bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC).
Authors: Finn Richard S. , Ryoo Baek-Yeol , Merle Philippe , Kudo Masatoshi , Bouattour Mohamed , Lim Ho-Yeong , Breder Valeriy Vladimirovich , Edeline Julien , Chao Yee , Ogasawara Sadahisa , Yau Thomas , Garrido Marcelo , Chan Stephen Lam , Knox Jennifer J. , Daniele Bruno , Ebbinghaus Scot , Chen Erluo , Siegel Abby B. , Zhu Andrew X. , Cheng Ann-Lii ,   for the KEYNOTE-240 Investigators
Published: May 2019

4004 Background: Pembro received accelerated approval based on results of KEYNOTE-224, a phase 2 trial in pts with advanced HCC in the second line setting. KEYNOTE-240 (NCT02702401) was a randomized, placebo (Pbo) controlled, phase 3 study of Pembro vs BSC in pts with previously treated advanced HCC. Methods: Eligible pts had a radiographic or pathologic diagnosis of HCC, radiographic progression on/intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to receive Pembro 200 mg + BSC or Pbo + BSC IV every 3 wk, stratified by geographic region, macrovascular invasion and ɑ-fetoprotein levels for ≤35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 wk per RECIST v1.1 by central imaging review. Co-primary endpoints were OS and PFS. Secondary endpoints included ORR, DOR and safety. Data cutoff was Jan 2 2019 for OS; Mar 26 2018 for PFS and ORR. Results: 413 patients were randomized; 278 to Pembro and 135 to Pbo. After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro and 3.0% on Pbo. Pembro improved OS (HR: 0.78; one sided p = 0.0238) and PFS (HR: 0.78; one sided p = 0.0209) vs Pbo; these differences did not meet significance per the prespecified statistical plan. ORR was 16.9% (95% CI 12.7-21.8%) for Pembro vs 2.2% (95% CI 0.5-6.4%) for Pbo (nominal one sided p = 0.00001); responses on Pembro were durable (median DOR: 13.8 mo [1.5-23.6+]). Off study, new therapy use was 42% for Pembro and 47% for Pbo. The safety profile including incidence of hepatitis and other immune mediated events was generally consistent with that previously reported in Pembro studies; no cases of HBV/HCV flare were identified. Conclusions: Pembro reduced the risk of death by 22% and improved PFS over Pbo in pts with advanced HCC, although significance was not reached per prespecified statistical criteria. ORR in the Pembro arm was consistent with that of KEYNOTE-224. Subsequent anticancer therapy in the Pbo arm likely impacted the OS results. The safety profile was comparable to that established for Pembro monotherapy. These results are overall consistent with those of KEYNOTE-224 further supporting second line therapy with Pembro in HCC pts. Clinical trial information: NCT02702401.
Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase 3 KEYNOTE-181 study.
Authors: Shah Manish A. , Adenis Antoine , Enzinger Peter C. , Kojima Takashi , Muro Kei , Bennouna Jaafar , Francois Eric , Hsu Chih-Hung , Moriwaki Toshikazu , Kim Sung-Bae , Lee Se-Hoon , Kato Ken , Shen Lin , Qin Shukui , Ferreira Paula , Wang Ruixue , Bhagia Pooja , Kang S. Peter , Metges Jean-Philippe , Doi Toshihiko 
Published: May 2019

4010 Background: The phase 3 KEYNOTE-181 study compared pembrolizumab (pembro) vs chemo as second-line therapy for patients (pts) with advanced/metastatic squamous cell carcinoma (SCC) and adenocarcinoma (ACC) of the esophagus (NCT02564263). Methods: Eligible pts were randomized 1:1 to pembro 200 mg Q3W for up to 2 years or choice of paclitaxel, docetaxel, or irinotecan. Randomization was stratified by histology (SCC vs adenocarcinoma) and region (Asia vs rest of world). Primary end points were OS in the SCC, PD-L1 combined positive score (CPS) ≥10, and the ITT. Secondary endpoints included PFS, ORR, safety; exploratory endpoints included health-related quality of life (HRQoL) in CPS ≥10. Results: 628 pts were randomized (401 with SCC; 222 with CPS ≥10). As of Oct. 15, 2018, median follow-up was 7.1 mo (pembro) vs 6.9 mo (chemo). In CPS ≥10, OS was superior with pembro vs chemo (median 9.3 vs 6.7 mo; HR 0.69; 95% CI 0.52-0.93; P= 0.0074). In CPS ≥10 SCC, median OS was 10.3 mo vs 6.7 mo and in CPS ≥10 ACC, median OS was 6.3 mo vs 6.9 mo; 12-mo OS rates were higher with pembro vs chemo (Table). In SCC, median OS was 8.2 mo vs 7.1 mo; HR 0.78; 95% CI 0.63-0.96; P= 0.0095. In the ITT, median OS was 7.1 mo vs 7.1 mo; HR 0.89; 95% CI 0.75-1.05; P= 0.0560. Updated OS will be presented. Grade 3-5 drug-related AEs (≥10% incidence in either arm) included decreased white blood cells (0% vs 10%), decreased neutrophils (0.3% vs 10%). In CPS ≥10, HRQoL improved with pembro vs chemo only for EQ-5D VAS (difference in LS mean change from baseline 5.57; 95% CI 0.58-10.56). Conclusions: Pembro significantly improved OS vs chemo as second-line therapy for advanced esophageal cancer with PD-L1 CPS ≥10, with a more favorable safety profile and stable and similar QOL. These data support pembro as a new second-line standard of care for esophageal cancer with PD-L1 CPS ≥10. Clinical trial information: NCT02564263. [Table: see text]
Impact of age and sex on chemotherapy (CTx) efficacy, toxicity and survival in early oesophagogastric (OG) cancer: A pooled analysis of 3265 patients from four large randomised trials (OE02, OE05, MAGIC & ST03).
Authors: Athauda Avani , Nankivell Matthew Guy , Langley Ruth E , Alderson Derek , Allum William H. , Grabsch Heike I , Chau Ian , Starling Naureen , Falk Stephen , Crellin Adrian , Mansoor Wasat , Coxon Fareeda , Darby Suzanne , Thompson Joyce , Cummins Sebastian J. , Beaumont Erica , West Nicholas , Langer Rupert , Pritchard Susan , Cunningham David 
Published: May 2019

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts <70 and ≥70 years and between males and females. Pts were allocated to receive neoadjuvant platinum and fluoropyrimidine +/- anthracycline and bevacizumab. Mandard tumour regression grade (TRG) and prevalence of ≥G3 toxicities were compared according to the same subgroups using Chi-squared test. Results: 3265 pts were included for survival analysis (2668 (82%) M, 597 (18%) F; 2626 (80%) <70, 639 (20%) ≥70). A significant improvement in disease specific survival (DSS) (HR 0.78; p<0.001) and OS (HR 0.78; p<0.001) was observed in females vs males. Although OS was worse in older vs younger pts (HR 1.15; p=0.01) no significant difference in DSS was observed (HR 1.04; p=0.52). For those pts who underwent resection following neoadjuvant CTx, older patients (19 vs 13%; p=0.01) and female patients (19% vs 13%, p=0.02) were more likely to achieve more favourable Mandard TRG 1&2 scores. Older pts experienced significantly more ≥G3 neutropaenia (30 vs 22%; p=0.004). Females experienced significantly more ≥G3 nausea (12 vs 7%; p=0.006), vomiting (10 vs 5%; p≤0.001) and diarrhoea (9 vs 4%; p=0.001). Conclusions: This study represents the largest pooled analysis of age and sex differences on safety of neoadjuvant CTx and survival in early OG cancer. Females had significantly improved survival while experiencing more GI toxicities. Older pts achieved comparable DSS and thus, dependent on fitness, should be offered the same treatment paradigm as younger pts.
Tumor mutation burden and immunogenicity in gastric cancer with HER2 alterations.
Authors: Wei Bo , Xing Xiaojing , Li Ziyu , Han Quanli , Hao Yingxue , Zhou Jing , Zhang Yuzi , Zhao Jing , Cai Shangli , Gu Yanhong , Chen Tufeng 
Published: May 2019

4024 Background: Human epidermal growth receptor 2 (HER2) is considered as an oncogenic driver gene in gastric cancer (GC). Immunotherapy has been proven to be effective in GC patients. Previous studies indicated that patients harboring driver mutations were considered as poor candidate for immunotherapy. But the efficacy of immunotherapy for HER2 positive GC has not been defined. We therefore analyzed the immunogenicity of HER2 alterations in GC. Methods: Genomic profiling of DNA from 448 GC was performed using next-generation sequencing on 381 cancer associated genes. The expression of PD-L1 protein was evaluated in 192 GC with the use of an automated immunohistochemical assay (Ventana, SP263). Whole-exome sequencing, copy number variations, RNA-seq and clinical data of 443 GC from The Cancer Genome Altas (TCGA) were also analyzed to further evaluate the immunogenicity of HER2 alterations. TMB was defined as number of somatic non-synonymous mutations in coding regions. HER2 amplification in TCGA was defined as “2” derived from the copy-number analysis algorithms GISTIC. Results: HER2 alterations including amplification, missense and fusion were present in 19.2% (85/443) of TCGA cohort and 11.4% (51/448) of clinical cohort. 14.0% (62/443) of TCGA cohort and 6.0% (27/448) of clinical cohort harbored HER2 amplification. Higher TMB was observed in MSS/MSI-L patients carrying any HER2 alterations in TCGA cohort (P = 0.009). On the contrary, HER2 alterations did not show a higher neoantigen level and HER2 alterations were associated with decreased immunogenicity in terms of immune-related gene mRNA expression and immune infiltrates. In clinical cohort, HER2 alterations was also significantly associated with higher TMB (P = 0.001). Meanwhile, a trend of shrinking proportion of PD-L1 expression was observed in HER2 alteration subgroup (2/23, 8.7%) than HER2 wild-type subgroup (47/169, 27.8%, P = 0.071). Furthermore, HER2 amplification had significant positive associations with HRD score (P = 0.0169) in TCGA cohort which indicated an increased degree of genome instability. Conclusions: Although HER2 alterations in GC were associated with increased TMB, HER2 alterations exhibited poor immunogenicity. These findings indicated that HER2 alterations might confer resistance to immune monotherapy.
A phase II study of S-1, oxaliplatin, and nab-paclitaxel, and itraconazole aimed at conversion surgery for advanced and recurrent gastric cancer.
Authors: Nakamoto Yoshihiko , Tsubamoto Hiroshi , Sawazaki Miyuki , Kakuno Ayako , Sonoda Takashi 
Published: May 2019

4026 Background: Preclinical and clinical studies demonstrated that itraconazole, a common anti-fungal agent, has anticancer activity. The purpose of this study was to evaluate the efficacy of the chemotherapy with itraconazole on unresectable, metastatic, and recurrent gastric cancer. Methods: All patients were referred to our clinic with a clinical diagnosis of unresectable gastric cancer. The regimen consisted of 160 mg/m2 nab-paclitaxel IV on day 1, 100 mg/m2 oxaliplatin IV on day 1, 60 mg/m2 S-1 orally on days 1-7, and 400mg itraconazole orally on days -1 to 3, repeated every 3 weeks. Conversion surgery was allowed. The primary endpoint was overall survival (OS). Results: Between 2015 and 2018. 23 patients were enrolled. Their median age was 68 years (range 40-80 years); stomach/gastroesophageal junction: 21/2; Stage IIIA/IIIB/IV: 2/1/20. Among 10 patients who had liver metastases, 2 had simultaneous lung metastases. Nine patients had peritoneal dissemination. Five patients with stage IV had recurrent disease after primary surgery followed by adjuvant S-1. The other 18 patients had no history of surgery or chemotherapy. Response rate was 70% (CR/PR: 2/14). Among 12 patients (67%) who had conversion surgery, R0 resection was conducted in 8 and no residual tumor was observed in 2. Among enrolled 23 patients, median OS was 22 months (95%CI: > 12 months) and 1-year OS rate was 81.8% (95%CI: 46.7%―95.5%). Grade 3/4 neutropenia in 5 (22%), no grade 3/4 thorombocytopenia, grade 2 peripheral sensory neuropathy in 6 (26%). Conclusions: The addition of itraconazole to chemotherapy showed promising efficacy with high conversion surgery rate and with acceptable toxicities. Clinical trial information: UMIN000021340.
Pembrolizumab in previously treated metastatic esophageal cancer: Longer term follow-up from the phase 2 KEYNOTE-180 Study.
Authors: Kato Ken , Kojima Takashi , Hochhauser Daniel , Bennouna Jaafar , Hollebecque Antoine , Lordick Florian , Kim Sung-Bae , Tajika Masahiro , Kim Heung Tae , Park Haeseong , Saba Nabil F. , Urba Susan , Desai Anjali , Liu Qi , Cruz Sandra , Shah Manish A. 
Published: May 2019

4032 Background: In the phase 2, open-label, KEYNOTE-180 (NCT02559687) study, after a median follow-up of 5.8 months, pembrolizumab (pembro) provided antitumor activity with durable responses in pts with previously treated, advanced/metastatic adenocarcinoma (EAC) including Siewert type 1 adenocarcinoma of the gastroesophageal junction or squamous cell carcinoma (ESCC) of the esophagus. Here we present results of an additional 10 months of follow-up. Methods: Eligible pts with metastatic esophageal cancer, ≥2 prior lines of therapy, and tumor samples evaluable for biomarker expression, received pembro 200 mg Q3W for up to 2 years, or until disease progression, unacceptable toxicity, or withdrawal. Tumor response was assessed Q9W (RECISTv1.1, central review). PD-L1+ pts had combined positive score ≥10 using IHC (22C3 antibody). Primary endpoint was objective response rate (ORR). Secondary endpoints included safety, DOR, PFS, and OS. Results: Of 121 pts enrolled, 63 (52%) had ESCC and 58 (48%) had PD-L1+ (combined positive score ≥10) tumors. As of July 30, 2018, median follow-up duration, from randomization to data cutoff, was 5.8 mo (range, 0.2 mo to 27.8+ mo). ORR (CR+PR) was 10% (95% CI, 5%-17%); 2 (2%) CR,10 (8%) PR, 25 (21%) SD. Median DOR was not reached ([NR] range, 2.1 mo to 25.1+ mo). Median PFS was 2 mo (95% CI, 1.9%-2.1%) with 9-mo PFS rate of 9%. Median OS was 5.8 mo (4.5-7.2) with 12 mo OS rate of 27%. In ESCC, ORR was 14% (95% CI, 7%-25%); 2 (3%) CR, 7 (11%) PR, with median DOR NR (range, 4.2 mo to 25.1+ mo). In EAC, ORR was 5% (95% CI, 1-14); 3 PR, with median DOR NR (range, 2.1 mo to 15.6+ mo). In PD-L1+ pts, ORR was 14% (95% CI, 6%-25%); 1 (2%) CR, 7 (12%) PR with median DOR NR (range, 4.2 mo to 25.1+ mo). In PD-L1- pts ORR was 6% (95% CI, 2%-16%); 1 (2%) CR, 3 (5%) PR; median DOR NR (range, 2.1 mo to 17.3+ mo). Overall, 19 (16%) pts had treatment-related grade 3-5 AEs. Seven (6%) pts discontinued due to a treatment-related AE. There was one treatment-related death from pneumonitis. Conclusions: Pembro continued to provide durable clinical benefit with a manageable safety profile for pts with heavily pretreated esophageal cancer, with conversions of PR to CR observed. Clinical trial information: NCT02559687.
Trifluridine/tipiracil (FTD/TPI) in patients (pts) aged ≥65 years with metastatic gastric/gastroesophageal junction cancer (mGC/mGEJC): Subgroup analysis from TAGS.
Authors: Shitara Kohei , Doi Toshihiko , Hosaka Hisashi , Thuss-Patience Peter C. , Santoro Armando , Jiménez-Fonseca Paula , Longo Federico , Ozyilkan Ozgur , Cicin Irfan , Park David , Tejani Mohamedtaki Abdulaziz , Zaanan Aziz , Bilancia Domenico , Pericay Carles , Ozguroglu Mustafa , ALSINA MARIA , Makris Lukas , McGuigan Sandra , Ilson David H. 
Published: May 2019

4037 Background: 60% of newly diagnosed GC pts are > 65 y of age, a proportion that is increasing. The global phase 3 study TAGS (NCT02500043) demonstrated the efficacy and safety of FTD/TPI in previously treated pts with mGC/mGEJC. Here we report results in the pt subgroup aged ≥65 in TAGS. Methods: Pts with mGC/mGEJC treated with ≥2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. A preplanned efficacy/safety analysis was performed in pts aged ≥65 y. Results: Of 507 randomized pts, 228 (45%) were aged ≥65 y (range 65–89). The pt subset aged ≥65 y was similar to the overall population, except for a higher incidence of moderate renal impairment in the elderly subgroup (31% vs 17%). For pts aged ≥65 y, baseline characteristics were generally balanced across the treatment groups, although more pts treated with FTD/TPI than with placebo had ECOG PS 1 (69% vs 59%). FTD/TPI had an efficacy benefit in pts aged ≥65 y, and the FTD/TPI safety profile was similar in this subgroup vs the overall population (table). Treatment-related deaths (one in each treatment group) did not occur in pts aged ≥65 y. No drug-related deaths associated with cardiotoxicity were reported in pts aged ≥65 y. Although dose modifications were used more often in this subgroup, there was no increase in discontinuations vs the overall population. Conclusions: FTD/TPI was safe and effective in pts aged ≥65 y, who had a higher incidence of moderate renal impairment vs the overall population. Clinical trial information: NCT02500043. [Table: see text]
Recurrence risk evaluation in stage IB gastric cancer with TP53 codon 72 polymorphism.
Authors: Nishizuka Satoshi , Ohmori Yukimi , Iwaya Takeshi , Koeda Keisuke ,   The Northern Japan Gastric Cancer Study Consortium
Published: May 2019

4044 Background: Post-operative adjuvant chemotherapy is not currently indicated for Stage IB gastric cancer. However, about 10% of these patients experience recurrence and metastasis. Our previous study on a panel of gastric cancer cell lines indicated that TP53 codon 72 polymorphisms may affect the degree of biological malignancy. Hence, we hypothesized that the TP53 codon 72 polymorphisms may have been associated with post-operative survival without adjuvant chemotherapy. In this study, we investigated the risk of recurrence after treatment of Stage IB gastric cancer patients carrying the TP53 codon 72 polymorphism and attempted to identify a subpopulation that should receive post-operative adjuvant chemotherapy. Methods: Among 658 gastric cancer patients who received gastrectomy with curative-intent, 130 Stage IB patients were enrolled in the present study. The TP53 codon 72 polymorphisms of formalin-fixed paraffin-embedded cancer tissue sections were assessed by direct sequencing using originally designed primers. Overall survival rate (OS) and relapse-free survival rate (RFS) were analyzed based on the status of TP53 codon 72 polymorphism "Arg/Arg", "Arg/Pro" and "Pro/Pro". The hazard ratio for each subgroup was compared by TP53 codon 72 polymorphism. All interaction p values were calculated using the likelihood test. Results: Of the 125 patients for whom polymorphism analysis results were available, the 5- and 10-year OS was 84.5% and 63.9%, respectively. The 5- and 10-year RFS was 82.2% and 64.3%, respectively. When the study cohort was divided into two groups according to polymorphism status (i.e., Arg/Arg and Arg/Pro vs. Pro/Pro), both the OS (hazard ratio [HR], 1.968; 95% confidence interval [CI], 0.770-7.430, p = 0.045) and RFS (HR, 1.976; 95% CI, 0.778-7.515, p = 0.033) of the Pro/Pro group across the entire observation period were significantly lower than those for the Arg/Arg and Arg/Pro group. The majority of recurrences in Pro/Pro occurred within three years from the operation. Conclusions: Among Stage IB gastric cancer patients that underwent gastrectomy with curative-intent, post-operative adjuvant chemotherapy may be considered immediately after surgery for patients carrying the TP53 codon 72 Pro/Pro polymorphism.
Total neoadjuvant chemo (ctx; TNT) for locally advanced gastric cancer (GC): The Memorial Sloan Kettering Cancer Center experience.
Authors: Greally Megan , Strong Vivian E. , Yoon Sam S. , Coit Daniel G. , Chou Joanne F , Capanu Marinela , Kelsen David Paul , Janjigian Yelena Yuriy , Ilson David H. , Ku Geoffrey Yuyat 
Published: May 2019

4046 Background: Peri-op chemo (ctx) and surgery is a standard in the treatment of GC, based on the MAGIC (NEJM 2006; 355:11) and FLOT4 (J Clin Oncol 35:4004 [abstr]) studies. However, less than half of patients (pts) completed ctx in the MAGIC and FLOT4 studies, mainly from issues delivering post-op therapy. We assessed safety and feasibility of TNT, where all ctx is given pre-op. Methods: We reviewed GC pts who received TNT or peri-op ctx and had surgery; decision for TNT was by physician preference, based on clinical or radiographic benefit to justify completing ctx pre-op. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank Sum tests. Post-op length of stay (LOS) was calculated from date of surgery (DOS) to date of discharge and surgical morbidity was determined using the Clavien-Dindo classification. Progression free survival (PFS) and overall survival (OS) were calculated from DOS using Kaplan-Meier methods and compared between groups using the log-rank test. Results: 120 pts were identified, median age 63, 62.5% male, 98% ECOG 0/1. 93 pts (77.5%) received peri-op ctx and 27 (22.5%) received TNT. In peri-op pts, 19%, 43% and 38% received FLOT, platinum/fluropyrimidine (FP) and ECF/EOX respectively. In TNT pts, 56%, 37% and 7% received FLOT, platinum/FP and ECF/EOX respectively. 57% had subtotal gastrectomy. Surgical outcomes were similar between groups; median LOS was 6 and 7 days (p = 0.31) in peri-op and TNT pts respectively. There was no significant difference in Clavien Dindo grade I-II or III-IV morbidity between groups (p = 0.103). There were no deaths. TNT pts received higher proportions of planned treatment than peri-op ctx pts: 90% vs. 60% FP (0.001); 85% vs. 41% platinum ( < 0.001); 100% vs. 9% epirubicin (0.015) and 53% vs. 28% docetaxel (p = 0.169). At median follow-up of 19 months, median PFS and OS were not reached. There was no significant difference in PFS (p = 0.089) or OS (p = 0.59) between groups. Conclusions: TNT appears safe with no increase in post-op LOS or surgical morbidity observed. TNT pts had higher percentage drug delivery, suggesting potential benefit for administering all ctx before surgery. While longer survival follow-up is required, TNT may be considered in pts with locally advanced GC who are candidates for ctx.