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Ramucirumab targeted therapy extends liver cancer survival

Liz Highleyman
09 July 2018

Ramucirumab (Cyramza), a type of targeted therapy that slows tumour growth by blocking blood vessel formation, led to improved overall survival and delayed disease progression in people with hepatocellular carcinoma (HCC), according to study results presented at the American Society of Clinical Oncology (ASCO) annual meeting last month in Chicago.

The REACH-2 study showed that second-line treatment with ramucirumab extended median survival by only about a month compared with placebo. However, the proportion of people who were still alive at 18 months after starting treatment more than doubled, from 11.3% to 24.5%.

Over years or decades, chronic hepatitis B or C infection, heavy alcohol use and other causes of liver damage can lead to cirrhosis and HCC, a type of primary liver cancer. HCC is often diagnosed late, when it is difficult to treat, making it a leading cause of cancer death worldwide. Antiviral therapy for hepatitis B reduces but does not eliminate the risk of developing liver cancer, and people with hepatitis C who have progressed to cirrhosis remain at risk for HCC even after being cured of the virus.


alpha-fetoprotein (AFP)

A protein found in the blood, used to detect early signs of liver cancer.

hepatocellular carcinoma (HCC)

Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.

Traditional chemotherapy does not work very well against liver cancer, but targeted therapies known as multi-kinase inhibitors, which target pathways involved in cell growth and blood vessel formation, have shown promise.

Sorafenib (Nexavar) is the standard first-line systemic therapy for advanced HCC, according to recently updated HCC guidelines from the European Association for the Study of the Liver (EASL). The guidelines also recommend lenvatinib (Lenvima). Regorafenib (Stivarga) is recommended for second-line treatment, and cabozantinib (Cabometyx) has shown good results in clinical trials. Although EASL does not yet recommend immunotherapy for liver cancer, the US Food and Drug Administration has approved the checkpoint inhibitor nivolumab (Opdivo) for HCC.

Ramucirumab (Cyramza) is a monoclonal antibody that interferes with angiogenesis, or blood vessel formation. By blocking activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), the drug prevents the development of new blood vessels needed to supply growing tumours.

A previous trial found that although ramucirumab did not improve overall survival among people with advanced HCC as a whole, it did lead to a significant survival benefit for those with highly elevated alpha-fetoprotein (AFP), a biomarker used for liver cancer screening that is associated with worse outcomes.

At the ASCO meeting, Andrew Zhu of Massachusetts General Hospital in Boston presented findings from REACH-2, a follow-up study focusing on people with advanced HCC and elevated AFP (> 400 ng/ml) who were previously treated with first-line sorafenib.

The study included 292 people with HCC in 20 countries in Europe, North America, Latin America and Asia. About 80% were men and the median age was 64 years. More than a third had liver cancer related to hepatitis B, 26% had hepatitis C, 24% had a history of heavy alcohol use and 8% had fatty liver disease.

The participants had liver cancer that was not considered treatable with local therapies or that had recurred after such treatment. They were classified as Child-Pugh Class A, meaning they had well-preserved liver function. Nearly three-quarters had cancer spread beyond the liver. They had stopped taking sorafenib due to disease progression or side-effects.

Participants were randomly assigned to receive intravenous infusions of ramucirumab (8 mg/kg) or placebo every two weeks, along with the best supportive care.

The median overall survival was 8.5 months in the ramucirumab arm vs 7.3 months in the placebo arm. Although the difference was small, it was statistically significant (p = 0.0199). At 12 months, 36.8% of ramucirumab recipients and 30.3% of placebo recipients were still alive (not a significant difference). However, the difference was greater, and became significant, by 18 months: 24.5% vs 11.3%, respectively (p = 0.0187).

The median progression-free survival, meaning people were still alive without worsening of disease, was 2.8 months in the ramucirumab arm vs 1.6 months in the placebo arm (P < 0.0001).

Overall response rates, meaning complete or partial tumour shrinkage, were 4.6% and 1.1% (not significantly different); no one had a complete response. However, looking at the disease control rate, meaning either tumour shrinkage or stable disease, ramucirumab performed significantly better than placebo: 59.9% vs 38.9% (P = 0.0006).

Treatment with ramucirumab was generally safe, but side-effects were common. Rates of discontinuation due to treatment-related adverse events were 10.7% in the ramucirumab arm vs 3.2% in the placebo arm; about a third of ramucirumab recipients adjusted their doses to reduce side-effects. The most notable severe treatment-emergent adverse event in the ramucirumab arm was high blood pressure (12% vs 5% in the placebo arm). About 18% experienced severe liver dysfunction or liver failure, but this was similar in the placebo arm (16%) and likely reflects underlying disease progression.

"REACH-2 is the first positive study in a biomarker-selected patient population, demonstrating a significant and meaningful overall survival benefit and favourable safety profile in HCC patients with baseline AFP >400 ng/ml, a population associated with poor prognosis," the investigators concluded.


Zhu AX et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. American Society of Clinical Oncology Annual Meeting, Chicago, abstract 4003, 2018.