Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score

Andrew X. Zhu, Ari David Baron, Peter Malfertheiner, Masatoshi Kudo, Seiji Kawazoe, Denis Pezet, Florian Weissinger, Giovanni Brandi, Carlo A. Barone, Takuji Okusaka, Yoshiyuki Wada, Joon Oh Park, Baek Yeol Ryoo, Jae Yong Cho, Hyun Cheol Chung, Chung Pin Li, Chia Jui Yen, Kuan Der Lee, Shao Chun Chang, Ling YangPaolo B. Abada, Ian Chau

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

IMPORTANCE REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). OBJECTIVE To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. DESIGN, SETTINGS, AND PARTICIPANTS Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). INTERVENTIONS Ramucirumab (8mg/kg) or placebo intravenously plus best supportive care every 2 weeks. MAIN OUTCOMES AND MEASURES Overall survival (OS), defined as time from randomization to death from any cause. RESULTS In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80 95%CI, 0.63-1.02 P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61 95%CI, 0.43-0.87 P = .01) and Child-Pugh 6 (HR, 0.64 95%CI, 0.42-0.98 P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. CONCLUSIONS AND RELEVANCE In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more.

Original languageEnglish
Pages (from-to)235-243
Number of pages9
JournalJAMA oncology
Volume3
Issue number2
DOIs
Publication statusPublished - Feb 1 2017
Externally publishedYes

Fingerprint

Hepatocellular Carcinoma
Fetal Proteins
Therapeutics
Liver Neoplasms
Survival
ramucirumab
Liver Diseases
Placebos
Asthenia
Poisons
Anniversaries and Special Events
Random Allocation
Ascites
Cause of Death
Fibrosis
Chronic Disease
Hemorrhage

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score. / Zhu, Andrew X.; Baron, Ari David; Malfertheiner, Peter; Kudo, Masatoshi; Kawazoe, Seiji; Pezet, Denis; Weissinger, Florian; Brandi, Giovanni; Barone, Carlo A.; Okusaka, Takuji; Wada, Yoshiyuki; Park, Joon Oh; Ryoo, Baek Yeol; Cho, Jae Yong; Chung, Hyun Cheol; Li, Chung Pin; Yen, Chia Jui; Lee, Kuan Der; Chang, Shao Chun; Yang, Ling; Abada, Paolo B.; Chau, Ian.

In: JAMA oncology, Vol. 3, No. 2, 01.02.2017, p. 235-243.

Research output: Contribution to journalArticle

Zhu, AX, Baron, AD, Malfertheiner, P, Kudo, M, Kawazoe, S, Pezet, D, Weissinger, F, Brandi, G, Barone, CA, Okusaka, T, Wada, Y, Park, JO, Ryoo, BY, Cho, JY, Chung, HC, Li, CP, Yen, CJ, Lee, KD, Chang, SC, Yang, L, Abada, PB & Chau, I 2017, 'Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score', JAMA oncology, vol. 3, no. 2, pp. 235-243. https://doi.org/10.1001/jamaoncol.2016.4115
Zhu, Andrew X. ; Baron, Ari David ; Malfertheiner, Peter ; Kudo, Masatoshi ; Kawazoe, Seiji ; Pezet, Denis ; Weissinger, Florian ; Brandi, Giovanni ; Barone, Carlo A. ; Okusaka, Takuji ; Wada, Yoshiyuki ; Park, Joon Oh ; Ryoo, Baek Yeol ; Cho, Jae Yong ; Chung, Hyun Cheol ; Li, Chung Pin ; Yen, Chia Jui ; Lee, Kuan Der ; Chang, Shao Chun ; Yang, Ling ; Abada, Paolo B. ; Chau, Ian. / Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score. In: JAMA oncology. 2017 ; Vol. 3, No. 2. pp. 235-243.
@article{95a33d026d7b41579fd3c32d53d391a4,
title = "Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score",
abstract = "IMPORTANCE REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). OBJECTIVE To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. DESIGN, SETTINGS, AND PARTICIPANTS Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). INTERVENTIONS Ramucirumab (8mg/kg) or placebo intravenously plus best supportive care every 2 weeks. MAIN OUTCOMES AND MEASURES Overall survival (OS), defined as time from randomization to death from any cause. RESULTS In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80 95{\%}CI, 0.63-1.02 P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61 95{\%}CI, 0.43-0.87 P = .01) and Child-Pugh 6 (HR, 0.64 95{\%}CI, 0.42-0.98 P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. CONCLUSIONS AND RELEVANCE In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more.",
author = "Zhu, {Andrew X.} and Baron, {Ari David} and Peter Malfertheiner and Masatoshi Kudo and Seiji Kawazoe and Denis Pezet and Florian Weissinger and Giovanni Brandi and Barone, {Carlo A.} and Takuji Okusaka and Yoshiyuki Wada and Park, {Joon Oh} and Ryoo, {Baek Yeol} and Cho, {Jae Yong} and Chung, {Hyun Cheol} and Li, {Chung Pin} and Yen, {Chia Jui} and Lee, {Kuan Der} and Chang, {Shao Chun} and Ling Yang and Abada, {Paolo B.} and Ian Chau",
year = "2017",
month = "2",
day = "1",
doi = "10.1001/jamaoncol.2016.4115",
language = "English",
volume = "3",
pages = "235--243",
journal = "JAMA oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "2",

}

TY - JOUR

T1 - Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score

AU - Zhu, Andrew X.

AU - Baron, Ari David

AU - Malfertheiner, Peter

AU - Kudo, Masatoshi

AU - Kawazoe, Seiji

AU - Pezet, Denis

AU - Weissinger, Florian

AU - Brandi, Giovanni

AU - Barone, Carlo A.

AU - Okusaka, Takuji

AU - Wada, Yoshiyuki

AU - Park, Joon Oh

AU - Ryoo, Baek Yeol

AU - Cho, Jae Yong

AU - Chung, Hyun Cheol

AU - Li, Chung Pin

AU - Yen, Chia Jui

AU - Lee, Kuan Der

AU - Chang, Shao Chun

AU - Yang, Ling

AU - Abada, Paolo B.

AU - Chau, Ian

PY - 2017/2/1

Y1 - 2017/2/1

N2 - IMPORTANCE REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). OBJECTIVE To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. DESIGN, SETTINGS, AND PARTICIPANTS Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). INTERVENTIONS Ramucirumab (8mg/kg) or placebo intravenously plus best supportive care every 2 weeks. MAIN OUTCOMES AND MEASURES Overall survival (OS), defined as time from randomization to death from any cause. RESULTS In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80 95%CI, 0.63-1.02 P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61 95%CI, 0.43-0.87 P = .01) and Child-Pugh 6 (HR, 0.64 95%CI, 0.42-0.98 P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. CONCLUSIONS AND RELEVANCE In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more.

AB - IMPORTANCE REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). OBJECTIVE To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. DESIGN, SETTINGS, AND PARTICIPANTS Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). INTERVENTIONS Ramucirumab (8mg/kg) or placebo intravenously plus best supportive care every 2 weeks. MAIN OUTCOMES AND MEASURES Overall survival (OS), defined as time from randomization to death from any cause. RESULTS In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80 95%CI, 0.63-1.02 P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to μg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61 95%CI, 0.43-0.87 P = .01) and Child-Pugh 6 (HR, 0.64 95%CI, 0.42-0.98 P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. CONCLUSIONS AND RELEVANCE In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more.

UR - http://www.scopus.com/inward/record.url?scp=85018696285&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018696285&partnerID=8YFLogxK

U2 - 10.1001/jamaoncol.2016.4115

DO - 10.1001/jamaoncol.2016.4115

M3 - Article

AN - SCOPUS:85018696285

VL - 3

SP - 235

EP - 243

JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

IS - 2

ER -