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Emerging Therapies in the Management of Advanced-Stage Gastric Cancer

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      Abstract

      Globally, gastric malignancy contributes to significant cancer-related morbidity and mortality. Despite a recent approval of two targeted agents, trastuzumab and ramucirumab, the treatment options for advanced-stage gastric cancer are limited. Consequently, the overall clinical outcomes for patients with advanced-stage gastric cancer remain poor. Numerous agents that are active against novel targets have been evaluated in the course of randomized trials; however, most have produced disappointing results because of the molecular heterogeneity of gastric cancer. The Cancer Genome Atlas (TCGA) project proposed a new classification system for gastric cancer that includes four different tumor subtypes based on molecular characteristics. This change led to the identification of several distinct and potentially targetable pathways. However, most agents targeting these pathways do not elicit any meaningful clinical benefit when employed for the treatment of advanced-stage gastric cancer. Most advanced-stage gastric cancer trials currently focus on agents that modulate tumor microenvironments and cancer cell stemness. In this review, we summarize data regarding novel compounds that have shown efficacy in early phase studies and show promise as effective therapeutic agents, with special emphasis on those for which phase III trials are either planned or underway.

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      Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

      Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).
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        Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.

        Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. F Hoffmann-La Roche. Copyright 2010 Elsevier Ltd. All rights reserved.
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          Comprehensive molecular characterization of gastric adenocarcinoma

          Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
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            Author and article information

            Affiliations
            1Brigham and Women's Hospital , Boston, MA, United States
            2Maimonides Medical Center , New York, NY, United States
            3Oncology, Yuma Regional Medical Center Cancer Center , Yuma, AZ, United States
            Author notes

            Edited by: Amit K. Tiwari, University of Toledo, United States

            Reviewed by: Andaleeb Sajid, National Institutes of Health (NIH), United States; Federica Barbieri, Università di Genova, Italy; Milankumar Prajapati, Brown University, United States

            *Correspondence: Abhinav B. Chandra abhinavbck@ 123456hotmail.com

            This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

            Contributors
            Journal
            Front Pharmacol
            Front Pharmacol
            Front. Pharmacol.
            Frontiers in Pharmacology
            Frontiers Media S.A.
            1663-9812
            13 September 2018
            2018
            : 9
            6146175
            10.3389/fphar.2018.00404
            Copyright © 2018 Kumar, Soni, Garg, Kamholz and Chandra.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 5, Tables: 3, Equations: 0, References: 132, Pages: 24, Words: 18110
            Categories
            Pharmacology
            Review

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