Tivantinib for second-line treatment of advanced hepatocellular carcinoma: A randomised, placebo-controlled phase 2 study

Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy.
The Lancet Oncology (Impact Factor: 24.69). 11/2012; 14(1). DOI: 10.1016/S1470-2045(12)70490-4
Source: PubMed


: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma.
Methods : In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as >= 2+ in >= 50% of tumour cells). This study is registered with, number NCT00988741.
Findings : 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1.6 months [95% CI 1.4-2.8]) than placebo (1.4 months [1.4-1.5]; hazard ratio [HR] 0.64, 90% CI 0.43-0.94; p=0.04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2.7 months [95% CI 1.4-8.5] for 22 MET-high patients on tivantinib vs 1.4 months [1.4-1.6] for 15 MET-high patients on placebo; HR 0.43, 95% CI 0.19-0.97; p=0.03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events.
Interpretation : Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily.

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Available from: Ziad Hassoun
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    • "Tivantinib demonstrated a manageable safety profile and preliminary antitumor activity in patients with HCC and Child's A or B cirrhosis. Further studies of tivantinib in a biomarker-selected patient population are warranted [84]. "
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    ABSTRACT: Background: Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Materials and methods: A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: "hepatocellular carcinoma," "molecular hepatocarcinogenesis," "targeted therapy," and "immunotherapy." Discussion and conclusion: Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.
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    • "The development of tivantinib, a small molecule inhibitor of the MET receptor can serve as a paradigm. A randomized phase II study was performed with correlative biomarker work showing that high Met-expression may identify a group of patients that benefit most from the drug [11]. While this is hypothesis generating , it is now a strategy for patient selection being employed in a prospective Phase III study. "

    Preview · Article · Feb 2014 · Journal of Hepatology
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    • "Second-line study Phase II: brivanib [7] Phase III: brivanib vs. placebo [8] Phase II: tivantinib [9] "
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    ABSTRACT: No approved therapy is available for patients with advanced hepatocellular carcinoma (HCC) who fail first-line therapy. The prognosis of these patients, especially those eligible for clinical trials of second-line therapy, is unclear. All patients who participated in clinical trials of first-line systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included. Their clinicopathologic characteristics when the first-line treatment failed were analyzed and correlated with the overall survival (OS) from the date of first-line treatment failure. A total of 192 patients were included. Before the start of the first-line therapy, all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program (CLIP) scores ⩽ 4. After the failure of the first-line therapy, the median OS of the entire group was 4.0 months. Patients with Child-Pugh class A liver reserves when the first-line treatment failed had significantly better OS than patients with Child-Pugh class B or C liver reserves (median, A vs. B vs. C = 7.5 vs. 1.3 vs. 1.0 mo, p < 0.001). According to the key eligibility criteria of 3 published clinical trials for second-line therapy, 41% to 56% of patients were potentially eligible. Compared to patients who were ineligible for clinical trials, potentially eligible patients had longer OS with a median of 7.8-8.6 months. Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials.
    Full-text · Article · Feb 2014 · Journal of Hepatology
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