Ramucirumab Improves Survival in HCC Subgroup

Photo by © ASCO/Todd Buchanan 2015

Andrew Zhu, MD

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

“Clinically meaningful improvement in overall survival was observed in populations with a baseline AFP greater than 400 ng/mL,” said lead author Andrew Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital.

Initiated in 2010, the double-blind phase III REACH study enrolled 565 patients across 27 countries. Patients with advanced HCC were randomized to receive best supportive care plus either the VEGFR-2 inhibitor ramucirumab or placebo following first-line treatment with sorafenib (Nexavar).

“After first-line sorafenib, no treatment has demonstrated a survival benefit in the second-line setting,” said Zhu.

In June 2014, Eli Lilly and Company, the manufacturer of ramucirumab, announced that REACH had missed its primary endpoint of a statistically significant improvement in OS.

The safety data for REACH were consistent with previous studies of single-agent ramucirumab, according to the company’s press release. The most common grade ≥3 adverse events occurring at a higher rate in the ramucirumab arm compared with the control arm were hypertension and fatigue.

In posthoc analysis of the trial results, it was observed that ramucirumab treatment led to a greater reduction in the risk of death in patients with progressively higher baseline AFP values (≥400 ng/mL). Thus, additional analyses were conducted to evaluate the relationship between baseline AFP and ramucirumab treatment.

The analyses found that with ramucirumab, the median OS for patients with a baseline AFP >400 ng/mL was 7.8 months, compared with 4.2 months for the placebo group (HR = 0.674; 95% CI, 0.51-0.90; P = .0059). In contrast, for patients with a baseline AFP <400 ng/mL, OS was 10.1 months with the treatment compared with 11.8 months for those receiving placebo.

“The forest plot of overall survival by subgroup in patients with baseline AFP above 400 clearly and numerically shows a favorable outcome with ramucirumab for overall survival in all subgroups tested,” Zhu noted.

“The overall survival decreases in both [ramucirumab and placebo] 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,” he added.

When asked by a member of the audience at the GI symposium to explain the underlying biology of this phenomenon—why patients with higher AFP levels responded to ramucirumab 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 endiogenesis, 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 ramucirumab’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.”

Ramucirumab 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.

In data from the phase III RAISE trial reported at the GI symposium, second-line ramucirumab combined with standard FOLFIRI extended survival by 1.6 months versus FOLFIRI alone in patients with metastatic colorectal cancer.

Zhu AX, Ryoo B-Y, Yen C-J, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 232.

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