Ramucirumab in Sorafenib-Pretreated Patients With Advanced Hepatocellular Carcinoma

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In the phase III REACH-2 trial reported in The Lancet Oncology, Andrew X. Zhu, MD, of Harvard Medical School and Massachusetts General Hospital, and colleagues found that ramucirumab improved overall and progression-free survival vs placebo in patients with advanced hepatocellular carcinoma and increased α-fetoprotein levels who had previously received sorafenib.1

Study Details

In the double-blind trial, 292 patients who had received first-line sorafenib and had advanced disease as well as α-fetoprotein concentrations ≥ 400 ng/mL from 92 sites in 20 countries were randomly assigned 2:1 between July 2015 and August 2017 to receive ramucirumab at 8 mg/kg intravenously every 2 weeks (n = 197) or placebo (n = 95). All patients received best supportive care. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Sorafenib was the only previous systemic treatment permitted. Patients had to have Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was overall survival in the intent-to-treat population.

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For the ramucirumab vs placebo groups, the median age was 64 years in both; 78% vs 83% were male; 52% vs 47% were Asian and 30% vs 33% were white; the ECOG performance status was 0 in 57% vs 58% and 1 in 43% vs 42%; 36% vs 35% had macrovascular invasion; 72% vs 74% had extrahepatic spread; causes of hepatocellular carcinoma were hepatitis B virus in 36% vs 38%, hepatitis C virus in 24% vs 29%, substantial alcohol use in 24% vs 22%, and steatohepatitis in 10% vs 4%; the median duration of prior sorafenib was 4.1 months in both; the reason for sorafenib discontinuation was progressive disease in 84% vs 80% and intolerance in 16% vs 20%; the time to the last sorafenib treatment was < 1 month in 52% vs 57%; prior therapy included surgery in 44% vs 41% and radiotherapy in 18% vs 20%; and 94% vs 93% had no ascites.

Overall and Progression-Free Survival

At a median follow-up of 7.6 months, the median overall survival was 8.5 months (95% confidence interval [CI] = 7.0–10.6 months) in the ramucirumab group vs 7.3 months (95% CI = 5.4–9.1 months) in the placebo group (hazard ratio [HR] = 0.710, P = .0199), and the median progression-free survival was 2.8 months (95% CI = 2.8–4.1 months) vs 1.6 months (95% CI = 1.5–2.7 months; HR = 0.452, P < .0001). In the pooled analysis of efficacy from REACH-2 and REACH, the median overall survival was significantly improved in the ramucirumab group than the placebo group (8.1 months [95% CI = 6.9–9.3 months] vs 5.0 months [4.3–6.1 months]; HR = 0.694 [95% CI = 0.571–0.842; P = .0002].

In a subgroup analysis, hazard ratios for overall and progression-free survival favored ramucirumab except among women (only 16 in placebo group). Postdiscontinuation systemic therapies were generally balanced between the groups; a sensitivity analysis showed that the difference in overall survival between the groups was still significant after censoring for postdiscontinuation systemic therapies. The objective response rate was 5% vs 1% per Response Evaluation Criteria in Solid Tumors, version 1.1 (P = .1697).

Adverse Events

The most common adverse events of any grade in the ramucirumab group were fatigue (27%), peripheral edema (25%), hypertension (25%), and decreased appetite (23%). Grade ≥ 3 adverse events that occurred in at least 5% of patients in either group were hypertension (13% in the ramucirumab group vs 5% in the placebo group), hyponatremia (6% vs 0%), and increased aspartate aminotransferase levels (3% vs 5%). Serious adverse events occurred in 35% vs 29% of patients. Adverse events led to treatment discontinuation in 18% vs 11% of patients. Adverse events considered related to treatment resulted in death in three patients in the ramucirumab group, with deaths due to acute kidney injury, hepatorenal syndrome, and renal failure.


  • Ramucirumab significantly improved overall and progression-free survival vs placebo in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations.
  • The median overall survival was 8.5 months vs 7.3 months.

The median time to deterioration in Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (3.7 months vs 2.8 months, HR = 0.799, P = .238) and ECOG performance status (HR = 1.082, P = .77) did not differ between the groups.

The investigators concluded: “REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase III trial done in a biomarker-selected patient population with hepatocellular carcinoma.” 

DISCLOSURE: The study was funded by Eli Lilly. For full disclosures of the study authors, visit


1. Zhu AX, Kang YK, Yen CJ, et al: Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:282-296, 2019.

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