Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

Abstract

ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC.Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant.Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials.

Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications

“…Despite this clinical need, a lack of progress in this field occurred due to the scarcity of HCC tissues, particularly those obtained at advanced stages and before sorafenib treatment. In a recent analysis, MET (the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) showed a significantly higher expression after than before sorafenib treatment [27]. This is in line with literature suggesting that high MET expression correlates with hypoxia, resistance to anti-angiogenic therapies, and poor prognosis in HCC, and further supports the prognostic role of MET.…”

Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date

“…A more recent study that specifically evaluated MET, HGF and AFP as circulating biomarkers (by 75 percentile) found that they were prognostic markers for overall survival in patients with HCC 57. Circulating MET was also a pharmacodynamic biomarker for tivantinib: patients on treatment with a ≥10% decrease in circulating MET levels demonstrated increased overall survival compared to those with a <10% decrease (13.3 months vs. 6.3 months; HR: 0.46 [95% CI: 0.24–0.86], p =0.01).…”

Systemic Therapy for Hepatocellular Carcinoma: 2017 Update

“…Therefore, refined patient selection by biomarkers (e.g., genetic abnormalities and expressed proteins) was recently proposed [55] . For example, c-MET overexpression was used as a biomarker in trials of tivantinib [46][47][48] , and RAS was used as a biomarker in a trial of an MEK inhibitor [56] . A trial of an FGFR inhibitor using FGF19 as a biomarker is currently ongoing.…”

“…This agent selectively inhibits the hepatocyte growth factor receptor c-MET; strong expression of c-MET in liver cancer tissues is associated with poor prognosis. Following a phase II study that showed significant improvements in OS and TTP among patients with c-MET overexpression who received tivantinib [46,47] , a placebo-controlled phase III study was conducted on patients overexpressing c-MET in liver cancer tissues; this was the first biomarker-selected clinical trial for HCC. To reflect ethnic differences in metabolizing enzyme activities, studies with fundamentally the same design were separately carried out globally (METIV-HCC) and in Japan (JET-HCC) ( Table 1 ).…”