PMID- 27704266 OWN - NLM STAT- MEDLINE DCOM- 20170911 LR - 20181113 IS - 1435-5922 (Electronic) IS - 0944-1174 (Print) IS - 0944-1174 (Linking) VI - 52 IP - 4 DP - 2017 Apr TI - Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. PG - 512-519 LID - 10.1007/s00535-016-1263-4 [doi] AB - BACKGROUND: Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC). METHODS: Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: Between July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5-9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7-25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without. CONCLUSIONS: Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight. TRIAL REGISTRATION ID: www.ClinicalTrials.gov NCT00946153. FAU - Ikeda, Kenji AU - Ikeda K AD - Department of Hepatology, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo, 105-8470, Japan. ikedakenji@tora.email.ne.jp. FAU - Kudo, Masatoshi AU - Kudo M AD - Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan. FAU - Kawazoe, Seiji AU - Kawazoe S AD - Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Centre KOSEIKAN, Saga, Japan. FAU - Osaki, Yukio AU - Osaki Y AD - Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan. FAU - Ikeda, Masafumi AU - Ikeda M AD - Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Okusaka, Takuji AU - Okusaka T AD - Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Tamai, Toshiyuki AU - Tamai T AD - Eisai Co., Ltd.,, Tokyo, Japan. FAU - Suzuki, Takuya AU - Suzuki T AD - Eisai Co., Ltd.,, Tokyo, Japan. FAU - Hisai, Takashi AU - Hisai T AD - Eisai Co., Ltd.,, Tokyo, Japan. FAU - Hayato, Seiichi AU - Hayato S AD - Eisai Co., Ltd.,, Tokyo, Japan. FAU - Okita, Kiwamu AU - Okita K AD - Shunan Memorial Hospital, Yamaguchi, Japan. FAU - Kumada, Hiromitsu AU - Kumada H AD - Department of Hepatology, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo, 105-8470, Japan. LA - eng SI - ClinicalTrials.gov/NCT00946153 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20161004 PL - Japan TA - J Gastroenterol JT - Journal of gastroenterology JID - 9430794 RN - 0 (Antineoplastic Agents) RN - 0 (Phenylurea Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Quinolines) RN - EE083865G2 (lenvatinib) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/administration & dosage/adverse effects/*therapeutic use MH - Body Weight MH - Carcinoma, Hepatocellular/diagnostic imaging/*drug therapy/pathology MH - Disease Progression MH - Drug Administration Schedule MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Liver Neoplasms/diagnostic imaging/*drug therapy/pathology MH - Male MH - Middle Aged MH - Neoplasm Staging MH - Phenylurea Compounds/administration & dosage/adverse effects/*therapeutic use MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/therapeutic use MH - Quinolines/administration & dosage/adverse effects/*therapeutic use MH - Tomography, X-Ray Computed MH - Young Adult PMC - PMC5357473 OTO - NOTNLM OT - E7080 OT - Hepatocellular carcinoma OT - Lenvatinib OT - Tyrosine kinase inhibitor OT - Vascular endothelial growth factor inhibitor COIS- Dr. K. Ikeda reports honoraria from Eisai, Dainippon, Sumitomo Pharmaceutical Co., and Olympus, and served in a consulting/advisory role for Eisai during the conduct of study. Dr. Kudo reports honoraria from Bayer, Eisai, MSD, Bristol Myers Squibb, Daiichi, and Sankyo, and served in a consulting/advisory role for Eisai, Bristol Myers Squibb, and Eli Lilly. Dr. Kawazoe has nothing to disclose. Dr. Osaki has nothing to disclose. Dr. M. Ikeda reports honoraria from Novartis, Bayer Yakuhin, Bristol Myers Squibb, Abbott Japan, Taiho Pharmaceutical, Eli Lilly Japan, Kowa, OncoTherapy Science, Nippon Kayaku, and Daiichi Sankyo; received research funding from Bayer Yakuhin, Novartis, Merck Serono, Kyowa Hakko Kirin, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Otsuka Pharmaceutical, OncoTherapy Science, Boehringer Ingelheim, Kowa, Ono Pharmaceutical, Eisai, AstraZeneca, Pfizer Japan, Glaxo Smith Kline, and Zeria Pharmaceutical; and reports travel, accommodation, and other expense reimbursement from Bayer Yakuhin and Eisai. Dr. Okusaka reports honoraria from Chugai Pharmaceutical Co., Ltd, Pfizer Japan Inc., Novartis Pharmaceutical K.K., Taiho Pharmaceutical Co., Ltd., Merck Serono Co., Ltd., Eli Lilly Japan K.K., Dainippon Sumitomo Pharmaceutical Co., Ltd, Eisai Co., Ltd, and Bayer Yakuhin Ltd.; served in a consulting/advisory role for Eli Lilly Japan K.K., Yakult Honsha Co., Ltd., Amgen, Dainippon Sumitomo Pharmaceutical Co., Ltd., Taiho Pharmaceutical Col, Ltd., OncoTherapy Science, Inc., Nobelpharma Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Nano Carrier Co., Ltd., Novartis Pharmaceutical K.K., and Zeria Pharmaceutical Co., Ltd.; and received research funding from Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Eisai Co., Ltd., Novartis Pharmaceutical K.K., Shizuoka Industry, Takeda Bio Development Center Limited, Yakult Honsha Co., Ltd., OncoTherapy Science, Inc., Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Sceti Medical Laboratory K.K., Nippon Boehringer Ingelheim Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd, Merck Serono Co., Ltd, Ono Pharmaceutical Co., Ltd. Bayer Yakuhin Ltd., Pfizer Japan Inc., AstraZeneca K.K., and Dainippon Sumitomo Pharmaceutical Co., Ltd. T. Tamai reports employment and stock/other ownership with Eisai Co., Ltd. T. Suzuki reports employment with Eisai Co., Ltd. T. Hisai has nothing to disclose. S. Hayato reports employment with Eisai Co., Ltd. Dr. Okita reports honoraria from Kowa and Eisai Co., Ltd. Dr. Kumada reports honoraria from, and served in a consulting/advisory role for, Eisai Co., Ltd. EDAT- 2016/10/06 06:00 MHDA- 2017/09/12 06:00 PMCR- 2016/10/04 CRDT- 2016/10/06 06:00 PHST- 2016/04/27 00:00 [received] PHST- 2016/09/06 00:00 [accepted] PHST- 2016/10/06 06:00 [pubmed] PHST- 2017/09/12 06:00 [medline] PHST- 2016/10/06 06:00 [entrez] PHST- 2016/10/04 00:00 [pmc-release] AID - 10.1007/s00535-016-1263-4 [pii] AID - 1263 [pii] AID - 10.1007/s00535-016-1263-4 [doi] PST - ppublish SO - J Gastroenterol. 2017 Apr;52(4):512-519. doi: 10.1007/s00535-016-1263-4. Epub 2016 Oct 4.