Cyramza Improves Survival in Subgroup of Liver Cancer Patients

An analysis of patients with advanced liver cancer and elevated alpha fetoprotein (AFP) who received second-line Cyramza (ramucirumab) showed a significant improvement in overall survival (OS), according to data from the randomized phase 3 REACH study presented at the 2015 Gastrointestinal Cancers Symposium.

Initiated in 2010, the double-blind study enrolled 565 patients across 27 countries. Patients with advanced liver cancer, also known as hepatocellular carcinoma (HCC), were randomized to receive best supportive care plus either the VEGFR-2 inhibitor Cyramza or placebo following first-line treatment with Nexavar (sorafenib).

“After first-line sorafenib, no treatment has demonstrated a survival benefit in the second-line setting,” said lead author Andrew Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital.

In June 2014, it was announced that REACH had missed its primary endpoint of a statistically significant improvement in OS.

In an analysis of the trial results, it was observed that Cyramza treatment led to a greater reduction in the risk of death in patients with progressively higher baseline AFP values. Thus, additional analyses were conducted to evaluate the relationship between baseline AFP and Cyramza treatment. AFP is a protein made by the liver and commonly used as a biomarker for liver cancer. About two-thirds of liver cancers produce high levels of the protein.

The analyses found that with Cyramza, the median OS for patients with a higher baseline AFP was 7.8 months compared with 4.2 months for the placebo group. In contrast, for patients with a lower baseline, OS was 10.1 months with the treatment compared with 11.8 months for those receiving placebo.

“The overall survival decreases in both arms as increasing AFP thresholds were applied because these patients represent worse prognosis. However, the difference between these arms was generally in the range of 3 to 3.5 months,” Zhu said.

When asked by a member of the audience at the symposium to explain the underlying biology of this phenomenon—why patients with higher AFP levels responded to Cyramza treatment—Zhu was uncertain, but stressed the importance of finding an answer.

“This is a critical question we are actively pursuing,” he said. “We think there may be an underlying link with increased (angiogenesis), but whether this is driven by VEGF or VEGFR-2, the literature is not clear. There is mounting evidence suggesting the high AFP group is really a unique subgroup of patients with a unique genetic signature,” he hypothesized, “but this is a critical question.”

Zhu noted that further investigation of the relationship between baseline AFP level and angiogenesis inhibition was ongoing to better understand Cyramza’s mechanism of action in HCC.

“The additional AFP threshold was posthoc analysis,” he concluded. “There are no clear data yet. Patients will probably benefit between the normal and upper-limit, too, but additional study is necessary.”

Cyramza has approved indications as a single-agent and in combination with paclitaxel to treat patients with advanced gastric or gastroesophageal junction adenocarcinoma. It is also approved in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer. It is also currently being examined in colorectal cancer.