Tivantinib Biomarker Analysis Validates Phase III Design

Treatment with tivantinib was highly effective in patients with hepatocellular carcinoma (HCC) with high MET expression, suggesting a prognostic and predictive biomarker of response, according to findings from a phase II study presented at the 2015 International Liver Cancer Association Annual Conference.

In the analysis, which was conducted on data from the ARQ-197-215 trial, the risk of death was reduced by 62% with tivantinib compared with placebo in patients with MET-high HCC (HR, 0.38; 95% CI, 0.18-0.81). Conversely, in MET-low tumors, placebo outperformed tivantinib (HR, 1.33; 95% CI, 0.58-3.03). In this analysis, immunohistochemistry (IHC) was an effective test for MET expression, if strict testing criteria were followed.

The ongoing phase III METIV-HCC study is currently exploring tivantinib in patients with MET-high inoperable HCC who have received prior treatment with sorafenib. The study remains open for recruitment, with the goal of randomizing 346 patients to tivantinib or placebo in a 2:1 ratio. By the end of 2015, the company developing the drug, ArQule anticipates that 300 patients will have enrolled (NCT01755767).

"The biomarker data from this trial demonstrates that patients with MET-high tumors are more likely to benefit from tivantinib therapy," Brian Schwartz, MD, head of research and development at ArQule, said in a statement. "On the basis of the results from the phase II trial and in partnership with Daiichi Sankyo, we are conducting the pivotal phase III METIV-HCC trial that is enrolling MET-high HCC patients as determined by a required companion diagnostic test."

In the phase II study that was the basis for the biomarker analysis, 107 patients were randomized to tivantinib (n = 71) or placebo (n = 36). This analysis did not restrict enrollment to MET-high individuals but did assess tumor samples for MET expression, with a high expression level defined as ≥2+ in ≥50% of tumor cells.

In the full population of the study, the median time to progression in patients treated with tivantinib was 6.9 weeks compared with 6.0 weeks with placebo (HR, 0.64;P= .04). The median progression-free survival was 1.7 months for the tivantinib group versus 1.5 months for the placebo arm (HR, 0.67;P= .06).

In the biomarker analysis, 77 samples were available for analysis. MET was overexpression more commonly in patients who received prior sorafenib. In this group, MET-high status was seen in 82% of patients compared with 40% for samples taken prior to the administration of sorafenib. Additionally, following sorafenib treatment, just 3 patients (18%) were MET-low.

As a prognostic factor, MET overexpression was associated with significantly worse outcomes. For patients treated with placebo, those with MET-low expression had a median overall survival (OS) of 9 months compared with 3.8 months in the MET-high group (HR, 0.34; 95% CI, 0.13-0.86;P= .02).

A significant interaction was seen between tivantinib and tumor MET levels as a predictive factor for OS (P= .039). The median OS in the placebo arm for patients with MET-low status was 9 months versus 7.2 months in the MET-high tivantinib group (HR, 0.72; 95 % CI, 0.30-1.70;P= .45).

In the presentation, lead investigator Lorenza Rimassa, MD, deputy director of the Medical Oncology Unit at Humanitas Cancer Center in Milan, Italy, noted that tumor MET status was the only prognostic and predictive factor out of the biomarkers analyzed.

"Overall, the biomarker data from this trial support the use of tivantinib in MET-high patients only," she said during her presentation of the results. "The ongoing phase III METIV-HCC trial will validate the role of biomarkers in HCC."

References

1. Rimassa L, Abbadessa G, Personeni N, et al. Tivantinib in Pretreated Hepatocellular Carcinoma (HCC): Tumor and Plasma Biomarker Analysis from the Randomized Controlled Phase 2 Trial (RCT) ARQ 197-215. Presented at: International Liver Cancer Association 9th Annual Conference; September 4-6; Paris, France. Abstract O-029.