BOSTON – The investigational drug tivantinib was associated with a modest but statistically significant slowing of time to progression as a second-line agent against hepatocellular carcinoma, investigators reported.
Tivantinib, a c-MET inhibitor, demonstrated no overall survival advantage over placebo, but improvement was seen in a subgroup of patients with high expression of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF).
Results of the randomized phase II trial were presented at the annual meeting of the American Association for the Study of Liver Diseases. The study enrolled patients whose hepatocellular carcinoma had advanced after first-line therapy with sorafenib (Nexavar).
Median time-to-progression, the primary end point, was 6.9 weeks for patients randomized to tivantinib, compared with 6.0 weeks for those on placebo (hazard ratio, 0.64; P = .04), reported Dr. Ivan Borbath from the Cliniques Universitaires Saint-Luc in Brussels.
Median overall survival was similar at 6.6 months for patients on tivantinib and. 6.2 months for controls. But in a subgroup of patients whose tumors had high levels of expression of MET, median overall survival was 7.2 months with tivantinib vs. 3.8 months with placebo (P = .01), Dr. Borbath said.
There were no significant differences in time-to-progression or overall survival among patients with low MET expression.
"We found that tivantinib can give a pronounced benefit to those poor-prognosis patients who show MET-high expression," Dr. Borbath said. "These are the first randomized data in HCC showing overall survival advantage with a MET inhibitor and identifying a biological subgroup responding to a targeted therapy."
High Cost for Modest Advantage?
A gastroenterologist who attended the session at which the data were presented questioned whether tivantinib was worth the anticipated expense.
"The increase in survival is modest, so the obvious question is, what is the additional cost going to be per additional month of survival? ... These targeted drugs for cancer treatment in general, and for hepatocellular carcinoma in particular, tend to be [priced] very high. One has to begin to ask that question because of the ever-escalating cost of health care in this and other countries," said Dr. Herbert Lloyd Bonkovsky, professor of medicine at Carolinas Medical Center and the University of North Carolina in Charlotte, in an interview.
Dr. Bonkovsky also pointed out that one of the coauthors of the study was Dr. Brian Schwartz, chief medical officer of ArQule, the maker of tivantinib, but the relationship was not disclosed during the presentation. Dr. Bonkovsky was not involved in the study. Dr. Schwartz was identified with ArQule clinical development in the abstract.
ArQule and its partner Daiichi Sankyo recently discontinued a phase III clinical trial of tivantinib, a select inhibitor of MET, for non–small cell lung cancer for lack of efficacy. ArQule is continuing to test the drug against HCC.
In the current study (ARQ 197-215), patients with advanced HCC that progressed after first therapy and who were in otherwise good clinical condition with preserved liver function were randomized 2:1 to receive either tivantinib orally twice daily (71 patients) or placebo (36).
Tivantinib was started at 360 mg twice daily, but after 57 patients were enrolled, the dose was reduced to 240 mg b.i.d. because of drug-related neutropenias of grade 3 or greater.
High MET Predicts Worse Survival
The study defined high MET expression as MET being present in 50% or more of tumor cells with moderate or strong staining intensity on immunohistochemistry assay.
The authors also found that higher MET expression was a significant predictor of poor survival. Among patients in the placebo group, those with low MET levels had a median overall survival of 9.0 months, compared with 3.8 months for those with high MET levels (HR, 2.94; P = .02).
The Food and Drug Administration has agreed to consider a phase III trial of the drug in patients with HCC and high MET expression.
ArQule sponsored the trial Dr. Borbath reported no conflict of interest. Coauthor Dr. Brian Schwartz is chief medical officer of ArQule, which makes tivantinib. Dr. Bonkovsky reported no conflict of interest.