Ramucirumab HCC Data Published Amid Launch of Second Phase III Trial

Andrew X. Zhu, MD

Second-line treatment with ramucirumab (Cyramza) did not improve overall survival (OS) compared with placebo in the full population of patients with advanced hepatocellular carcinoma (HCC) examined in the phase III REACH study, according to findings published in The Lancet Oncology.¹

Lilly Oncology, the company that manufactures the VEGFR-2 inhibitor, had announced the lack of OS benefit in June 2014. Further analyses of the study have been undertaken, including a subgroup analysis presented at the 2015 GI Cancers Symposium, which demonstrated that patients with high expression of alpha-fetoprotein (AFP) did experience an OS benefit with the VEGFR-2 inhibitor.² Based on these findings, the phase III REACH-2 study was established, with the goal of assessing ramucirumab specifically in patients with AFP-high HCC.

"Further analyses from the REACH study have identified AFP as a potential marker for selecting patients with advanced hepatocellular carcinoma who may benefit from ramucirumab treatment," principal investigator of the REACH trial Andrew X. Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital Cancer Center, said in a statement. "Advanced liver cancer carries a poor prognosis with limited treatment options. Several phase III studies to date have not been able to demonstrate improved survival in the second-line setting following sorafenib failure."

In the randomized phase III REACH study, 565 patients with HCC were randomized to receive intravenous ramucirumab at 8 mg/kg every 2 weeks (n = 283) or placebo (n = 282). All patients received best supportive care. The primary endpoint was OS in the intention-to-treat population, with progression-free survival (PFS) and other measures of response as secondary endpoints.

In the full population of the study, the median OS was 9.2 months with ramucirumab compared with 7.6 months with placebo (HR = 0.87; 95% CI, 0.72—1.05; P = .14). The numerical difference of 1.6 months between the two arms did not cross the barrier for statistical significant.

In the planned analysis of patients with HCC and elevated AFP, the median OS for patients with a baseline AFP >400 ng/mL was 7.8 months in the ramucirumab arm compared with 4.2 months with placebo (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 ramucirumab versus 11.8 months for those receiving placebo.

The most frequently reported grade ≥3 adverse events in the ramucirumab arm compared with placebo, respectively, were hypertension (12% vs 4%), malignant neoplasm progression (6% vs 4%), ascites (5% vs 4%), asthenia (5% vs 2%), and thrombocytopenia (5% vs <1%). Malignant neoplasm progression was the most frequently reported serious adverse event.

Some grade ≥3 adverse events were more common with placebo compared with ramucirumab, respectively, including increased aspartate aminotransferase concentration (8% vs 5%), hyperbilirubinaemia (5% vs 1%), and increased blood bilirubin (5% vs 2%). "Globally, a high unmet need exists in second-line hepatocellular carcinoma, and currently there are no therapies approved in the United States, European Union, or Japan to treat patients in this setting," Richard Gaynor, MD, senior vice president, product development and medical affairs for Lilly Oncology, said in a statement. "We are encouraged by the efficacy seen overall in the REACH study, especially in specific subpopulations, and we hope to confirm those results with the new Cyramza phase III trial."

The glycoprotein AFP is overexpressed in approximately 70% of patients with HCC, representing a large population of patients for the REACH-2 trial. This phase III study will compare second-line ramucirumab at 8 mg/kg every 2 weeks with placebo for patients with AFP-elevated advanced HCC. The study plans to enroll 399 participants, with an estimated study completion date of April 2018 (NCT02435433).

In addition to HCC, Ramucirumab has been approved for a number of indications, all within a relatively short timeframe. The agent is approved as a monotherapy and in combination with paclitaxel for patients with gastric cancer. Additionally, ramucirumab is approved in combination with docetaxel for non—small cell lung cancer and with FOLFIRI for patients with colorectal cancer.

1. Zhu AX, Park JO, Ryoo B-Y, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial [published online June 18, 2015]. Lancet Oncol. 2015.
2. 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.