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

Yamashita, Tatsuya; Kudo, Masatoshi; Ikeda, Kenji; Izumi, Namiki; Tateishi, Ryosuke; Ikeda, Masafumi; Aikata, Hiroshi; Kawaguchi, Yasunori; Wada, Yasuhiko; Numata, Kazushi; Inaba, Yoshitaka; Kuromatsu, Ryoko; Kobayashi, Masahiro; Okusaka, Takuji; Tamai, Toshiyuki; Kitamura, Chifumi; Saitô, Kenichi; Haruna, Katsuya; Okita, Kiwamu; Kumada, Hiromitsu

doi:10.1007/s00535-019-01642-1

Cited by 147 publications

(160 citation statements)

References 39 publications

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“…Additionally, when we used the standard cut-off value for objective response, that is, ETS ≥ 30%, the specificity for predicting PFS was considerably worse, compared with ETS ≥ 10%, because only 15% of the patients achieved that ETS. In the present study, median PFS was 5.0 months, which was shorter than that in the phase 3 REFLECT trial, revealing median PFS was 7.4 months in the overall population and 7.2 months in the Japanese subset [18]. However, in real-world settings, median PFS ranging from 4.4 to 5.4 months has been reported, consistent with our results [19,20].…”

Section: Discussionsupporting

confidence: 89%

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Takahashi

Moriguchi

Seko

et al. 2020

Cancers

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We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.

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Section: Discussionsupporting

confidence: 89%

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Takahashi

Moriguchi

Seko

et al. 2020

Cancers

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“…Furthermore, in our study, the ORR and DCR were 33% and 74%, respectively. Yamashita et al previously reported an MST of 17.6 months in Japanese patients with unresectable HCC treated with LEN in a phase 3, multinational, randomized, non-inferiority trial (REFLECT) [33]. Thus, the therapeutic effect of LEN in our study appears to be similar to that reported previously [7,11,33], suggesting that the enrolled subjects and treatment effects in our study are typical.…”

Section: Discussionsupporting

confidence: 87%

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study

et al. 2020

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We aimed to investigate the impact of the controlling nutritional status (CONUT) score, an immuno-nutritional biomarker, on the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). This retrospective study enrolled 164 patients with HCC and treated with LEN (median age 73 years, Barcelona Clinic Liver Cancer (BCLC) stage B/C 93/71). Factors associated with overall survival (OS) were evaluated using multivariate and decision tree analyses. OS was calculated using the Kaplan–Meier method and analyzed using the log–rank test. Independent factors for OS were albumin–bilirubin grade 1, BCLC stage B, and CONUT score <5 (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.58–5.31, p < 0.001). The CONUT score was the most important variable for OS, with OS rates of 70.0% and 29.0% in the low and high CONUT groups, respectively. Additionally, the median survival time was longer in the low CONUT group than in the high CONUT group (median survival time not reached vs. 11.3 months, p < 0.001). The CONUT score was the most important prognostic variable, rather than albumin–bilirubin grade and BCLC stage, in patients with HCC treated with LEN. Accordingly, immuno-nutritional status may be an important factor in the management of patients with HCC treated with LEN.

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“…however, the data were consistent with the results of a Japanese subpopulation analysis (ORR=61.3%) [16] Japanese subpopulation analysis [16]. Preserved liver function is an important factor for ORR and outcome of HCC patients in systemic therapy [36,37].…”

Section: Efficacy and Safetysupporting

confidence: 88%

“…In patients with intermediate-stage HCC, who had prior TACE history and become TACE failure, lenvatinib showed significantly and clinically meaningful anti-cancer efficacy by reducing tumour size or enhancement on dynamic CT in a large proportion of patients (ORR=61.3%) [9,[16][17][18]. In addition, systemic therapy has an advantage over TACE by preserving liver function during the treatment [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Lenvatinib as an Initial Treatment in Patients with Intermediate-stage Hepatocellular Carcinoma Beyond up-to-seven Criteria and Child-Pugh A Liver Function: A Proof-of-Concept Study

Kudo¹,

Ueshima²,

Chan³

et al. 2019

Preprint

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Background: Although transcatheter arterial chemoembolisation (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be more favourable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. Methods: This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected for the study. Propensity score matching was used to adjust for patient demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p < 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p < 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). Conclusion: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides more favorable outcome than TACE.

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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

Cited by 147 publications

References 39 publications

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Controlling Nutritional Status (CONUT) Score is Associated with Overall Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Cohort Study

Lenvatinib as an Initial Treatment in Patients with Intermediate-stage Hepatocellular Carcinoma Beyond up-to-seven Criteria and Child-Pugh A Liver Function: A Proof-of-Concept Study

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