Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study

Kudo, Masatoshi; Cheng, Ann‐Lii; Park, Joong-Won; Park, Jae Hyung; Liang, Po-Chin; Hidaka, Hiroyoshi; Izumi, Namiki; Heo, Jeong; Lee, Youn Jae; Sheen, I‐Shyan; Chiu, Chang‐Fang; Arioka, Hitoshi; Morita, Satoshi; Arai, Yasuaki

doi:10.1016/s2468-1253(17)30290-x

Cited by 157 publications

(141 citation statements)

References 27 publications

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“…The TACE-2 trial, which was conducted at 20 sites in England, was designed to test the hypothesis that combination treatment with sorafenib and DEB-TACE would inhibit tumor progression and extend OS [10]. …”

Section: Reasons For the Failure Of Past Negative Trialsmentioning

confidence: 99%

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Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial

Kudo¹

2018

Liver Cancer

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Section: Reasons For the Failure Of Past Negative Trialsmentioning

confidence: 99%

“…Therefore, the trials failed for different reasons [8, 10]. These reasons will not be discussed in this paper but are discussed elsewhere [16].…”

Section: Reasons For the Failure Of Past Negative Trialsmentioning

confidence: 99%

Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial

Kudo¹

2018

Liver Cancer

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“…The results showed improved progression-free survival (PFS), the primary endpoint of the study, suggesting the additive effect of the combination of orantinib and TACE [14] . Accordingly, a phase III (ORIENTAL) study was conducted in Japan, Korea, and Taiwan [15] .…”

Section: Oriental Studymentioning

confidence: 99%

Transarterial Chemoembolization in Combination with a Molecular Targeted Agent: Lessons Learned from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2)

Kudo

Arizumi²

2017

Oncology

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sessment Randomized Protocol (SHARP) and Asia-Pacific studies [1,2] . In 2007, sorafenib was approved in the EU and USA, where it became a first-line agent for unresectable advanced HCC. Transarterial chemoembolization (TACE) is the first-line treatment option for intermediate-stage HCC [3][4][5][6] ; however, repeated TACE sessions tend to impair liver functional reserve. Reducing the frequency of TACE, which is generally repeated upon tumor progression, is a challenging issue in the treatment of patients with intermediate-stage HCC. To address this issue, previous trials combined molecular targeted agents with TACE; however, the safety and efficacy of this combination could not be demonstrated, and none of the combination therapies is currently recommended.In the SHARP study, subanalysis showed that the hazard ratio (HR) for overall survival (OS) in patients with HCC with no vascular invasion or extrahepatic spread, which are regarded as good indications for TACE, was 0.52 and, thus, extremely good in the sorafenib group. The median survival of these patients was extended approximately 1.5-fold [7] , suggesting that the addition of sorafenib as adjuvant therapy to TACE improves prognosis. The combination of TACE with sorafenib does not simply represent the administration of 2 types of treatment; the combination is expected to extend the period during which TACE controls tumor progression because sorafenib strongly suppresses post-TACE tumor recur- AbstractThe multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC). However, as with other drugs, sorafenib has its limitations, and various clinical trials have been conducted to develop novel molecular targeted agents for use alone or in combination with existing locoregional therapies. Despite this, clinical trials of molecular targeted agents combined with transarterial chemoembolization (TACE) have not reported major treatment outcomes to date. In this review, we describe previous clinical trials of combination therapy with TACE and a molecular targeted agent in patients with unresectable HCC.

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“…The ORIENTAL study was a randomized, double-blind, placebo-controlled study of orantinib in patients with unresectable HCC [20]. After informed consent had been obtained, the patients were randomly assigned to the orantinib or placebo arms at a 1:1 ratio.…”

Section: Oriental Studymentioning

confidence: 99%

“…Orantinib (TSU-68) is a molecular targeted drug that inhibits VEGF, platelet-derived growth factor, and fibroblast growth factor receptors, and suppresses angiogenesis in tumor tissues. A phase III study of orantinib combined with TACE in patients with HCC (ORIENTAL) was conducted to verify if coadministration of TACE and orantinib inhibits the deterioration of HCC, and the OS in the orantinib arm was prolonged [20]. Patients were enrolled in Japan, Korea, and Taiwan.…”

Section: Introductionmentioning

confidence: 99%

Subgroup analysis of efficacy and safety of orantinib in combination with TACE in Japanese HCC patients in a randomized phase III trial (ORIENTAL)

et al. 2019

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A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo (ORIENTAL study). A subgroup analysis was conducted to evaluate the efficacy and safety of orantinib in Japanese patients enrolled in the ORIENTAL study. The data of Japanese patients from this study were analyzed. The overall survival (OS), time to progression (TTP), and time to TACE failure (TTTF) were compared between orantinib and placebo arms using stratified log-rank test. Since TTTF in patients with Barcelona Clinic Liver Cancer stage B (BCLC-B) showed favor outcome in this study, the OS and TTTF according to BCLC staging system were also analyzed. The subgroup analysis consisted of 219 and 213 patients in the orantinib and placebo arms. Median OS was 32.5 vs 33.0 months (p = 0.906), median TTP was 4.7 vs 3.1 months (p = 0.011), and median TTTF was 25.3 vs 18.2 months (p = 0.160) in the orantinib and placebo groups, respectively. Patients with BCLC-B in the orantinib and placebo groups showed a median OS of 33.7 and 30.1 months, respectively (p = 0.260), while the corresponding median TTTF were 25.3 and 14.0 months (p = 0.125). The Japanese population safety profile was similar to all over population in the ORIENTAL study. No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study.

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Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study

Cited by 157 publications

References 27 publications

Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial

Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial

Transarterial Chemoembolization in Combination with a Molecular Targeted Agent: Lessons Learned from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2)

Subgroup analysis of efficacy and safety of orantinib in combination with TACE in Japanese HCC patients in a randomized phase III trial (ORIENTAL)

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