Second-line ramucirumab (Cyramza) following treatment with sorafenib (Nexavar) modestly extended overall survival (OS) compared with placebo for selected patients with advanced hepatocellular cancer, findings from the REACH-2 trial showed.
At 7.6 months follow-up, median OS was 29% longer in patients who received second-line ramucirumab, at 8.5 months compared with 7.2 months for those on placebo (HR 0.71, 95% CI 0.53-0.94, P=0.019), reported Andrew Zhu, MD, of the University of Ulsan in Seoul, South Korea, and colleagues in Lancet Oncology.
Median progression-free survival (PFS) with the vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor ramucirumab was also 55% longer, at 2.8 months compared with 1.6 months in the control arm (HR 0.45, 95% CI 0.33-0.60, P<0.0001).
“To our knowledge, REACH-2 is the first phase III, randomized, placebo-controlled trial done in patients with hepatocellular carcinoma who were enrolled on the basis of a biomarker,” the investigators wrote. The trial enrolled only patients with alpha-fetoprotein concentrations ≥400 ng/mL — high levels of this marker are a poor prognostic factor in liver cancer.
The positive results of REACH-2 support the use of VEGFR2 as a therapeutic target in hepatocellular carcinoma, the team concluded.
A total of 292 patients with hepatocellular carcinoma and high levels of alpha-fetoprotein were randomized to receive either ramucirumab or placebo following a median of 4.1 months of sorafenib therapy. Patients received intravenous ramucirumab (8 mg/kg) or placebo for 1 hour every 14 days until disease progression, unacceptable toxicity, or withdrawal of consent, the researchers reported. The median duration of therapy was 12 weeks in the ramucirumab group versus 8 weeks for the placebo group.
The median time to radiographic progression was 58% longer, at 3.0 months in the ramucirumab group compared with 1.6 months among placebo patients (HR 0.42, 95% CI 0.31-0.58, P<0.0001). Median time to deterioration, as reflected by scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 and ECOG performance status, were not significantly different between the two groups.
Objective response rates were also similar in both groups, at 5% with ramucirumab versus 1% with placebo. However, more patients in the ramucirumab group achieved stable disease (59.9% vs 38.9% with placebo, P=0.0006), the researchers said.
The most frequently reported treatment-emergent adverse events of any grade in the VEGFR2 arm were fatigue at 27%, peripheral edema at 25%, hypertension again at 25%, and decreased appetite at 23%. Still, the investigators characterized ramucirumab as “well-tolerated” with a clinically manageable safety profile.
They noted that the initial REACH trial failed to show an improvement in OS with second-line ramucirumab in the intent-to-treat population compared with placebo. However, in a pooled analysis from REACH and REACH-2, 542 patients with baseline alpha-fetoprotein levels ≥400 ng/mL receiving second-line ramucirumab lived 31% longer, at a median of 8.1 months compared with 5.0 months for placebo (P=0.0002).
Potential limitations of REACH-2 include the exclusion of patients with severe liver cirrhosis because of their high risk of mortality independent of cancer, said Ghassan Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York City, writing in an accompanying editorial.
He also took issue with the authors referring to alpha-fetoprotein as a “biomarker.” As he argued, high alpha-fetoprotein levels may be a marker of patients with different disease biology from others with “standard” hepatocellular cancer. Higher levels of alpha-fetoprotein are also likely to manifest in patients with advanced disease, as the patients in REACH-2 clearly were.
Abou-Alfa also suggested that alpha-fetoprotein concentrations depend on when in the disease course they are measured, since levels are highly variable depending on disease stage. “All tested tyrosine kinase inhibitors are geared towards same targets,” he wrote, concluding that while the findings of REACH-2 are positive, they are not “the first positive findings from a phase III study done in a biomarker-selected patient population with hepatocellular carcinoma,” as claimed by the study authors.
The study was funded by Eli Lilly.