Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein: Pooled results from two phase 3 studies (REACH and REACH-2)

Masatoshi Kudo; Richard S. Finn; Manabu Morimoto; Kun Ming Rau; Masafumi Ikeda; Chia Jui Yen; Peter R. Galle; Josep M. Llovet; Bruno Daniele; Ho Yeong Lim; David W. McIlwain; Reigetsu Yoshikawa; Kenichi Nakamura; Kun Liang; Chunxiao Wang; Paolo Abada; Ryan C. Widau; Andrew X. Zhu

doi:10.1159/000516605

Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein: Pooled results from two phase 3 studies (REACH and REACH-2)

Masatoshi Kudo, Richard S. Finn, Manabu Morimoto, Kun Ming Rau, Masafumi Ikeda, Chia Jui Yen, Peter R. Galle, Josep M. Llovet, Bruno Daniele, Ho Yeong Lim, David W. McIlwain, Reigetsu Yoshikawa, Kenichi Nakamura, Kun Liang, Chunxiao Wang, Paolo Abada, Ryan C. Widau, Andrew X. Zhu

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Abstract

Background: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0-1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. Results: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546-1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23-0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59-0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. Conclusions: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.

Original language	English
Pages (from-to)	451-460
Number of pages	10
Journal	Liver Cancer
Volume	10
Issue number	5
DOIs	https://doi.org/10.1159/000516605
State	Published - 1 Sep 2021

Keywords

Barcelona clinic liver cancer stage
Ramucirumab
α-fetoprotein

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10.1159/000516605

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Kudo, M., Finn, R. S., Morimoto, M., Rau, K. M., Ikeda, M., Yen, C. J., Galle, P. R., Llovet, J. M., Daniele, B., Lim, H. Y., McIlwain, D. W., Yoshikawa, R., Nakamura, K., Liang, K., Wang, C., Abada, P., Widau, R. C., & Zhu, A. X. (2021). Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein: Pooled results from two phase 3 studies (REACH and REACH-2). Liver Cancer, 10(5), 451-460. https://doi.org/10.1159/000516605

@article{4630bd15b1a7468db5e112aee05aa8a5,

title = "Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein: Pooled results from two phase 3 studies (REACH and REACH-2)",

abstract = "Background: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0-1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. Results: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546-1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23-0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59-0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. Conclusions: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.",

keywords = "Barcelona clinic liver cancer stage, Ramucirumab, α-fetoprotein",

author = "Masatoshi Kudo and Finn, {Richard S.} and Manabu Morimoto and Rau, {Kun Ming} and Masafumi Ikeda and Yen, {Chia Jui} and Galle, {Peter R.} and Llovet, {Josep M.} and Bruno Daniele and Lim, {Ho Yeong} and McIlwain, {David W.} and Reigetsu Yoshikawa and Kenichi Nakamura and Kun Liang and Chunxiao Wang and Paolo Abada and Widau, {Ryan C.} and Zhu, {Andrew X.}",

note = "Funding Information: M. Kudo is the Editor-in-Chief of Liver Cancer and reports grant and personal fees from Eisai and EA Pharma; grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, and Abbvie; and personal fees from Roche, Ono, Eli Lilly and Company, BMS, and Bayer. R. Finn is an Editorial Board Member of Liver Cancer and reports personal fees from AstraZeneca and Cstone; grants and personal fees from Bayer, Eisai, Bristol-Myers Squibb, Roche/Genentech, Merck, Pfizer, and Eli Lilly and Company. M. Morimoto, K. Rau, H. Lim, and K. Liang have nothing to disclose. M. Ikeda is an Editorial Board Member of Liver Cancer and reports fees for honoraria, advisory board, & research funding from Eli Lilly and Company, Bayer, Eisai, AstraZeneca, Chugai, Takeda, & Novartis; honoraria and research funding from Bristol-Myers Squibb, MSD, & EA Pharma; fees for advisory boards and research funding from Nihon Servier and Aslan; fees for research funding from Merck Serono, Yakult, Ono, J-Pharma, Pfizer, Chiome Bioscience, & GlaxoSmithKline; honoraria fees from Taiho, Teijin Pharma, Astellas, Sumitomo Dainippon, Gilead, & Otsuka. C. Yen has nothing to disclose. P. Galle reports grants from Bayer as well as personal fees from Bayer, BMS, AstraZeneca, Sirtex, MSD, Eisai, Ipsen, and Roche. J. Llovet reports grants and personal fees from Bayer Pharmaceuticals, Eisai, Boehringer Ingelheim, & Ipsen, grants from Bristol-Myers Squibb, and personal fees from Eli Lilly and Company, Celsion, Merck, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha, AstraZeneca, Axis, & Medscape. B. Daniele reports personal fees and nonfinancial support from Ipsen, Sanofi, & Bayer as well as personal fees from Esiai, Eli Lilly and Company, AstraZeneca, MSD, Roche, & Amgen. D. McIlwain is an employee and stockholder of Eli Lilly and Company. R. Yoshikawa is a full-time employee and shareholder of Eli Lilly and Company. K. Nakamura is an employee of Eli Lilly Japan KK. C. Wang is an employee and stockholder of Eli Lilly and Company. P. Abada is an employee of Eli Lilly and Company. R. Widau is an employee and stockholder of Eli Lilly and Company. A. Zhu is an Associate Editor of Liver Cancer and reports personal fees from Roche, Lilly, Eisai, Bayer, Merck, Exelixis, & Sanofi. Funding Information: This study was funded by Eli Lilly and Company. Publisher Copyright: {\textcopyright} 2021 ",

year = "2021",

month = sep,

day = "1",

doi = "10.1159/000516605",

language = "English",

volume = "10",

pages = "451--460",

journal = "Liver Cancer",

issn = "2235-1795",

publisher = "S. Karger AG",

number = "5",

}

Kudo, M, Finn, RS, Morimoto, M, Rau, KM, Ikeda, M, Yen, CJ, Galle, PR, Llovet, JM, Daniele, B, Lim, HY, McIlwain, DW, Yoshikawa, R, Nakamura, K, Liang, K, Wang, C, Abada, P, Widau, RC & Zhu, AX 2021, 'Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein: Pooled results from two phase 3 studies (REACH and REACH-2)', Liver Cancer, vol. 10, no. 5, pp. 451-460. https://doi.org/10.1159/000516605

TY - JOUR

T1 - Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein

T2 - Pooled results from two phase 3 studies (REACH and REACH-2)

AU - Kudo, Masatoshi

AU - Finn, Richard S.

AU - Morimoto, Manabu

AU - Rau, Kun Ming

AU - Ikeda, Masafumi

AU - Yen, Chia Jui

AU - Galle, Peter R.

AU - Llovet, Josep M.

AU - Daniele, Bruno

AU - Lim, Ho Yeong

AU - McIlwain, David W.

AU - Yoshikawa, Reigetsu

AU - Nakamura, Kenichi

AU - Liang, Kun

AU - Wang, Chunxiao

AU - Abada, Paolo

AU - Widau, Ryan C.

AU - Zhu, Andrew X.

N1 - Funding Information: M. Kudo is the Editor-in-Chief of Liver Cancer and reports grant and personal fees from Eisai and EA Pharma; grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, and Abbvie; and personal fees from Roche, Ono, Eli Lilly and Company, BMS, and Bayer. R. Finn is an Editorial Board Member of Liver Cancer and reports personal fees from AstraZeneca and Cstone; grants and personal fees from Bayer, Eisai, Bristol-Myers Squibb, Roche/Genentech, Merck, Pfizer, and Eli Lilly and Company. M. Morimoto, K. Rau, H. Lim, and K. Liang have nothing to disclose. M. Ikeda is an Editorial Board Member of Liver Cancer and reports fees for honoraria, advisory board, & research funding from Eli Lilly and Company, Bayer, Eisai, AstraZeneca, Chugai, Takeda, & Novartis; honoraria and research funding from Bristol-Myers Squibb, MSD, & EA Pharma; fees for advisory boards and research funding from Nihon Servier and Aslan; fees for research funding from Merck Serono, Yakult, Ono, J-Pharma, Pfizer, Chiome Bioscience, & GlaxoSmithKline; honoraria fees from Taiho, Teijin Pharma, Astellas, Sumitomo Dainippon, Gilead, & Otsuka. C. Yen has nothing to disclose. P. Galle reports grants from Bayer as well as personal fees from Bayer, BMS, AstraZeneca, Sirtex, MSD, Eisai, Ipsen, and Roche. J. Llovet reports grants and personal fees from Bayer Pharmaceuticals, Eisai, Boehringer Ingelheim, & Ipsen, grants from Bristol-Myers Squibb, and personal fees from Eli Lilly and Company, Celsion, Merck, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha, AstraZeneca, Axis, & Medscape. B. Daniele reports personal fees and nonfinancial support from Ipsen, Sanofi, & Bayer as well as personal fees from Esiai, Eli Lilly and Company, AstraZeneca, MSD, Roche, & Amgen. D. McIlwain is an employee and stockholder of Eli Lilly and Company. R. Yoshikawa is a full-time employee and shareholder of Eli Lilly and Company. K. Nakamura is an employee of Eli Lilly Japan KK. C. Wang is an employee and stockholder of Eli Lilly and Company. P. Abada is an employee of Eli Lilly and Company. R. Widau is an employee and stockholder of Eli Lilly and Company. A. Zhu is an Associate Editor of Liver Cancer and reports personal fees from Roche, Lilly, Eisai, Bayer, Merck, Exelixis, & Sanofi. Funding Information: This study was funded by Eli Lilly and Company. Publisher Copyright: © 2021

PY - 2021/9/1

Y1 - 2021/9/1

N2 - Background: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0-1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. Results: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546-1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23-0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59-0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. Conclusions: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.

AB - Background: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0-1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. Results: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546-1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23-0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59-0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. Conclusions: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.

KW - Barcelona clinic liver cancer stage

KW - Ramucirumab

KW - α-fetoprotein

UR - http://www.scopus.com/inward/record.url?scp=85111642243&partnerID=8YFLogxK

U2 - 10.1159/000516605

DO - 10.1159/000516605

M3 - Article

AN - SCOPUS:85111642243

SN - 2235-1795

VL - 10

SP - 451

EP - 460

JO - Liver Cancer

JF - Liver Cancer

IS - 5

ER -

Ramucirumab for patients with intermediate-stage hepatocellular carcinoma and elevated alpha-fetoprotein: Pooled results from two phase 3 studies (REACH and REACH-2)

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