• Cancers of the Accessory Digestive Organs
• Oncology Clinical Trials
• Gastrointestinal Cancers

• Cancers of the Accessory Digestive Organs
• Oncology Clinical Trials
• Gastrointestinal Cancers

As second-line therapy for hepatocellular carcinoma (HCC), ramucirumab (RAM) did not improve overall survival (OS) compared with placebo (PBO) in a phase 3 randomized study, but benefit was observed in a selected population with an elevated baseline level of alpha-fetoprotein (AFP). The results of the randomized, phase 3 Ramucirumab Second-Line Treatment in Patients With Hepatocellular Carcinoma After First-Line Therapy With Sorafenib study [REACH; NCT01140347] were presented by Andrew X. Zhu, MD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Currently, no treatment has demonstrated a survival benefit in a second-line setting (after sorafenib) in HCC [Zhu AX et al. JAMA. 2014; Llovet JM et al. J Clin Oncol. 2013]. Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signaling and angiogenesis are likely contributors to HCC tumor growth. RAM is a human immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of VEGFR-2, preventing ligand binding and receptor activation. Preliminary evidence of RAM's anticancer activity was demonstrated in patients with treatment-naïve HCC in a single-arm phase 2 study [Zhu AX et al. Clin Cancer Res. 2013].

REACH evaluated the safety and efficacy of RAM in 565 patients with advanced HCC following first-line therapy with sorafenib. The primary end point was OS with progression-free survival (PFS), objective response rate (ORR), and safety included as secondary end points. Eligible patients had advanced HCC confirmed by histology or radiographic imaging to be Barcelona Clinic Liver Cancer stage C or B, were refractory or not amenable to locoregional therapy, were Child-Pugh Class A, and had disease progression during or following sorafenib therapy (or were intolerant to sorafenib). Patients were randomized to RAM 8 mg/kg intravenously (n = 283) plus best supportive care (BSC), or PBO (n = 282) plus BSC every 2 weeks per cycle, until disease progression or unacceptable toxicity. Baseline demographics and characteristics were balanced between the 2 arms.

The safety population consisted of 553 patients (277 in the RAM arm and 276 in the PBO arm). Grade ≥ 3 treatment-related adverse events reported in ≥ 3% of patients in the RAM arm included hypertension (12% in the RAM arm vs 4% in the PBO arm), thrombocytopenia (5% vs < 1%), hepatic encephalopathy (3% vs < 1%), and neutropenia (3% vs 1%). Bleeding or hemorrhage of any grade occurred in 33% of the RAM group and 20% of the PBO group; liver injury or failure in 51% and 37%, respectively; and proteinuria in 17% and 5%, respectively (Table 1).

In the intention-to-treat population, median OS was 9.2 months in the RAM arm and 7.6 months in the PBO arm (HR, 0.866; P = .1391). Median PFS was 2.8 months in the RAM arm and 2.1 months in the PBO arm (HR, 0.625; P < .0001). The median time to progression was 3.5 months in the RAM arm vs 2.6 months in the PBO arm (P < .0001). The 6-month PFS rates were 37.0% in RAM recipients and 14.9% in PBO recipients, and the 9-month PFS rates were 27.0% and 10.8%, respectively. The objective response rates were 7.1% in the RAM arm and 0.7% in the PBO arm (P < .0001), and the disease control rates were 56.2% and 45.7% (P = .0110), respectively (Table 2).

Two hundred and fifty patients had a baseline AFP level ≥ 400 ng/mL. In a prespecified analysis of OS in this subgroup, the OS HR in the RAM group compared with PBO was 0.674 (P = .0059), with a median OS of 7.8 months in the RAM group vs 4.2 months in the PBO group.

Dr Zhu concluded that although REACH did not demonstrate a significant improvement in OS with RAM in the intent-to-treat population, an elevated baseline AFP may select a population likely to benefit. Further investigation of RAM is warranted based on the REACH results and the unmet need in this disease.

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