Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study

Masatoshi Kudo, Richard S. Finn, Shukui Qin, Kwang Hyub Han, Kenji Ikeda, Ann Lii Cheng, Arndt Vogel, Francesco Tovoli, Kazuomi Ueshima, Hiroshi Aikata, Carlos López López, Marc Pracht, Zhiqiang Meng, Bruno Daniele, Joong Won Park, Daniel Palmer, Toshiyuki Tamai, Kenichi Saito, Corina E. Dutcus, Riccardo Lencioni

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2 Citations (Scopus)


Background & Aims: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. Methods: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. Results: Median OS was 21.6 months (95% CI 18.6–24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7–12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49–0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51–0.72; p <0.001 and HR 0.50; 95% CI 0.39–0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49–0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51–0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54–0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44–0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38–0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. Conclusions: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. ClinicalTrials.gov number: NCT01761266. Impact and implications: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.

Original languageEnglish
Pages (from-to)133-141
Number of pages9
JournalJournal of Hepatology
Issue number1
Publication statusPublished - 2023 Jan

Bibliographical note

Funding Information:
This work was supported by Eisai Inc. , (Nutley, NJ, USA), and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. , Rahway, NJ, USA. The sponsors collaborated with the first and last authors (MK and RL) to design the study. The authors employed by the sponsors (CED, TT, and KS) played a significant part in study design, data collection, analysis, and interpretation, and writing the report. The corresponding author, MK, had full access to all the data and had final responsibility for the decision to submit for publication. The sponsors ( Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA) participated in manuscript review, manuscript approval, and decision to submit for publication. Medical writing support was provided by Caroline Leitschuh, PhD, of Oxford PharmaGenesis Inc, Newtown, PA, USA, with funding provided by the study sponsors.

Publisher Copyright:
© 2022 The Authors

All Science Journal Classification (ASJC) codes

  • Hepatology


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