Ramucirumab improves progression-free survival, time to progression and response rate without prolonging overall survival in the second-line treatment of hepatocellular carcinoma

The phase III REACH trial comparing ramucirumab (RAM) with placebo in the second-line treatment of advanced hepatocellular carcinoma (HCC) failed to show an overall survival (OS) benefit in favor of RAM. Nevertheless, RAM was associated with a significantly longer progression-free survival (PFS), a longer time to progression (TTP) and a significantly higher objective response rate (ORR) than placebo. Furthermore, in a selected patient population with an elevated baseline alfa-fetoproteïne (AFP) level, a meaningful OS improvement in the RAM arm was observed.

Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. Sorafenib is the only approved first-line treatment in HCC and currently no treatment has demonstrated a survival benefit in the second-line setting. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. In the phase III REACH study, patients with advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy, with intolerance to sorafenib despite dose reduction, or with disease progression during or following sorafenib, were randomized 1:1 to receive RAM (8 mg/kg IV) (N= 272) plus best supportive care (BSC) or placebo plus BSC (N= 272) every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was OS, while secondary endpoints included PFS, ORR and safety.

The OS in the intent-to-treat population was 9.2 months with RAM compared to 7.6 months with placebo (HR[95%CI]: 0.866 [0.717-1.046]; p = 0.14). The median PFS with RAM was 2.8 months and with placebo 2.1 months, translating in a significant HR of 0.63 (95%CI: 0.52–0.75; p < 0.0001). The TTP in the RAM arm was 3.5 months, compared to 2.6 months with placebo (HR[95%CI]: 0.593 [0.487-0.722]; p < 0.0001). Also, the ORR was significantly higher with RAM at 7.1% compared to 0.7% with placebo (p < 0.0001). In the subgroup of patients with baseline AFP ≥ 400 ng/mL (N= 250), the OS was significantly higher with RAM compared with placebo (7.8 vs. 4.2 months; HR[95%CI]: 0.67 [0.51–0.90]; p = 0.0059).

Grade ≥ 3 adverse events occurring in more than 5% of the RAM treated patients included: hypertension (12.3% RAM vs. 3.6% placebo), asthenia (5.1% vs. 1.8%), aspartate aminotransferase increase (5.4% vs. 8.3%) and malignant neoplasm progression (6.5% vs. 4.0%).

In summary, second line RAM was associated with a significantly longer PFS, TTP and a higher ORR compared to placebo in patients with HCC. Nevertheless, this clinical benefit did not translate in a significantly longer OS in the intent-to-treat population. In a selected patient population with an elevated baseline alfa-fetoproteïne level, a meaningful OS improvement in the RAM arm was observed. Given the high unmet medical need in second-line HCC, further investigation of RAM is warranted in this setting.

Reference

Zhu A, Ryoo B, Yen C, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC) following first-line therapy with sorafenib: results from the randomized phase III REACH study. Presented at ESMO 2014; Abstract LBA 16.