Ramucirumab Misses OS Endpoint in Phase III REACH Trial

June 20, 2015

Treatment with ramucirumab did not demonstrate a statistically significant improvement in overall survival compared with placebo for patients with hepatocellular carcinoma who had received prior treatment with sorafenib.

Andrew X. Zhu, MD

Treatment with ramucirumab (Cyramza) did not demonstrate a statistically significant improvement in overall survival (OS) compared with placebo for patients with hepatocellular carcinoma (HCC) who had received prior treatment with sorafenib, according to results from the phase III REACH trial published in The Lancet Oncology.1

In 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.

"Advanced liver cancer carries a poor prognosis with limited treatment options," 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. "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.

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.

A subgroup analysis presented at the 2015 GI Cancers Symposium demonstrated that patients with high expression of alpha-fetoprotein (AFP) did experience an OS benefit with the VEGFR-2 inhibitor.2The 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.

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. This 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).

"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," Zhu said.

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.

References

  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 &alpha;-fetoprotein (AFP) from the randomized phase III REACH study. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 232.