Masatoshi Kudo1, Richard S Finn2, Manabu Morimoto3, Kun-Ming Rau4,5, Masafumi Ikeda6, Chia-Jui Yen7, Peter R Galle8, Josep M Llovet9,10,11, Bruno Daniele12, Ho Yeong Lim13, David W McIlwain14, Reigetsu Yoshikawa15, Kenichi Nakamura15, Kun Liang14, Chunxiao Wang14, Paolo Abada14, Ryan C Widau14, Andrew X Zhu16,17. 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.
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.
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Authors: Giuseppe Cabibbo; Maria Reig; Ciro Celsa; Ferran Torres; Salvatore Battaglia; Marco Enea; Giacomo Emanuele Maria Rizzo; Salvatore Petta; Vincenza Calvaruso; Vito Di Marco; Antonio Craxì; Amit G Singal; Jordi Bruix; Calogero Cammà Journal: Liver Cancer Date: 2021-11-23 Impact factor: 11.740