 12-, and 18-month DFS rates for AT group were 84.7%, 61.8%, and 58.7%, and were 62.9%, 48.1%, and 38.6% for FU group, respectively. The OS and DFS were significantly better in AT group than in FU group (p=0.037 and 0.023, respectively). No patients in AT group experienced grade 3 or more severe adverse events (AEs). Conclusions: Adjuvant TAI after hepatectomy may bring survival benefits of OS and DFS for HCC patients with MVI. Clinical trial information: NCT03192618.
Cisplatin plus irinotecan versus cisplatin plus gemcitabine in the treatment of advanced or metastatic gallbladder or biliary tract cancer: Results of a randomized phase II trial (NCT01859728)– the Gambit trial.
Authors: dos Santos Lucas Vieira , Pinto Gustavo Sanches Faria , Ferraz Mauricio Wagner Souto , Bragagnoli Arinilda , Santos Florinda , Haddad Sarah , Barros Ana , Cordeiro Dias Isadora Clarissa , Lima Joao Paulo SN , Abdalla Kathia C
Published: February 2020

529

Background: The combination of gemcitabine-cisplatin (GC) is the current standard of care chemotherapy for metastatic/unresectable biliary tract cancer (BTC). However, the prognosis remains poor. This randomized trial aimed to evaluate the efficacy and safety of irinotecan plus cisplatin (IP) versus GC in advanced or metastatic BTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic BTC, ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent were stratified by ECOG (0 or 1 vs 2) and distant metastases and randomized to receive irinotecan 65 mg/m² IV D1 and D8 plus cisplatin 60 mg/m² D1 repeated every 3 weeks (IP) or gemcitabine 1000 mg/m² IV D1 and D8 plus cisplatin 25 mg/m² IV D1 and D8 repeated every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: Between January 2013 and April 2018, 47 pts were randomized (1:1) to receive IP (N = 24) or GC (N = 23). Overall, groups were well balanced according to prognostic factors. The ORR was 35% (complete response 5%, partial response 30%) and 31.8% in IP and GC arms, respectively. Median progression-free survival were 5.3 vs 7.8 months (HR = 1.165, 95%CI 0.628-2.161, p = 0.628) and median overall survival were 11.9 and 9.8 months (HR = 0.859, 95%CI 0.431 – 1.710, p = 0.665) for IP and GC, respectively. Adverse events were not statistically different between arms, and results were consistent with previous experiences with these regimens. No therapy-related death were reported. Conclusions: Irinotecan-cisplatin combination is active in BTC, with similar ORR, PFS and OS when compared to gemcitabine-cisplatin. Irinotecan-cisplatin were well tolerated, and adverse events were manageable. Irinotecan-cisplatin could be considered as an alternative to gemcitabine-cisplatin. Clinical trial information: NCT01859728.