bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant chemotherapy versus perioperative chemotherapy (CTx) for resectable gastric signet ring cell (SRC) gastric cancer: A multicenter, randomized phase II study (PRODIGE 19).
Authors: Eveno Clarisse , Adenis Antoine , Bouche Olivier , Le Malicot Karine , Hautefeuille Vincent , Faroux Roger , Thirot Bidault Anne , Egreteau Joëlle , Meunier Bernard , Mabro May , Carrere Nicolas , Barriere Nicolas , Ben Abdelghani Meher , Mauvais François , Di Fiore Frédéric , Malka David , Manfredi Sylvain , Piessen Guillaume 
Published: May 2019

4019 Background: The incidence of SRC gastric cancers is markedly increasing in Western countries. SRC cancers may harbor intrinsic resistance to chemotherapy (CTx) leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach. The primary objective of this study was to assess whether upfront surgery plus adjuvant CTx would provide enough survival benefit for study in a phase III trial when compared to perioperative CTx. Methods: Patients with stage IB-III SRC gastric cancer were randomly assigned to receive upfront surgery plus adjuvant CTx (epirubicin, cisplatin and 5-fluorouracil [ECF regimen], 6 cycles; experimental arm [SurgFirst]) or perioperative CTx (ECF, 3 cycles before and 3 cycles after surgery; control arm [CTxFirst]). Randomization (1:1) was stratified by tumor stage, tumor location, performance status and center. The primary endpoint was overall survival (OS) at 2 years (OS2; target (H1): OS2 > 26%). Results: 83 eligible patients were included in 27 centers from 11/12 to 09/16 (median age, 61 years (range: 32-80 years); male, 59%; ECOG PS 0-1, 99%). Results were (CTxFirst/SurgFirst): full completion of CTx, 87%/77%; surgical resection, 82.5%/90%; major postoperative complications (Clavien Dindo III-IV), 24%/23%; R0 resection rate, 88%/78%; OS2, 60%/53.5%; and median OS, 39/28 months (exploratory hazard ratio, 0.71 [95%CI: 0.40-2.64]). Conclusions: This trial met its primary endpoint (OS2 > 26% in the experimental arm). With OS2 rates > 50%, both CTx modalities deserve further evaluation in Phase III studies in stage IB-III SRC gastric cancer. Clinical trial information: NCT01717924.
Association of frequent amplification of chromosome 11q13 in esophageal squamous cell cancer with clinical benefit to immune check point blockade.
Authors: Wang Feng , Ren Chao , Zhao Qi , Xu Nong , Shen Lin , Dai Guanghai , Yuan Xianglin , Chen Ye , Yang Shujun , Shi Jianhua , Hu Xichun , Lin Xiaoyan , Zhang Qingyuan , Feng Jifeng , Ba Yi , Liu Yunpeng , Li Wei , Shu Yongqian , Wang Fenghua , Xu Rui-hua ,   Shanghai Junshi Biosciences Co., LTD
Published: May 2019

4036 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in South America and East Asian countries and remains an unmet medical need worldwide. Previous studies have shown the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic ESCC. However, robust predictive biomarkers to PD-1 antibody-based immunotherapy remain undefined. Methods: Patients included in this analysis were part of multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in solid tumors. To identify molecular determinants of response, we performed whole exome sequencing (WES), messenger RNA sequencing and immunohistochemistry on patients’ samples and evaluated genomic and transcriptional biomarkers, PD-L1 expression and tumor mutational burden (TMB) for correlation with clinical efficacy. Results: Sixty advanced chemo-refractory ESCC patients were enrolled and 59 were treated with toripalimab. 94.9% (56/59) patients experienced at least one treatment related adverse event after 16 months; mostly grade 1 or grade 2. Treatment-related grade 3 or higher AEs occurred in 30.5% (18/59) of subjects. By the data cutoff date, 11 (18.6%; 95%CI 9.7 to 30.9) patients achieved an objective response, while the disease control rate was 47.5% (95%CI 34.3 to 60.9). Copy number analysis identified 24 out of 50 (48%) patients with amplifications of chromosome 11q13 region, which was consistent with elevated mRNA expression of amplified genes, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Patients without 11q13 amplification, had significantly better objective response rate (ORR 30.8% versus 4.2%, p= 0.024) and progression free survival (3.7 versus 2.0 months, HR = 0.47 [95%CI 0.24 to 0.91], p= 0.025) when compared with 11q13 amplified individuals. In contrast, patients with high TMB (≥12 Mutations/Mb; 11/47, 23.4%) or positive PD-L1 expression (TC or IC 1%; 19/57, 33.3%) showed no significant advantage in ORR or survival. Conclusions: Toripalimab has demonstrated a manageablesafety profile and promising anti-tumor activity in chemo-refractory ESSC patients. Genomic amplification of 11q13 region may serve as a negative predictive marker for advanced ESSC patients receiving anti-PD-1 based immunotherapy. Further interrogation of putative resistance genes that lie within this region is under study. Clinical trial information: NCT02915432.
Safety of neoadjuvant chemoradiation (CRT) in combination with avelumab (A) in the treatment of resectable esophageal and gastroesophageal junction (E/GEJ) cancer.
Authors: Uboha Nataliya Volodymyrivna , Maloney James D. , McCarthy Daniel , Deming Dustin A. , LoConte Noelle K. , Matkowskyj Kristina , Eickhoff Jens C. , Emmerich Philip , DeCamp Malcolm M. , Lubner Sam Joseph , Turk Anita Ahmed , Bassetti Michael Frederick 
Published: May 2019

4041 Background: Neoadjuvant CRT followed by surgery is the standard of care (SOC) for patients (pts) with stage II/III E/GEJ cancer. However, recurrence rates are high. Immunotherapy has demonstrated promising activity in advanced E/GEJ cancer. This trial evaluates safety and efficacy of perioperative A with CRT in resectable E/GEJ cancer. Methods: This is a 2-part phase I/II trial. Part 1 is a run-in phase with 6 pts for safety evaluation. Part 2 will enroll additional 18 pts in the expansion cohort. Pts with E/GEJ cancer of any histology receive CRT (41.4 Gy in 23 fractions) with carboplatin and paclitaxel as per SOC. Three doses of A (10 mg/kg, q14 days) are administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Surgery is performed ~8 weeks after CRT completion. Pts receive 6 doses of A after resection. Dose-limiting toxicity (DLT) evaluations are completed on the first post-operative clinic visit, 2-4 weeks post resection. Results: Between 6/2018 and 2/2019, 6 pts (all male, median age 62) enrolled in part 1: 6 adenocarcinoma (100%); 1 E, 3 Siewert 1, 2 Siewert 2; 1 cT2N0, 2 cT3N0, 3 cT3N1. All pts underwent successful resection with negative surgical margins. 1/6 pts had R1 resection due to tumor extension to inked adventitial surface without invasion of surrounding structures. There were no unexpected surgical complications. At resection, 2 pts had ypT0N0, 2 ypT1N0, 1 ypT2N0, and 1 ypT3N1 disease. Combination of CRT and A had an acceptable toxicity profile. No DLTs were seen in the first 5 pts, so expansion cohort is open to enrollment. No grade ≥3 immune-related AEs were observed. Immune-related hypothyroidism was seen in 1 patient (grade 2). 6/6 pts had reversible grade 3 or 4 lymphopenia; 1/6 had grade 3 neutropenia. Correlative studies are ongoing and will be presented at the meeting. Conclusions: Perioperative CRT with A is well tolerated with no unexpected toxicities. Additional safety and correlative data will be presented at the meeting. This study is actively enrolling pts to an expansion cohort at University of Wisconsin. Clinical trial information: NCT03490292.
Perioperative (P) UGT1A1 genotype guided irinotecan (iri) dosing ‘gFOLFIRINOX’ for gastroesophageal adenocarcinoma (GEA).
Authors: Catenacci Daniel V.T. , Chase Leah , Lomnicki Samantha , Karrison Theodore , Marsh Robert de Wilton , Rampurwala Murtuza M. , Narula Sunil , Alpert Lindsay , Setia Namrata , Xiao Shu-Yuan , Hart John , Siddiqui Uzma , Liao Chih-Yi , Polite Blase N. , Kindler Hedy L. , Turaga Kiran , Prachand Vivek N. , Roggin Kevin K. , Ferguson Mark K. , Posner Mitchell C. 
Published: May 2019

4050 Background: Complete resection (R0) and pathologic response grade (PRG) correlate with long-term GEA outcome. FOLFIRINOX demonstrated efficacy in advanced GEA; gFOLFIRINOX improved tolerability. We evaluated R0, PRG and tolerability in this pilot P study. Methods: Gastric body (GB) + esophagogastric (EGJ) GEA patients (pts) with ≥T3Nx or TxN+ were enrolled & treated with 4 pre + 4 postoperative biweekly cycles of gFOLFIRINOX (5-FU 2400mg/m2 over 46 hrs; oxaliplatin 85mg/m2; iri: 180mg/m2 for UGT1A1 genotype 6/6, 135mg/m2 for 6/7, 90mg/m2 for 7/7) (+ trastuzumab (T) 6mg/kg then 4mg/kg for HER2+) with prophylactic peg-filgastrim. 1°endpoint R0 resection required 36 pts to assess for a 90% R0 rate (intention to treat (ITT)) with 90% power + 0.05 alpha; ≥30/36 R0 considered positive. Co-1°endpoint was PRG (Becker); 36 pts provided 85% power with 0.05 alpha for a complete (pCR G1a) rate of 16%. 2°endpoints were safety/toxicity, PET response, & R0/PRG by tumor site, histologic subtype, HER2 status, & UGT1A1 genotype. We report efficacy and toxicity data from the neoadjuvant (Neo) portion of the study; postop data & survival outcomes will be presented at the meeting. Results: 4 sites enrolled 36 ITT pts between 2/2014-8/2018; 75% male, median age 66 (range 27-85). All pts completed all 4 cycles of Neo therapy: 10% had any dose reduction of iri (16%/0%/25% by genotype 6/6, 6/7, 7/7); any G3+ toxicity occurred in 35% of pts (32% 6/6, 29% 6/7, 75% 7/7). G3+ toxicity in ≥5% of pts: diarrhea (17.5%; 6/6 21%, 6/7 11%, 7/7 25%), anemia (5%), vomiting (5%). Efficacy is shown in the Table. Of pts going to surgery, both R1 resections were GB linitus. PRG1(a+b) was achieved in 36% of ITT pts, 46% of intestinal type histology. Conclusions: Neo gFOLFIRINOX was tolerable with surrogate efficacy comparable to FLOT. Clinical trial information: NCT02366819. [Table: see text]
The quality of life in neoadjuvant versus adjuvant therapy of esophageal cancer treatment trial (QUINTETT).
Authors: Malthaner Richard , Yu Edward , Sanatani Michael Susmoy , Lewis Debra , Warner Andrew , Dar A. Rashid , Yaremko Brian P , Bierer Joel , Palma David A. , Rodrigues George , Fortin Dalilah , Inculet Richard , Frechette Eric , Raphael Jacques , Gaede Steward , Kuruvilla Sarah , Younus Jawaid , Vincent Mark David 
Published: May 2019

4052 Background: We compared the health-related quality-of-life (HRQOL) of standard neoadjuvant cisplatin and 5-FU chemotherapy plus radiotherapy (N) followed by surgical resection to adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy (A) following surgical resection for resectable esophageal carcinoma. Methods: 96 patients with stage I to III resectable cancer of the esophagus were enrolled into a prospective randomized trial (NCT00907543) from April 2009 to November 2016. Patients were randomized into 2 groups: N (47 cases) and A (49 cases). The primary end point was HRQOL using the FACT-E at one year. The secondary endpoints included other HRQOL measures, overall survival (OS), disease-free survival (DFS), and adverse events. Results: The median follow-up was 5.0 years [95% CI :4.6 to 5.5]. The majority of patients had adenocarcinomas of the distal esophagus/gastroesophageal junction (80.9% vs 87.8%). The stage distribution was: I 9%; II 22%; III 58%; TxN0-1 10%. Using an intention-to-treat analysis there was no significant difference in the FACT-E total scores between arms at one year (p = 0.759), with 35.5% vs. 41.2% respectively showing an increase of ≥ 15 points ( a priori minimal clinical difference) compared to pre-treatment (p = 0.638). The HRQOL was temporarily significantly inferior at 2 months in the N arm for FACT-E, EORTC OG25, and EQ-5D-3L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). There were no 30-day mortalities but 2.1% vs. 10.2% 90-day mortalities (p = 0.204). There were no significant differences in either 5-year OS (37.9% vs 28.9%, p = 0.321) or DFS (34.0% vs 25.5%, p = 0.551. 48.9% of patients required chemotherapy to be modified or stopped in the N arm compared to 57.1% in the A arm (p = 0.421). 51.1% of patients were able to complete the prescribed N arm chemotherapy without modification compared to only 14.3% in the A arm (p < 0.001). Chemotherapy related adverse events significantly more frequent in the neoadjuvant arm (p < 0.05). Surgery related adverse events were significantly more frequent in the neoadjuvant arm (p < 0.05). Conclusions: Trimodality therapy is challenging for patients with resectable esophageal cancer regardless if it is given before or after surgery. Less toxic protocols are needed. Clinical trial information: 00907543.
Safety results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma (ESO-Shanghai 2).
Authors: Ai Dashan , Chen Yun , Liu Qi , Zheng Xiangpeng , Li Yunhai , Wei Shihong , Ye Jinjun , Zhou Jialiang , Lin Qin , Luo Hui , Cao Jianzhong , Li Jiancheng , Huang Guang , Wu Kailiang , Fan Min , Yang Huanjun , Zhu Zhengfei , Zhao Weixin , Li Ling , Zhao Kuaile 
Published: May 2019

4055 Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC) . Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m2/d, d1-3, PTX 175 mg/m2, d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m2, civ 96h, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m2, civ 72h, PTX 175 mg/m2, d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. TP group had a significant higher incidence of acute grade 3/4 neutropenia (59.7% vs. 16.8%(TF) or 32.4%(TC)), thrombocytopenia (12.7% vs. 3.5%(TF) or 6.2%(TC)), anemia (6.4% vs. 4.4%(TF) or 4.4%(TC)), fatigue (10.0% vs. 0.9%(TF) or 0.9%(TC)) and vomiting (5.5% vs. 0%(TF) or 0.9%(TC)) than other two groups ( P < 0.05). TF group had a significant higher incidence of grade 3/4/5 esophagitis (13.1% vs. 1.8%(TP) or 5.3%(TC)) and pneumonitis (4.4% vs. 0%(TP) or 1.8%(TC)) than other two groups ( P < 0.05). One patient in TF group died of acute pneumonitis. One patient in TF group and one in TC group died of acute esophagitis. Conclusions: TP and TF regimen showed different severe AEs in CCR in ESCC patients and TC showed mild AEs. Clinical trial information: NCT02459457.
Landscape of innate and adaptive immunity targets in oesophagogastric adenocarcinoma (OGA).
Authors: Smyth Elizabeth Catherine , Linossi Constanza , Jammula Sriganesh , Devonshire Ginny , Fitzgerald Rebecca C. 
Published: May 2019

4063 Background: Anti-PD-1 therapy modestly improves survival in chemorefractory OGA. Combining PD-1 blockade with novel checkpoint inhibitors, T-cell co-stimulatory molecules, or myeloid suppressors could enhance PD-1 inhibition. Herein, we explore the landscape of known targetable immune markers in non-Asian OGA. Methods: OGA patient biopsies were prospectively collected and clinically annotated from 19 UK cancer centres (Oesophageal Cancer Clinical and Molecular Stratification – OCCAMs network). Genomic (WGS) and transcriptomic (bulk-RNA seq) data were generated using Illumina and processed using a validated in-house pipeline (Frankell, Nat Genetics 2019). Gene expression was computed in transcripts per kilobase. Using unsupervised clustering patient clusters were selected according to the expression of gene targets for immune therapy - PD-L1, LAG3, TIM3, TIGIT, ICOS, CCR2, CCR5, CXCR4, and CSF1R. Immune cell infiltration was extrapolated using GSVA gene set enrichment analysis. Results: RNAseq data were available for 251 patients; 96% had operable tumours (Stage I: 6%, II: 63%, III: 22%, IV: 4%). In untreated patients (n = 156) 3 subgroups were identified: immune low (83, 53%) with low level expression of all 9 markers, immune high (14, 9%) with high expression of all or majority of markers and intermediate (59, 38%) with heterogenous marker expression. Clinicopathological variables (sex, age, smoking, tumour location (gastric/GEJ/esophagus) and tumour regression grade) were similarly distributed across subgroups. In a cohort of 114 patients with matched WGS and RNAseq data tumour mutation burden was not different between subgroups. In post-chemotherapy biopsies (n = 95) a similar co-expression pattern was observed. Gene enrichment analysis supported infiltration by cells of innate and adaptive immune system in immune high patients. Neoantigen results, phenotypic immunohistochemistry and optimised survival outcomes according to lymphoid and myeloid target expression will be presented. Conclusions: High level co-expression of immune regulatory targets in OGA patients may limit the efficacy of anti-PD-1 monotherapy. Combination immune directed therapies may be required in this patient group.
Comprehensive molecular characterization of clinical response in ramucirumab-treated gastric cancer patients: Phase II trial with integrated genomic profiling.
Authors: Kim Seung , Oh Sung Yong , Park Se Hoon , Kim Kyung , Park Joon Oh , Park Young Suk , Kang Won Ki , Lee Jeeyun 
Published: May 2019

4064 Background: The absence of tumor cells enables an enriched stromal environment to generate RNA signatures and through assembling genes involved in tumor stroma, four distinct stromal signatures that reflected biological processes such as signature vascular mature (VM), vascular mature/inflammatory (VMI), vascular immature/noninflammatory (VINI) and inflammatory alone (I) depending on mature of vasculature. We hypothesized that these stromal specific signatures may provide additional information to the pre-existing TCGA/ACRG subtypes when predicting response to anti-angiogenesis agent such as ramucirumab. Methods: We conducted a single-center phase II trial in which we treated 61 unselected patients with metastatic GC with ramucirumab plus paclitaxel as second line therapy and performed pre-planned integrated genomic profiling. Results: Sixty-two patients were enrolled in this study between May 2014 and June 2017. The cut-off date for treatment outcome analysis was January 2, 2019, at which time response evaluations were available for 57 patients with a median follow-up of 30.2months. In an intent-to-treat analysis cohort, there was no CR and 22 patients achieved confirmed PRs resulting in an ORR of 35.5% (95% CI: 23.6 – 47.4). The response rate to ramucirumab was considerably enriched in VM/VMI group (29.2%) (P = 0.0003) when compared to I ( < 10%) or VINI group ( < 10%). The strongest response defined by maximal response to ramucirumab was shown in GC patients with VM/VMI signatures. Of note, VM/VMI patients had prolonged duration of response to ramucirumab/paclitaxel demonstrating that these patients not only respond to ramucirumab but also had durable response. Conclusions: This is the first study to demonstrate a clinically robust correlation between stromal-based signature and response to anti-angiogenesis inhibitor in GC. Clinical trial information: 02628951.
Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies.
Authors: Bang Yung-Jue , Ueno Makoto , Malka David , Chung Hyun Cheol , Nagrial Adnan , Kelley Robin Kate , Piha-Paul Sarina Anne , Ros Willeke , Italiano Antoine , Nakagawa Kazuhiko , Rugo Hope S. , De Braud Filippo G. , Varga Andrea I. , Hansen Aaron Richard , Gao Chao , Krishnan Suba , Norwood Kevin , Doi Toshihiko 
Published: May 2019

4079 Background: Antitumor activity with pembro, an anti–PD-1 antibody, has been observed in patients (pts) with advanced/metastatic biliary tract cancers (BTC), who have limited treatment options. We present follow-up data from pts with advanced BTC treated with pembro in the KN158 (NCT02628067; phase 2) and KN028 (NCT02054806; phase 1) studies. Methods: Eligible pts ≥18 y in the KN158/KN028 BTC cohorts had histologically/cytologically confirmed incurable advanced BTC that progressed after/failed any number of prior standard treatment regimens, measurable disease per RECIST v1.1, ECOG PS of 0/1, and no prior immunotherapy. PD-L1–positivity (membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma) was required for eligibility in KN028, but not KN158. Pts received pembro 200 mg Q3W (KN158) or 10 mg/kg Q2W (KN028) for up to 2 y. Radiographic imaging occurred Q9W for 12 mo (KN158) or Q8W for 6 mo (KN028) and Q12W thereafter. Primary efficacy endpoint in both studies was ORR by RECIST 1.1. Response assessed by independent central review is reported. Results: Median (range) follow-up was 7.5 (0.6–29.5) mo in the 104 pts from KN158 and 6.5 (0.6–33.1) mo in the 24 pts from KN028 with BTC. All pts in KN028 and 61 in KN158 had PD-L1–positive tumors. No pt had MSI-H tumors (not assessed in KN028). In KN158, ORR was 5.8% (6/104, all PR [including 1 pt with PD-L1–negative tumor]; 95% CI, 2.1%–12.1%) and median duration of response (DOR) was not reached (NR; range, 6.2 to 23.2+ mo). Median OS and PFS were 7.4 mo (95% CI, 5.5–9.6) and 2.0 mo (95% CI, 1.9–2.1). 12-mo OS rate was 32.7%. In KN028, ORR was 13.0% (3/23, all PR; 95% CI, 2.8%‒33.6%) and median DOR was NR (range, 21.5 to 29.4+ mo). Median OS and PFS were 6.2 mo (95% CI, 3.8‒10.3) and 1.8 mo (95% CI, 1.4‒3.7), respectively. 12-mo OS rate was 27.6%. Grade 3–5 treatment-related AEs occurred in 13.5% in KN158 (1 pt had grade 5 renal failure) and 16.7% of pts in KN028 (no grade 5). 18.3% in KN158 and 20.8% of pts in KN028 had an immune-mediated AE or infusion reaction. Conclusions: Pembro provides durable antitumor activity, regardless of PD-L1 expression, and manageable toxicity in a subset of pts with advanced BTC. Clinical trial information: NCT02054806 and NCT02628067.