Author information

• ¹University Medical Center, Mainz, Germany.
• ²Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
• ³Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
• ⁴Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain.
• ⁵Institució Catalana d'Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
• ⁶University of California, Los Angeles, California, USA.
• ⁷University of Iowa Hospitals and Clinics, University of Iowa Health Care, Iowa City, IA, USA.
• ⁸Estaing Hospital, Aubrac, Clermont-Ferrand, France.
• ⁹Seoul National University Hospital, Seoul, Korea.
• ¹⁰Chang Gung Memorial Hospital, Taoyuan, Taiwan, China.
• ¹¹Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
• ¹²Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic.
• ¹³University Hospital Saint-Etienne North, Saint Etienne, France.
• ¹⁴CHU Hôtel-Dieu, Nantes, France.
• ¹⁵Division of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
• ¹⁶University Hospital Inselspital and University of Bern, Bern, Switzerland.
• ¹⁷Eli Lilly and Company, Indianapolis, IN, USA.
• ¹⁸Massachusetts General Hospital Cancer Center, Boston, MA, USA.
• ¹⁹Jiahui International Cancer Center, Jiahui Health, Shanghai, China.

Abstract

Background & aims: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying etiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease etiology and baseline serum viral load.

Methods: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N=542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by etiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pretreatment serum HBV-DNA and HCV-RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study).

Results: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N=225, HCV: N=127, Other: N=190). No significant difference in treatment effect by etiology subgroup was detected (OS interaction p-value= 0.23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74; 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82; 95% CI 0.55-1.23) for HCV, and 8.5 versus 5.4 (HR 0.56; 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function, and liver-specific adverse events.

Conclusions: Ramucirumab improved survival across etiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.