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

doi:10.1016/j.jhep.2022.09.006

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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	133-141
Number of pages	9
Journal	Journal of Hepatology
Volume	78
Issue number	1
DOIs	https://doi.org/10.1016/j.jhep.2022.09.006
Publication status	Published - 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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10.1016/j.jhep.2022.09.006

Cite this

Kudo, M., Finn, R. S., Qin, S., Han, K. H., Ikeda, K., Cheng, A. L., Vogel, A., Tovoli, F., Ueshima, K., Aikata, H., López, C. L., Pracht, M., Meng, Z., Daniele, B., Park, J. W., Palmer, D., Tamai, T., Saito, K., Dutcus, C. E., & Lencioni, R. (2023). Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. Journal of Hepatology, 78(1), 133-141. https://doi.org/10.1016/j.jhep.2022.09.006

@article{22a9e1a638874b69854e601957e896a8,

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

abstract = "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.",

author = "Masatoshi Kudo and Finn, {Richard S.} and Shukui Qin and Han, {Kwang Hyub} and Kenji Ikeda and Cheng, {Ann Lii} and Arndt Vogel and Francesco Tovoli and Kazuomi Ueshima and Hiroshi Aikata and L{\'o}pez, {Carlos L{\'o}pez} and Marc Pracht and Zhiqiang Meng and Bruno Daniele and Park, {Joong Won} and Daniel Palmer and Toshiyuki Tamai and Kenichi Saito and Dutcus, {Corina E.} and Riccardo Lencioni",

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: {\textcopyright} 2022 The Authors",

year = "2023",

month = jan,

doi = "10.1016/j.jhep.2022.09.006",

language = "English",

volume = "78",

pages = "133--141",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "1",

}

Kudo, M, Finn, RS, Qin, S, Han, KH, Ikeda, K, Cheng, AL, Vogel, A, Tovoli, F, Ueshima, K, Aikata, H, López, CL, Pracht, M, Meng, Z, Daniele, B, Park, JW, Palmer, D, Tamai, T, Saito, K, Dutcus, CE & Lencioni, R 2023, 'Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study', Journal of Hepatology, vol. 78, no. 1, pp. 133-141. https://doi.org/10.1016/j.jhep.2022.09.006

TY - JOUR

T1 - Overall survival and objective response in advanced unresectable hepatocellular carcinoma

T2 - A subanalysis of the REFLECT study

AU - Kudo, Masatoshi

AU - Finn, Richard S.

AU - Qin, Shukui

AU - Han, Kwang Hyub

AU - Ikeda, Kenji

AU - Cheng, Ann Lii

AU - Vogel, Arndt

AU - Tovoli, Francesco

AU - Ueshima, Kazuomi

AU - Aikata, Hiroshi

AU - López, Carlos López

AU - Pracht, Marc

AU - Meng, Zhiqiang

AU - Daniele, Bruno

AU - Park, Joong Won

AU - Palmer, Daniel

AU - Tamai, Toshiyuki

AU - Saito, Kenichi

AU - Dutcus, Corina E.

AU - Lencioni, Riccardo

N1 - 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

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

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

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