Tivantinib Fails Phase III HCC Test

Antoine Yver, MD

Tivantinib failed to improve overall survival (OS) compared with placebo as a second-line therapy for patients with MET-overexpressing inoperable hepatocellular carcinoma (HCC) in the phase III METIV-HCC study, according to a statement from Daiichi Sankyo and ArQule, the companies codeveloping the MET inhibitor.

The phase III study randomized 340 patients following treatment with sorafenib (Nexavar) in a 2:1 ratio to tivantinib or placebo. All patient received best supportive care. The primary endpoint of the study was OS, with secondary endpoints focused on progression-free survival (PFS) and safety. While the companies did not release findings from the study, they did note that OS, PFS, and safety data would be presented at an upcoming medical meeting.

“Despite the negative outcome of this study, we remain committed to applying rigorous science to unmet needs for patients with cancer,” Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development, Daiichi Sankyo, said in a statement. “We would like to take this opportunity to thank all of the investigators, and especially the patients, for their participation in this study.”

The METIV-HCC study was based on an analysis of the phase II ARQ-197-215 trial, which showed that the risk of death was reduced by 62% with tivantinib compared with placebo in patients with MET-overexpressing HCC (HR, 0.38; 95% CI, 0.18-0.81). In MET-low tumors, placebo outperformed tivantinib (HR, 1.33; 95% CI, 0.58-3.03).

In the phase II study, 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 PFS was 1.7 months for tivantinib versus 1.5 months for placebo (HR, 0.67; P = .06).

In the biomarker analysis, 77 samples were assessable. MET was overexpressed 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 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).

Despite these early signals of efficacy, the phase III study did not show superiority, as has been the case for several prior studies for HCC. In general, exploration of a second-line systemic therapy for patients with HCC has been met with few successes over the past decades.

“HCC is a disease with high unmet need, especially in the second-line setting, so these results are disappointing for the patients as well as the investigators and the companies,” Paolo Pucci, chief executive officer of ArQule, said in a statement.

The one recent exception to the many disappointments seen in second-line HCC has been regorafenib (Stivarga), which showed an improvement in OS in the phase III RESORCE study. A new drug application for regorafenib is currently pending with the FDA, with an approval anticipated within the next few months.

In the phase III RESORCE trial, regorafenib improved OS by 2.8 months compared with placebo as a second-line therapy for patients with HCC. Median OS was 10.6 months with regorafenib versus 7.8 months for placebo (HR, 0.62; 95% CI, 0.50-0.78; P <.001).

Other trials are also assessing second-line systemic therapies for HCC, including phase III studies for cabozantinib (NCT01908426) and ramucirumab (NCT02435433). Immunotherapy trials are also under way for nivolumab as a frontline therapy (NCT02576509).