A Phase II and Biomarker Study of Ramucirumab, a Human Monoclonal Antibody Targeting the VEGF Receptor-2, as First-Line Monotherapy in Patients with Advanced Hepatocellular Cancer

Abstract

Purpose To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers. Experimental Design Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients. Results Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6–5.7], ORR was 9.5% (95% CI, 2.7–22.6; 4/42 patients had apartial response), and median OS was 12.0 months (95% CI, 6.1–19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5–9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1–23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2. Conclusion Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.

Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer

“…Consistent with multiple prior studies of anti-VEGF/VEGFR agents, including bevacizumab in sarcoma, rectal, breast, and ovarian cancer, we found that anti-VEGF therapy led to a sustained increase in PlGF, suggesting that this may be a pharmacodynamic marker of activity (21)(22)(23)(24)(25)(26)(27)(28). We also found that, although pretreatment plasma VEGF does not associate with outcome, higher levels of sVEGFR1 before combination therapy were associated with worse survival.…”

“…We also found that, although pretreatment plasma VEGF does not associate with outcome, higher levels of sVEGFR1 before combination therapy were associated with worse survival. Multiple previous studies have shown that high levels of sVEGFR1 are correlated with worse clinical outcomes, making sVEGFR1 a potential biomarker of intrinsic resistance to antiangiogenic therapy (22,28). Finally, the number of circulating CD14+ monocytes, a potential biomarker of systemic inflammation, associated with poor survival.…”

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

“…The majority of patients enrolled in this trial have wellpreserved liver function. An interesting aspect in this trial is the observed OS stratified by liver function difference, showing longer OS favoring ramucirumab Child-Pugh B group than Child-Pugh A group (18.0 mo vs 4.4 mo, both are barcelona clinic liver cancer-C) [47] . This positive study spurred the initiation of REACH (NCT01140347).…”

Diagnosis and treatment of hepatocellular carcinoma: An update

“…There is also VEGF gene overexpression (vascular endothelial growth factor) that correlates with the tumor's angiogenic capacity [10] and has led to attempts to develop target therapies against VEGF [11] . Other oncogenic factors include the overexpression of extracellular matrix metalloprotease inducers (EMMPRIN or CD147) that have been associated to increased vascularization, invasion, metastases development and tumor recurrence [12] .…”