The future of tivantinib, like that of many other drugs, rests on appropriate patient selection. The identification of biomarkers for tivantinib sensitivity is an active area of research with promising early results. The first biomarker for tivantinib in HCC patients was tumor MET status. It was published that patients with MET-high tumors showed a significant survival benefit, with longer median TTP (2.7 months vs. 1.4 months), longer median PFS (2.2 months vs. 1.4 months) and longer median overall survival (7.2 months vs. 3.8 months) on tivantinib compared to placebo.34 No difference in efficacy was found between tivantinib and placebo in patients with MET-low tumors. In a combination study of tivantinib with sorafenib, the combination therapy demonstrated a trend toward significance regarding increased disease control rate, defined as the combination of complete responses, partial responses and stable disease for at least 8 weeks.44 While only four cases of MET-high HCC were observed, three of the four patients achieved disease control. Based on these promising results, both of the active Phase III trials are evaluating tivantinib in HCC patients with MET-high tumor status.
A preclinical study evaluated whether HGF tumor concentration could be used as a marker for HCC, but no significant differences were found between HGF-high and HGF-low groups in clinicopathological factors or patient outcomes.56 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). Additionally, tumor MET levels were correlated with response to tivantinib treatment, the only biomarker thus far to predict response to treatment. These results support the use of tivantinib exclusively in MET-high tumor patients, although more definitive data will be forthcoming with the results of the METIV-HCC trial, which will analyze over 900 tumor samples and validate the use of select biomarkers in HCC.
Additional studies are needed to assess the use of tivantinib in those with more severe cirrhosis. The vast majority of trials have evaluated tivantinib in patients who are Child-Pugh Class A, with only a few trials including patients who are Child-Pugh Class B. Although theoretically tivantinib could also be used for those who are Child-Pugh Class C, this has not yet been studied. Moreover, it may not be safe to attempt such a trial given the anticipated side effects. Nevertheless, future development of more specific targeted biologic markers may enable treating physicians to administer agents such as tivantinib in a safer and more effective way.
Tivantinib, a potent inhibitor of c-MET, appears to be a promising therapy for those with advanced-stage HCC that has progressed or is intolerant to sorafenib. Tivantinib has demonstrated increased overall survival, PFS and TTP compared to placebo in patients with MET-high tumors. Serious hematologic side effects (neutropenia, anemia and leukopenia) are anticipated to be less prominent at lower dosing regimens (120 mg BID), at which dose good treatment efficacy is still maintained. Two large Phase III trials, METIV-HCC and JET-HCC, are currently ongoing. To date, there is no FDA-approved salvage or second-line therapy for patients with HCC who have failed or progressed with sorafenib. Whether tivantinib will be able to fill that need still remains to be determined.
The authors report no conflicts of interest in this work.
Daniel Pievsky,1 Nikolaos Pyrsopoulos2
1Department of Internal Medicine, 2Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, University Hospital, Newark, NJ, USA
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