REFLECT—a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

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Abstract

Background

A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported.

Methods

The intent-to-treat population enrolled in Japan was analyzed.

Results

Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm ( N = 81) or the SOR arm ( N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm.

Conclusions

The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.

Trial registration ID

ClinicalTrials.gov. No. NCT01761266.

Electronic supplementary material

The online version of this article (10.1007/s00535-019-01642-1) contains supplementary material, which is available to authorized users.

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Most cited references 12

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Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase.

Toshimitsu Uenaka, Makoto Asada, Yasuhiro Funahashi … (2008)

Vascular endothelial growth factor (VEGF)-C/VEGF-receptor 3 (VEGF-R3) signal plays a significant role in lymphangiogenesis and tumor metastasis based on its effects on lymphatic vessels. However, little is known about the effect of inhibiting VEGF-R3 on lymphangiogenesis and lymph node metastases using a small-molecule kinase inhibitor. We evaluated the effect of E7080, a potent inhibitor of both VEGF-R2 and VEGF-R3 kinase, and bevacizumab on lymphangiogenesis and angiogenesis in a mammary fat pad xenograft model of human breast cancer using MDA-MB-231 cells that express excessive amounts of VEGF-C. Lymphangiogenesis was determined by lymphatic vessel density (LVD) and angiogenesis by microvessel density (MVD). In contrast to MDA-MB-435 cells, which expressed a similar amount of VEGF to MDA-MB-231 cells with an undetectable amount of VEGF-C, only MDA-MB-231 exhibited lymphangiogenesis in the primary tumor. E7080 but not bevacizumab significantly decreased LVD within the MDA-MB-231 tumor. E7080 and bevacizumab decreased MVD in both the MDA-MB-231 and MDA-MB-435 models. E7080 significantly suppressed regional lymph nodes and distant lung metastases of MDA-MB-231, whereas bevacizumab significantly inhibited only lung metastases. E7080 also decreased both MVD and LVD within the metastatic nodules at lymph nodes after resection of the primary tumor. Inhibition of VEGF-R3 kinase with E7080 effectively decreased LVD within MDA-MB-231 tumors, which express VEGF-C. Simultaneous inhibition of both VEGF-R2 and VEGF-R3 kinases by E7080 may be a promising new strategy to control regional lymph node and distant lung metastases.

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Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis?

E Cholongitas, G V Papatheodoridis, M Vangeli … (2005)

Prognosis in cirrhotic patients has had a resurgence of interest because of liver transplantation and new therapies for complications of end-stage cirrhosis. The model for end-stage liver disease score is now used for allocation in liver transplantation waiting lists, replacing Child-Turcotte-Pugh score. However, there is debate as whether it is better in other settings of cirrhosis. To review studies comparing the accuracy of model for end-stage liver disease score vs. Child-Turcotte-Pugh score in non-transplant settings. Transjugular intrahepatic portosystemic shunt studies (with 1360 cirrhotics) only one of five, showed model for end-stage liver disease to be superior to Child-Turcotte-Pugh to predict 3-month mortality, but not for 12-month mortality. Prognosis of cirrhosis studies (with 2569 patients) none of four showed significant differences between the two scores for either short- or long-term prognosis whereas no differences for variceal bleeding studies (with 411 cirrhotics). Modified Child-Turcotte-Pugh score, by adding creatinine, performed similarly to model for end-stage liver disease score. Hepatic encephalopathy and hyponatraemia (as an index of ascites), both components of Child-Turcotte-Pugh score, add to the prognostic performance of model for end-stage liver disease score. Based on current literature, model for end-stage liver disease score does not perform better than Child-Turcotte-Pugh score in non-transplant settings. Modified Child-Turcotte-Pugh and model for end-stage liver disease scores need further evaluation.

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Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors.

Kazuhiko Yamada, Yutaka Fujiwara, Fumiaki Koizumi … (2011)

E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors. In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis. Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma concentration-time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect. E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors. ©2011 AACR.

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Author and article information

Contributors

Tatsuya Yamashita: ytatsuya@m-kanazawa.jp

Journal

Journal ID (nlm-ta): J Gastroenterol

Journal ID (iso-abbrev): J. Gastroenterol

Title: Journal of Gastroenterology

Publisher: Springer Japan (Tokyo )

ISSN (Print): 0944-1174

ISSN (Electronic): 1435-5922

Publication date (Electronic): 12 November 2019

Publication date PMC-release: 12 November 2019

Publication date (Print): 2020

Volume: 55

Issue: 1

Pages: 113-122

Affiliations

[1 ]GRID grid.9707.9, ISNI 0000 0001 2308 3329, Department of Gastroenterology, , Kanazawa University, ; Kanazawa, Japan

[2 ]GRID grid.258622.9, ISNI 0000 0004 1936 9967, Department of Gastroenterology and Hepatology, , Kindai University Faculty of Medicine, ; Osaka, Japan

[3 ]GRID grid.410813.f, ISNI 0000 0004 1764 6940, Department of Hepatology, , Toranomon Hospital, ; Tokyo, Japan

[4 ]GRID grid.416332.1, ISNI 0000 0000 9887 307X, Department of Gastroenterology and Hepatology, , Musashino Red Cross Hospital, ; Musashino, Japan

[5 ]GRID grid.26999.3d, ISNI 0000 0001 2151 536X, Department of Gastroenterology, Graduate School of Medicine, , The University of Tokyo, ; Tokyo, Japan

[6 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Hepatobiliary and Pancreatic Oncology, , National Cancer Center Hospital East, ; Kashiwa, Japan

[7 ]GRID grid.257022.0, ISNI 0000 0000 8711 3200, Department of Gastroenterology and Metabolism, , Hiroshima University, ; Hiroshima, Japan

[8 ]Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Center Koseikan, Saga, Japan

[9 ]Department of Gastroenterology, Asakura Medical Association Hospital, Asakura, Japan

[10 ]GRID grid.415613.4, Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, , National Hospital Organization Kyushu Medical Center, ; Fukuoka, Japan

[11 ]GRID grid.413045.7, ISNI 0000 0004 0467 212X, Gastroenterological Center, , Yokohama City University Medical Center, ; Yokohama, Japan

[12 ]GRID grid.410800.d, ISNI 0000 0001 0722 8444, Department of Diagnostic and Interventional Radiology, , Aichi Cancer Center Hospital, ; Nagoya, Japan

[13 ]GRID grid.410781.b, ISNI 0000 0001 0706 0776, Division of Gastroenterology, Department of Medicine, , Kurume University School of Medicine, ; Kurume, Japan

[14 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Hepatobiliary and Pancreatic Oncology, , National Cancer Center Hospital, ; Tokyo, Japan

[15 ]GRID grid.418765.9, ISNI 0000 0004 1756 5390, Eisai Co., Ltd., ; Tokyo, Japan

[16 ]Department of Hepatology, Shunan Memorial Hospital, Kudamatsu, Japan

Article

Publisher ID: 1642

DOI: 10.1007/s00535-019-01642-1

PMC ID: 6942573

PubMed ID: 31720835

SO-VID: 06c3537e-f048-40cc-ac49-787be083a998

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 12 April 2019

Date accepted : 27 October 2019

Funding

Funded by: Eisai Inc.

Award ID: N/A

Funded by: Merck Sharp & Dohme Corp.

Award ID: N/A

Funded by: FundRef http://dx.doi.org/10.13039/501100003769, Eisai;

Award ID: N/A

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: reflect trial,hepatocellular carcinoma,lenvatinib,sorafenib,japanese population

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: reflect trial, hepatocellular carcinoma, lenvatinib, sorafenib, japanese population

REFLECT—a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

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Abstract

Background

Methods

Results

Conclusions

Trial registration ID

Electronic supplementary material

Related collections

Karger: Gastroenterology

Most cited references 12

Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase.

Systematic review: The model for end-stage liver disease--should it replace Child-Pugh's classification for assessing prognosis in cirrhosis?

Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors.

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