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)

Liver Cancer. 2021 Jul 12;10(5):451-460. doi: 10.1159/000516605. eCollection 2021 Sep.

Authors

Masatoshi Kudo¹, Richard S Finn², Manabu Morimoto³, Kun-Ming Rau^{4

5}, Masafumi Ikeda⁶, Chia-Jui Yen⁷, Peter R Galle⁸, Josep M Llovet^{9

10

11}, Bruno Daniele¹², Ho Yeong Lim¹³, David W McIlwain¹⁴, Reigetsu Yoshikawa¹⁵, Kenichi Nakamura¹⁵, Kun Liang¹⁴, Chunxiao Wang¹⁴, Paolo Abada¹⁴, Ryan C Widau¹⁴, Andrew X Zhu^{16

17}

Affiliations

¹ Departments of Gastroenterology and Hepatology, Kindai University, Osaka, Japan.
² Geffen School of Medicine, University of California, Los Angeles, California, USA.
³ Kanagawa Cancer Center, Yokohama, Japan.
⁴ Chang Gung Memorial Hospital - Kaohsiung Branch, Kaohsiung City, Taiwan.
⁵ Hematology-Oncology Department, E-Da Cancer Hospital, Kaohsiung, Taiwan.
⁶ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁷ Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁸ Department of Internal Medicine, Mainz University Medical Center, Mainz, Germany.
⁹ Mount Sinai Liver Cancer Program, Department of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁰ Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
¹¹ Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
¹² Ospedale del Mare, Naples, Italy.
¹³ Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
¹⁴ Eli Lilly and Company, Indianapolis, Indiana, USA.
¹⁵ Eli Lilly Japan K.K., Kobe, Japan.
¹⁶ Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
¹⁷ Jiahui International Cancer Center, Jiahui Health, Shanghai, China.

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.