bluuebunny/crossref_metadata_2025_split huggingface dataset:
ARTIST 2: Interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC).
Authors: Park Se Hoon , Zang Dae Young , Han Boram , Ji Jun Ho , Kim Tae Gyu , Oh Sung Yong , Hwang In Gyu , Kim Jung Hoon , Shin Dongbok , Lim Do Hoon , Kim Kyoung Mee , An Ji Yeong , Choi Min-Gew , Lee Jun-Ho , Sohn Tae Sung , Bae Jae-Moon , Kim Sung , Kim Seung , Lee Jeeyun , Kang Won Ki 
Published: May 2019

4001 Background: Adjuvant chemotherapy and/or chemoradiotherapy have been the standard of care in GC for years, supported by randomized trials. We compared the efficacy of different chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II/III, node-positive GC. Methods: From Feb 2013 through Nov 2018, we randomly assigned, in a 1:1:1 ratio, patients with pathologically-staged II or III, node-positive, D2-resected GC, to receive adjuvant S-1 (40-60 mg twice daily 4-weeks-on/2-weeks-off) for one year, S-1 (2-weeks-on/1-week-off) plus oxaliplatin 130 mg/m2 (SOX) for six months, or SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to the type of surgery (total or subtotal gastrectomy), stage (II or III), and Lauren histologic classification (diffuse or intestinal). The primary endpoint was disease-free survival (DFS). A total of 900 patients had to be enrolled to demonstrate superiority of SOX or SOXRT to S-1 (hazard ratio [HR] 0.667), with 90% power at a two-sided significance level of 5%. Results: A total of 538 patients were included for this interim efficacy analysis. Median age was 58 years, men constituted 65%, and stage II and III were 31% and 69%, respectively. Baseline tumor and patient characteristics were balanced between treatment arms. Adverse events were as anticipated in each arm, generally well-tolerated and manageable. DFS in the control arm (S-1) were significantly shorter than in SOX and SOXRT arms (stratified HR for recurrence): S-1 vs. SOX, 0.617 (P = 0.016) and S-1 vs. SOXRT, 0.686 (P = 0.057). The DFS at 3-years was found to be 65%, 78% and 73% in S-1, SOX and SOXRT arms, respectively. No difference in DFS between SOX and SOXRT was found (HR 0.910, P = 0.667). Based on the results after the observation of 145 recurrence events at the cutoff date of Dec 27, 2018, the independent data monitoring committee considered the results sufficient to meet the endpoint of the trial and recommended early stopping of the trial. Conclusions: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared to S-1 monotherapy. Clinical trial information: NCT0176146.
Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) (Alliance A021202).
Authors: Bergsland Emily K. , Mahoney Michelle R. , Asmis Timothy R. , Hall Nathan , Kumthekar Priya , Maitland Michael L. , Niedzwiecki Donna , Nixon Andrew B. , O'Reilly Eileen Mary , Schwartz Lawrence Howard , Strosberg Jonathan R. , Meyerhardt Jeffrey A. 
Published: May 2019

4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) < 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.
Optimizing chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): The GO2 phase III trial.
Authors: Hall Peter S , Swinson Daniel , Waters Justin S. , Wadsley Jonathan , Falk Stephen , Roy Rajarshi , Tillett Tania , Nicoll Jonathan , Cummings Sebastian , Grumett Simon Aird , Kamposioras Konstantinos , Garcia Angel , Allmark Christine , Marshall Helen , Ruddock Sharon , Katona Eszter , Velikova Galina , Petty Russell D. , Grabsch Heike I. , Seymour Matthew T. 
Published: May 2019

4006 Background: Many pts with aGOAC are elderly and/or frail. We previously compared epirubin/ oxaliplatin/ capecitabine (EOCap) vs OCap vs Cap in a pick-the-winner study and found OCap best. GO2 was designed to find the optimum dose of OCap and to explore the use of an objective baseline geriatric assessment to individualize doses for maximum Overall Treatment Utility (OTU), a composite of clinical benefit, tolerability, QL and patient value. Methods: Pts with aGOAC were eligible if unsuitable for full-dose EOCap due to age or frailty, but fit for OCap; GFR ≥ 30, bili <2x ULN. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m2d1, Cap 625 mg/m2bd d1-21, q21d), B (80% Level A doses) or C (60% Level A doses). Pts with GFR 30-50 ml/min or bili 1.5-2.0 xULN received 75% of the allocated dose of Cap. At 9 wks, pts were scored for OTU. Continuation thereafter was based on clinical judgement. Non-inferiority (vs A) was assessed using PFS censored at 12 months, with boundary HR 1.34 (based on discussion with pts and clinicians), needing 284 PFS events per 2-way comparison. Baseline fitness was assessed as predictive of OTU, overall and by interaction with dose level. Results: 514 pts were randomised, 2014-17, at 61 UK centres. Clinical trial information: 44687907. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C pts had less toxicity and better OTU outcomes than A or B. When analysed by baseline age, frailty and PS, Level C produced the best OTU even in younger, less frail and better PS patients; no group was identified who benefit more from the higher dose levels. Conclusions: This is the largest RCT to date specifically investigating frail and/or elderly aGOAC pts, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS and produced less toxicity and better overall treatment utility.[Table: see text]
Efficacy and safety of pembrolizumab (pembro) alone or in combination with chemotherapy (chemo) in patients (pts) with advanced gastric or gastroesophageal (G/GEJ) cancer: Long-term follow up from KEYNOTE-059.
Authors: Wainberg Zev A. , Yoon Harry H. , Catenacci Daniel V.T. , Jalal Shadia Ibrahim , Muro Kei , Garrido Marcelo , Golan Talia , Doi Toshihiko , Geva Ravit , Ku Geoffrey Yuyat , Bleeker Jonathan Scott , Bang Yung-Jue , Hara Hiroki , Chung Hyun Cheol , Wang Jiang Dian , Hazzard Andrea , Shah Sukrut , Fuchs Charles S. 
Published: May 2019

4009 Background: Interim analysis of a global, phase 2 KEYNOTE-059 study (NCT02335411) reported manageable safety and promising antitumor activity for pembro alone or pembro + chemo in pts with G/GEJ cancer. Here we report long-term efficacy and safety data of all cohorts. Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled in 3 cohorts. Cohort 1 pts (PD-L1positive or negative) received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts (PD-L1positive or negative) received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts (PD-L1positive, combined positive score ≥1% using the PD-L1 IHC 22C3 pharmDx assay) received pembro alone as first-line. All pts received pembro 200 mg Q3W for up to 2 years. End points included safety, ORR, DOR, and OS. Results: At data cutoff (Aug 8, 2018), median (range) follow-up was 6 (1-38), 14 (2-40), and 21 (2-36) months for cohorts 1 (n = 259), 2 (n = 25), and 3 (n = 31), respectively. In cohort 1, confirmed ORR (95% CI) was 11.6% (8-16) overall, 15.5% (10-22) in PD-L1positive, and 6.4% (3-13) in PD-L1negative tumors. In cohort 2, confirmed ORR was 60.0% (39-79) overall, 73.3% (45-92) in PD-L1positive, and 37.5% (9-76) in PD-L1negative tumors. In cohort 3, confirmed ORR was 25.8% (12-45). Median (range) DOR in months was 16.1 (2-35+), 4.6 (3-37+), and not reached (2.1-32.5+) in cohorts 1, 2, and 3, respectively. OS at 1 year/2 years was 24.6%/12.5%, 52%/32%, and 63.6%/40.1% in cohorts 1, 2, and 3, respectively. In cohorts 1, 2, and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 20 (80%), and 8 (26%) respectively. TRAEs led to discontinuation in 6 (2%) and 3 (12%) pts in cohorts 1 and 2, respectively, and to death in 2 (1%) pts in cohort 1. No TRAEs led to discontinuation or death in cohort 3. Conclusions: These updated results demonstrate manageable safety, durable clinically meaningful activity of pembro in heavily pretreated pts, and promising efficacy of first-line pembro (alone or + chemo) in pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.
First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma.
Authors: Janjigian Yelena Yuriy , Maron Steven Brad , Chou Joanne F , Gabler Amelia , Simmons Marc , Momtaz Parisa , Sanchez-Vega Francisco , Shcherba Marina , Ku Geoffrey Yuyat , Won Elizabeth , Chong Curtis Robert , Gerdes Hans , Kelsen David Paul , Ilson David H. , Solit David B. , Schultz Nikolaus , Shah Pari M. , Capanu Marinela , Hechtman Jaclyn Frances 
Published: May 2019

4011 Background: Trastuzumab stimulates HER2-specific T cell responses and increases tumor PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. Methods: Patients (pts) with previously untreated HER2 IHC 3+ or FISH+ tumors irrespective of PD-L1 status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kg load), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off. 22 pts received 1 cycle of induction P/T prior to initiation of chemotherapy. The primary endpoint was 6-months PFS; with target accrual of 37 pts. Secondary endpoints included safety, OS, ORR, and biomarker analysis. Results: Accrual completed and 100% of the 32 evaluable pts had tumor regression (ranging from -20% to -100%). The RECIST 1.1 ORR was 87% (25 PR, 3 CRs), and 12 (52%) of pts that received induction P/T x 1 cycle showed reduction in target lesions. Median PFS was 11.3 months (mo), with 67% 6 mo PFS. Median follow up was only 6.6 mo. In pts with available material, 14/36 (40%) had PD-L1 CPS >1 and median TMB was 4.4 mut/Mb (0-10.6). There was no correlation between PD-L1 status and PFS or OS. ERBB2 amplification was evident by tissue-NGS in 17/29 (61%) and ctDNA-NGS in 17/30 (58%) pre-treatment, while the remaining pts were ERBB2- by NGS likely due to tumor heterogeneity or low tumor content. CtDNA maxVAF decreased in 16/24 tested pts after 1 cycle of induction T/P alone. irAEs included interstitial nephritis Gr4 (3%), transaminitis Gr3 (11%), Gr4 (3%), colitis Gr3 (3%). Conclusions: Most pts (51%) remain on therapy, and so the primary endpoint should be reached by 6/19. Updated survival, correlative studies and will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial. Clinical trial information: NCT02954536.
Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.
Authors: Yau Thomas , Kang Yoon-Koo , Kim Tae-You , El-Khoueiry Anthony B. , Santoro Armando , Sangro Bruno , Melero Ignacio , Kudo Masatoshi , Hou Ming-Mo , Matilla Ana , Tovoli Francesco , Knox Jennifer J. , He Aiwu Ruth , El-Rayes Bassel F. , Acosta-Rivera Mirelis , Neely Jaclyn , Shen Yun , Baccan Carlos , Dela Cruz Christine Marie , Hsu Chiun 
Published: May 2019

4012 Background: NIVO monotherapy (mono) is approved for sorafenib (SOR)-treated pts with HCC based on data from CheckMate 040 (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (mOS) of 16 months (mo). This is the first report of efficacy and safety of the NIVO + IPI combination in SOR-treated pts with aHCC. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Cutoff was 25 Sep 2018. Results: 148 SOR-treated pts were randomized. Minimum follow-up for OS from last pt randomization date to data cutoff was 24 mo. At baseline: 88% had vascular invasion or extrahepatic spread, 91% had BCLC stage C, 84% discontinued SOR due to disease progression and 14% due to toxicity. Overall, ORR was 31% (7 had a complete response [CR]) with a median DOR of 17 mo; DCR was 49% and 24-mo OS rate was 40%. Pts in arm A had a mOS of 23 mo and 4 pts had a CR. The table shows additional efficacy results by arm. Overall, NIVO + IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE; most common: pruritus and rash); 5% had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + IPI led to clinically meaningful responses and had an acceptable safety profile in SOR-treated pts, with an ORR twice that of NIVO mono (31% and 14%, respectively). Pts in arm A had the most promising mOS of 23 mo. Clinical trial information: NCT01658878. [Table: see text]
Tumor mutational burden identifies chemorefractory gastric cancer with overall survival advantage after receiving toripalimab, a PD-1 antibody.
Authors: Xu Rui-Hua , Wang Feng , Wei Xiao-Li , Wang Fenghua , Xu Nong , Shen Lin , Dai Guanghai , Yuan Xianglin , Chen Ye , Yang Shujun , Shi Jianhua , Hu Xi-Chun , Lin Xiaoyan , Zhang Qingyuan , Feng Ji Feng , Ba Yi , Liu Yunpeng , Wu Hai , Feng Hui , Yao Sheng 
Published: May 2019

4021 Background: Tumor mutational burden (TMB) is correlated with enhanced objective response rate (ORR) and progression-free survival for certain cancers receiving immunotherapy. This study aimed to investigate the safety and activity of toripalimab, a humanized PD-1 antibody, in advanced gastric cancer (AGC), and the efficacy predictive value of biomarkers including TMB and PD-L1. Methods: This study was a part of phase Ib/II trial evaluating the safety and activity of toripalimab as a single agent therapy or in combination with chemotherapy in chemo-refractory or treatment-naïve AGC, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. This report focused on the chemo-refractory AGC cohort receiving toripalimab (3 mg/Kg d1, Q2W) as a single agent therapy. Primary endpoint was ORR. Biomarkers including tumor PD-L1 expression, TMB, microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection status were evaluated for their correlation with clinical efficacy as preplanned. Tumor PD-L1 expression was assessed with the SP142 immunohistochemistry assay, and the other biomarkers were assessed with whole exome sequencing based on tumor samples. Results: There were 58 subjects included in this cohort. The ORR was 12.1% and the disease control rate was 39.7%. Only 1 subject was MSI-H and achieved partial response. One out of 4 EBV positive subjects achieved partial response. Significant higher ORR was observed in subjects with positive PD-L1 expression (ORR 37.5%, 3/8) or TMB ≥12 Mutations/Mb (ORR 33.3%, 4/8) than those with negative PD-L1 expression (ORR 8.5%) or TMB < 12 Mutations/Mb (ORR 7.0%). The TMB-high subgroup showed significant superior OS than the TMB-low subgroup (HR = 0.48 [96% CI 0.24 to 0.96], p = 0.038), while PD-L1 expression status failed to differentiate OS. Conclusions: Toripalimab demonstrated promising anti-tumor activity in chemo-refractory AGC patients. TMB might serve as a better predictive marker for OS than PD-L1 expression for chemo-refractory AGC patients receiving PD-1 blockade immunotherapy. Clinical trial information: NCT02915432.
Pooled safety analysis from phase 3 studies of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric/gastroesophageal junction cancer (mGC/mGEJC) and metastatic colorectal cancer (mCRC).
Authors: Van Cutsem Eric , Hochster Howard S. , Shitara Kohei , Mayer Robert J. , Ohtsu Atsushi , Falcone Alfredo , Yoshino Takayuki , Doi Toshihiko , Ilson David H. , Arkenau Hendrik-Tobias , George Ben , McGuigan Sandra , Makris Lukas , Tabernero Josep 
Published: May 2019

4039 Background: FTD/TPI was approved in 2015 for pretreated pts with mCRC based on the phase 3 RECOURSE trial. FTD/TPI recently demonstrating significantly improved overall survival vs placebo in pretreated pts with mGC/mGEJC in the phase 3 TAGS trial. Methods: We evaluated the pooled safety of FTD/TPI in TAGS and RECOURSE in all pts who received ≥1 dose of FTD/TPI (safety population). Pts were required to have ECOG PS 0/1 and to have received ≥2 previous chemotherapy lines. Results: FTD/TPI and placebo were administered to 335 and 168 pts, respectively, in TAGS, and 533 and 265 pts in RECOURSE. Baseline characteristics were balanced across treatment groups and reflected the disease populations. In the pooled population, 66% of pts were men and 75% had received ≥3 prior systemic treatments. The safety profile of FTD/TPI was comparable between studies (table). In TAGS and RECOURSE, the most common any-cause grade (gr) ≥3 AEs in FTD/TPI-treated pts were neutropenia (34%; 35%), anemia (19%; 17%), and leukopenia (9%; 13%). Gr ≥3 febrile neutropenia occurred in 2% and 4% of pts and gr ≥3 GI AEs in 21% and 12%. Gr ≥3 cardiac AEs were reported in 1% of FTD/TPI-treated pts (both studies), in contrast to results obtained with other third-line agents. Similar proportions of FTD/TPI-treated pts in both studies had AEs leading to dosing delay, dose reduction, or treatment discontinuation. Dosing delay was used more often than dose reduction to manage AEs. TRAEs leading to death occurred in one FTD/TPI-treated pt ( < 1%) in each trial. Conclusions: In a pooled analysis, FTD/TPI was well tolerated with a consistent safety profile in pts with mGC/mGEJC or mCRC. The most frequent AEs were hematologic and GI, which were managed with dosing delays/dose reductions. Clinical trial information: NCT02500043; NCT01607957. [Table: see text]
Efficacy and safety of sintilimab in combination with XELOX in first-line gastric or gastroesophageal junction carcinoma (GC/GEJC).
Authors: Xu Nong , Shen Lin , Jiang Haiping , Zheng Yulong , Qian Jiong , Mao Chenyu , Zhou Hui , Wang Shuyan 
Published: May 2019

4042 Background: Immune checkpoint inhibitors have shown clinical benefit in advanced GC/GEJC. This phase 1b study evaluates the efficacy and safety of sintilimab, an anti-programmed cell death-1 antibody (PD-1 Ab) in combination with XELOX for GC/GEJC in first-line setting. Methods: This phase 1b study enrolled treatment-naïve unresectable locally advanced or metastatic GC/GEJC patients without HER2 amplification in cohort F. Patients received sintilimab 200mg IV q3w until disease progression, unacceptable toxicity or death, in combination with XELOX regimen (oxaliplatin 130mg/m2 IV D1 and capecitabine 1000mg/m2 PO BID D1-14) for up to 6 cycles. The primary objective was to evaluate the efficacy of the combination per RECIST v1.1 and safety and tolerability. Results: Totally 20 patients were enrolled in cohort F. As data cutoff (15 Jan 2019), median follow up was 5.8 months (range, 2.4 to 12.5). The median dose of sintilimab was 6.5 (range, 4 to 12). The objective response rate (ORR) was 85.0% (95%CI, 62.1 to 96.8) and disease control rate (DCR) was 100.0% (95%CI, 83.2 to 100.0). Among 17 patient with BOR of PR, two patients achieved a complete response (CR) of the target lesion. The median duration of response (DOR) and median progression free survival (PFS) had not been met. Three patients underwent resection of primary tumor after achieving a BOR of partial response (N=2) and stable disease (N=1). The incidence of treatment emergent adverse events (TEAEs) was 85.0%. Treatment-related AEs (TRAEs) occurred in 14 (70.0%) patients. The incidence of TRAE ≥ Grade 3 was 15%. AEs of immune-related etiology, occurred in 6 patients (30.0%). There were no AEs that resulted in death. As data cutoff, 12 patients were still in treatment and 8 had discontinued treatment and were under survival follow up. The biomarker analysis including PD-L1 expression in tumor specimen was ongoing. Conclusions: Sintilimab in combination with XELOX in first-line GC/GEJC shows promising anti-tumor efficacy and a tolerable safety profile. The further randomized, phase 3 study of Sintilimab in combination with XELOX in this setting is ongoing (NCT03745170). Clinical trial information: NCT02937116.