Journal ArticleDOI
Ramucirumab Versus Placebo as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib (REACH): A Randomised, Double-Blind, Multicentre, Phase 3 Trial
Andrew X. Zhu,Joon Oh Park,Baek Yeol Ryoo,Chia Jui Yen,Ronnie T.P. Poon,Davide Pastorelli,Jean-Frédéric Blanc,Hyun Cheol Chung,Ari David Baron,Tulio Eduardo Flesch Pfiffer,Takuji Okusaka,Katerina Kubackova,Jörg Trojan,Javier Sastre,Ian Chau,Shao Chun Chang,Paolo Abada,Ling Yang,Jonathan D. Schwartz,Masatoshi Kudo +19 more
TLDR
Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma and the safety profile is manageable.Abstract:
Summary Background VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Findings Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0–10·6) versus 7·6 months (6·0–9·3) for the placebo group (HR 0·87 [95% CI 0·72–1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [ vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Funding Eli Lilly and Co.read more
Citations
More filters
Journal ArticleDOI
EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma
Peter R. Galle,Alejandro Forner,Josep M. Llovet,Vincenzo Mazzaferro,Fabio Piscaglia,Jean-Luc Raoul,Peter Schirmacher,Valérie Vilgrain +7 more
TL;DR: The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.
Journal ArticleDOI
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial
Jordi Bruix,Shukui Qin,Philippe Merle,Alessandro Granito,Yi Hsiang Huang,György Bodoky,Marc Pracht,Osamu Yokosuka,Olivier Rosmorduc,Valeriy Breder,René Gerolami,Gianluca Masi,Paul Ross,Tianqiang Song,Jean-Pierre Bronowicki,Isabelle Ollivier-Hourmand,Masatoshi Kudo,Ann-Lii Cheng,Josep M. Llovet,Josep M. Llovet,Josep M. Llovet,Richard S. Finn,Marie Aude Leberre,Annette Baumhauer,Gerold Meinhardt,Guohong Han +25 more
TL;DR: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenIB treatment, and future trials should explore combinations of regorAFenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafanib and regorafinib.
Journal ArticleDOI
Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update
Masao Omata,Ann-Lii Cheng,Norihiro Kokudo,Masatoshi Kudo,Jeong Min Lee,Jidong Jia,Ryosuke Tateishi,Kwang Hyub Han,Yoghesh K. Chawla,Shuichiro Shiina,Wasim Jafri,Diana A. Payawal,Takamasa Ohki,Sadahisa Ogasawara,Pei-Jer Chen,Cosmas Rinaldi Adithya Lesmana,Laurentius A. Lesmana,Rino Alvani Gani,Shuntaro Obi,A. Kadir Dokmeci,Shiv Kumar Sarin +20 more
TL;DR: The latest guidelines for the treatment of HCC recommend evidence-based management and are considered suitable for universal use in the Asia–Pacific region, which has a diversity of medical environments.
Journal ArticleDOI
Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma.
TL;DR: Studies now aim to identify molecular markers and imaging techniques that can detect patients with HCC at earlier stages and better predict their survival time and response to treatment.
Journal ArticleDOI
Molecular therapies and precision medicine for hepatocellular carcinoma
TL;DR: Treatment advances have been made in the past few years, and further advancements are expected in the near future, including biomarker-driven treatments and immunotherapies, as discussed in this Review.
References
More filters
Journal ArticleDOI
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
Jacques Ferlay,Isabelle Soerjomataram,Rajesh Dikshit,Sultan Eser,Colin Mathers,Marise Souto Rebelo,Donald Maxwell Parkin,David Forman,Freddie Bray +8 more
TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Journal ArticleDOI
Sorafenib in Advanced Hepatocellular Carcinoma
Josep M. Llovet,Sergio Ricci,Vincenzo Mazzaferro,Philip Hilgard,Edward Gane,Jean-Frédéric Blanc,André Cosme de Oliveira,Armando Santoro,Jean-Luc Raoul,Alejandro Forner,Myron Schwartz,Camillo Porta,Stefan Zeuzem,Luigi Bolondi,Tim F. Greten,Peter R. Galle,Jean Francois Seitz,Ivan Borbath,Dieter Häussinger,Tom Giannaris,Minghua Shan,M. Moscovici,D. Voliotis,Jordi Bruix +23 more
TL;DR: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Journal ArticleDOI
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
Ann-Lii Cheng,Yoon-Koo Kang,Zhendong Chen,Chao Jung Tsao,Shukui Qin,Jun Suk Kim,Rongcheng Luo,Jifeng Feng,Sheng-Long Ye,Tsai Sheng Yang,Jianming Xu,Yan Sun,Houjie Liang,Jiwei Liu,Jiejun Wang,Won Young Tak,Hongming Pan,Karin Burock,Jessie Zou,D. Voliotis,Zhongzhen Guan +20 more
TL;DR: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated.
Journal ArticleDOI
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
Charles S. Fuchs,Jiri Tomasek,Cho Jae Yong,Filip Dumitru,Rodolfo Passalacqua,Chanchal Goswami,Howard Safran,Lucas Vieira dos Santos,G. Aprile,David Ferry,Bohuslav Melichar,Mustapha Tehfe,Eldar Topuzov,John Zalcberg,John Zalcberg,Ian Chau,William Campbell,Choondal Sivanandan,Joanna Pikiel,Minori Koshiji,Yanzhi Hsu,Astra M. Liepa,Ling Gao,Jonathan D. Schwartz,Josep Tabernero +24 more
TL;DR: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy, and validate VEGFR-2 signalling as an important therapeutic target in advanced Gastric cancer.
Related Papers (5)
Sorafenib in Advanced Hepatocellular Carcinoma
Josep M. Llovet,Sergio Ricci,Vincenzo Mazzaferro,Philip Hilgard,Edward Gane,Jean-Frédéric Blanc,André Cosme de Oliveira,Armando Santoro,Jean-Luc Raoul,Alejandro Forner,Myron Schwartz,Camillo Porta,Stefan Zeuzem,Luigi Bolondi,Tim F. Greten,Peter R. Galle,Jean Francois Seitz,Ivan Borbath,Dieter Häussinger,Tom Giannaris,Minghua Shan,M. Moscovici,D. Voliotis,Jordi Bruix +23 more
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial
Jordi Bruix,Shukui Qin,Philippe Merle,Alessandro Granito,Yi Hsiang Huang,György Bodoky,Marc Pracht,Osamu Yokosuka,Olivier Rosmorduc,Valeriy Breder,René Gerolami,Gianluca Masi,Paul Ross,Tianqiang Song,Jean-Pierre Bronowicki,Isabelle Ollivier-Hourmand,Masatoshi Kudo,Ann-Lii Cheng,Josep M. Llovet,Josep M. Llovet,Josep M. Llovet,Richard S. Finn,Marie Aude Leberre,Annette Baumhauer,Gerold Meinhardt,Guohong Han +25 more
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial
Masatoshi Kudo,Richard S. Finn,Shukui Qin,Kwang Hyub Han,Kenji Ikeda,Fabio Piscaglia,Ari David Baron,Joong-Won Park,Guohong Han,Jacek Jassem,Jean-Frédéric Blanc,Arndt Vogel,Dmitry Komov,T.R. Jeffry Evans,Carlos Lopez,Corina E. Dutcus,Matthew Guo,Kenichi Saito,Silvija Kraljevic,Toshiyuki Tamai,Min Ren,Ann-Lii Cheng +21 more
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma
Ghassan K. Abou-Alfa,Tim Meyer,Ann-Lii Cheng,Anthony B. El-Khoueiry,Lorenza Rimassa,Baek Yeol Ryoo,Irfan Cicin,Philippe Merle,Yen-Hsun Chen,Joong-Won Park,Jean-Frédéric Blanc,Luigi Bolondi,Heinz Josef Klümpen,Heinz Josef Klümpen,Stephen L. Chan,Vittorina Zagonel,Tiziana Pressiani,Min Hee Ryu,Alan P. Venook,Alan P. Venook,Colin Hessel,Anne E. Borgman-Hagey,Gisela Schwab,Robin Kate Kelley +23 more