In the phase III REACH-2 trial reported in The Lancet Oncology, Zhu et al found that ramucirumab improved overall and progression-free survival vs placebo in patients with advanced hepatocellular carcinoma (HCC) and increased α-fetoprotein levels who had previously received sorafenib.
In the double-blind trial, 292 patients who had received first-line sorafenib and had advanced disease and 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 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was overall survival in the intent-to-treat population.
For the ramucirumab vs placebo groups: median age was 64 years in both; 78% vs 83% were male; 52% vs 47% were Asian and 30% vs 33% were white; 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 HCC 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%.
Median duration of prior sorafenib therapy was 4.1 months in both groups; the reason for sorafenib discontinuation was progressive disease in 84% vs 80% and intolerance in 16% vs 20%; time to 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, 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). 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 subgroup analysis, hazard ratios for overall survival and progression-free survival favored ramucirumab except among women (only 16 in placebo group). Postdiscontinuation systemic therapies were generally balanced between groups; sensitivity analysis showed that the difference in overall survival between groups was still significant after censoring for postdiscontinuation systemic therapies. Objective response rates were 5% vs 1% (P = .1697).
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 ≥ 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 (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 3 patients in the ramucirumab group, with deaths due to acute kidney injury, hepatorenal syndrome, and renal failure.
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 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.”
Andrew X. Zhu, MD, of the Department of Medicine, Harvard Medical School, Massachusetts General Hospital, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Eli Lilly. The study authors' full disclosures can be found at thelancet.com.
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