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

Kudo, Masatoshi ORCID: 0000-0002-4102-3474, Finn, Richard S ORCID: 0000-0003-2494-2126, Qin, Shukui, Han, Kwang-Hyub, Ikeda, Kenji, Cheng, Ann-Lii ORCID: 0000-0002-9152-6512, Vogel, Arndt ORCID: 0000-0003-0560-5538, Tovoli, Francesco ORCID: 0000-0002-8350-1155, Ueshima, Kazuomi ORCID: 0000-0002-7577-5789, Aikata, Hiroshi ORCID: 0000-0002-3409-2156
et al (show 10 more authors) (2023) Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. Journal of hepatology, 78 (1). pp. 133-141.

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<h4>Background & aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Clinicaltrials</h4><h4>Gov number</h4>NCT01761266.<h4>Impact and implications</h4>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.

Item Type: Article
Uncontrolled Keywords: Humans, Carcinoma, Hepatocellular, Liver Neoplasms, Antineoplastic Agents, Retrospective Studies, Sorafenib
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 15 Mar 2023 15:30
Last Modified: 15 Mar 2023 15:31
DOI: 10.1016/j.jhep.2022.09.006
Open Access URL: https://doi.org/10.1016/j.jhep.2022.09.006
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3169108