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  • 1
    Language: English
    In: Critical Reviews in Oncology / Hematology, October 2018, Vol.130, pp.13-26
    Description: The use of immune checkpoint inhibitors constitutes an emerging therapeutic field for the therapy of gastrointestinal (GI) malignancies following the recent FDA approvals of PD-1 inhibitors for esophago-gastric adenocarcinoma, hepatocellular carcinoma and for microsatellite-instable tumors, which are mainly colorectal cancers. This paper reviews the clinical evidence end of 2017 and discusses the clinical development programs of atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab in GI-tract cancers. Since 2014, these antagonists of the PD-1/PD-L1 axis have gained approval for use in numerous other tumors. Phase II trials and phase I expansion cohorts demonstrate clinical activity in patients with oesophageal, gastric, colorectal, anal and hepatic cancer. Signals of outstanding efficacy are particularly observed in biomarker selected populations and for certain combination regimen. Comprehensive phase III development programs have been initiated in oesophageal and gastric cancer, with randomized trials ongoing in hepatocellular and colorectal cancer as well.
    Keywords: Tumors ; Drug Approval ; Medical Schools ; Colorectal Cancer;
    ISSN: 1040-8428
    E-ISSN: 18790461
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  • 2
    Language: English
    In: Lancet Oncology, 2018, Vol.19(7), p.940
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/S1470-2045(18)30351-6 Byline: Prof Andrew X Zhu, MD [azhu@mgh.harvard.edu] (a,b,*), Richard S Finn, MD (c), Julien Edeline, MD (d), Stephane Cattan, MD (e), Sadahisa Ogasawara, MD (f), Prof Daniel Palmer, PhD (g), Prof Chris Verslype, MD (h), Vittorina Zagonel, MD (i), Laetitia Fartoux, MD (j), Prof Arndt Vogel, MD (k), Debashis Sarker, PhD (l), Gontran Verset, MD (m), Stephen L Chan, MRCP (n), Jennifer Knox, MD (o), Bruno Daniele, MD (p), Andrea L Webber, PhD (q), Scot W Ebbinghaus, MD (q), Junshui Ma, PhD (q), Abby B Siegel, MD (q), Prof Ann-Lii Cheng, MD (r), Masatoshi Kudo, MD (s), Angela Alistar, Jamil Asselah, Jean-Frederic Blanc, Ivan Borbath, Timothy Cannon, Ki Chung, Allen Cohn, David P Cosgrove, Nevena Damjanov, Mukul Gupta, Yoshivasu Karino, Mark Karwal, Andreas Kaubisch, Robin Kelley, Jena-Luc Van Laethem, Timothy Larson, James Lee, Daneng Li, Atisha Manhas, Gulam Abbas Manji, Kazushi Numata, Benjamin Parsons, Andrew S. Paulson, Carmine Pinto, Robert Ramirez, Suresh Ratnam, Magnus Rizell, Olivier Rosmorduc, Yvonne Sada, Yutaka Sasaki, Per I Stal, Simone Strasser, Joerg Trojan, Gina Vaccaro, Hans Van Vlierberghe, Alan Weiss, Karl-Heinz Weiss, Tatsuya Yamashita Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0--1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11--26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc. Author Affiliation: (a) Department of Medicine, Harvard Medical School, Boston, MA, USA (b) Massachusetts General Hospital Cancer Center, Boston, MA, USA (c) Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA (d) Department of Medical Oncology, Centre Eugene Marquis, Rennes, France (e) Department of Medical Oncology and Gastroenterology, Hopital Claude Huriez, Centre Hospitalier Regional Universitaire de Lille, Lille, France (f) Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan (g) Department of Medical Oncology, University of Liverpool, Liverpool, UK (h) Department of Hepatology, University Hospital Gasthuisberg, Leuven, Leuven, Belgium (i) Istituto Oncologico Veneto-Istituto di Ricovero e Cura a Carattere Scientifico (IOV-IRCCS), Padua, Italy (j) Department of Gastroenterology and Hepatology, Hopital Universitaire Pitie-SalpA*triere, Paris, France (k) Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule, Hannover, Germany (l) Department of Medical Oncology, King's College Hospital, London, UK (m) Gastrointestinal Oncology Unit, Hopital Erasme, Brussels, Belgium (n) Department of Clinical Oncology, State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong (o) Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada (p) Department of Oncology, Azienda Ospedaliera Gaetano Rummo, Benevento, Italy (q) Department of Global Clinical Development, Merck & Co, Kenilworth, NJ, USA (r) Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan (s) Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan * Correspondence to: Prof Andrew X Zhu, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA (footnote)[Dagger] Investigators listed in the
    Keywords: Hepatocellular Carcinoma – Care and Treatment ; Antineoplastic Agents – Product Development
    ISSN: 1470-2045
    E-ISSN: 14745488
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