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Novel Therapies on the Horizon in Hepatocellular Carcinoma

Jennifer Gregg, PhD
Published Online: Apr 19,2016

Despite sorafenib’s ability to improve clinical outcomes, the average overall survival (OS) is limited to between 7 and 11 months

Regorafenib is a multikinase inhibitor of VEGF receptors, c-kit, Ret, and FGF receptor, and targets various pathways important for angiogenesis, oncogenesis, and the tumor microenvironment. The FDA has previously approved regorafenib for the treatment of advanced gastrointestinal stromal tumors and previously treated metastatic colorectal cancer.
Jordi Bruix, MD, University of Barcelona, Spain, and colleagues reported phase II findings of regorafenib in the November 2013 issue of European Journal of Cancer.11 The analysis evaluated the safety and efficacy of regorafenib as a second-line therapy following sorafenib failure in 36 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC.
Adverse events related to treatment were mostly mild and occurred in 39% of patients; 14% of patients experienced serious AEs. During the median treatment duration of nearly 20 weeks, 72% of patients exhibited disease control, reaching a TTP of 4.3 months and OS of 13.8 months.11
The results of the phase II trial prompted further investigation in a phase III trial, RESOURCE, which is currently ongoing. Eligible patients, who have failed prior sorafenib therapy, will be randomly assigned to receive either regorafenib or placebo in a 2:1 ratio. The primary endpoint is OS, and the anticipated trial completion is later in 2016.12
Cabozantinib is a small-molecule inhibitor of multiple receptor tyrosine kinases, including HGF receptor (MET), Ret, and the VEGF receptor. The FDA has approved the agent for the treatment of progressive, metastatic medullary thyroid cancer, and an application is pending for metastatic renal cell carcinoma.
In advanced HCC, cabozantinib has shown promising results in a phase II trial, and ongoing data are being gathered in a phase III trial. The phase II data were presented by Chris Verslype, MD, PhD, University Hospital Gasthuisberg, Leuven, Belgium, and colleagues at the 2012 ASCO annual meeting.13
In the phase II randomized discontinuation trial, 41 patients with HCC who had received 1 line of prior systemic therapy and classified as Child-Pugh score A were eligible to participate. Among patients who received cabozantinib in the lead-in phase of the trial, 5% achieved a PR, 78% achieved SD, and 7% had progressive disease. The median OS was 15.1 months, and the median progression-free survival (PFS) was 4.4 months, independent of prior sorafenib therapy. The most common grade 3 or higher AEs were diarrhea, palmar-plantar erythrodysesthesia, and thrombocytopenia.13
The ongoing phase III trial, CELESTIAL, will compare the OS of cabozantinib versus placebo in patients who have received prior sorafenib therapy. The primary completion date is estimated for late 2016.14 
“Patients with advanced HCC who have progressed on sorafenib have few therapeutic options, and new approaches to managing their disease are much needed,” said Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York City, the lead investigator of CELESTIAL. “Phase II data investigating cabozantinib in this patient population are worthy of more study, and cabozantinib’s target profile, which includes inhibition of both MET and VEGFR, is highly relevant in HCC.”15
Tivantinib is a receptor TKI that is selective for MET. Ongoing studies are evaluating MET as a prognostic and predictive indicator of tumor progression and response to tivantinib. Lorenza Rimassa, MD, Humanitas Cancer Center, Rozzano, Milan, Italy, and colleagues recently presented their findings at the 2016 ASCO Gastrointestinal Cancers Symposium.16
In the phase II analysis, 107 patients who had previously failed prior first-line treatment were randomized to receive tivantinib or placebo. Patients were stratified by high or low circulating levels of MET and hepatocyte growth factor (HGF), and also by levels of alpha-fetoprotein (AFP). Circulating levels of MET were prognostic (OS: 4.6 months high vs 8.9 months low; HR, 0.61; P =.023). MET expression also correlated with sorafenib treatment; 40% of patient biopsies prior to treatment were MET-high compared with 82% of biopsies after sorafenib. A significant interaction in OS between tivantinib and MET expression was observed (P =.039). The other biomarkers examined were not predictive of tivantinib response.16

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