Zosia Chustecka

June 28, 2012

June 28, 2012 — The investigational drug tivantinib (Daicchi Sankyo) has shown promising results in a phase 2 trial in liver cancer and was described as one of the "most thrilling new agents reported in the last few months" by Jordi Bruix, MD, PhD, head of the Barcelona Clinic Liver Cancer Group, Spain.

Chairing a session at the 14th World Congress on Gastrointestinal Cancer, which was organized in partnership with the European Society for Medical Oncology and held in Barcelona, Spain, Dr. Bruix said that liver cancer has been relatively neglected in the past, but now increased research efforts are being directed at this disease. So far, however, there have been few successes, he noted.

Tivantinib is one of the few, and it represents a new approach to the treatment of liver cancer. It is an oral tyrosine kinase inhibitor but is selective for cMET and it showed a "major advantage" in patients whose tumors showed high expression of MET when tested by immunohistochemistry (MET+).

"This is the first ever trial showing a survival advantage with a MET inhibitor, and identifying a subgroup of patients who have responded," reported lead investigator Camillo Porta, MD, from the Universitario San Matteo, Pavia, Italy.

The phase 2 trial investigated tivantinib as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) in whom 1 systemic therapy had failed. Of 107 enrolled patients, 71 patients received tivantinib (of whom 22 were MET+) and 36 received placebo (of whom 15 were MET+).

In the subgroup of patients who were MET+, there was a significant improvement in median overall survival (OS; 7.2 months with tivantinib vs 3.8 months on placebo; P = .01) and in the time to treatment progression (TTP; 11.7 weeks vs 6.1 weeks; P = .01). The relative risk for dying was reduced by 60% and the relative risk for TTP was reduced by 56%, Dr. Porta commented.

However, neither OS nor TTP was improved in patients with Met– tumors.

The safety profile of tivantinib was predictable and manageable, Dr. Porta commented, and the main adverse effect was neutropenia.

A phase 3 trial of tivantinib in MET+ HCC is now planned, he said. In answer to a question from the audience, he said that MET+ expression should be seen in a similar percentage of previously untreated patients with HCC, so he would expect to see similar results from first-line use of the drug.

Biopsies for Research

These new data on tivantinib were highlighted in an overview of new agents on the horizon in HCC delivered by Ghassan Abou-Alfa, MD, from the Memorial Sloan-Kettering Cancer Center in New York, New York. He emphasized that this is a new direction in liver cancer research.

This is a "promising start," he said, and noted that this is the first time that clinical research in HCC has moved to a phase 3 trial with an "enrichment approach" (ie, selecting the trial participants by a biomarker that increases the chances of responding to therapy).

Testing tumors for MET+, as for any other biomarkers, requires a liver biopsy, but Dr. Bruix noted that this is usually required only for research purposes, and hence much be preceded by informed consent, he emphasized.

"There is a difference here between research and clinical practice," he said. Liver cancer is not a case of "no meat, no treat" as is the case for some other types of cancer. Usually, liver cancer can be diagnosed after imaging, he said, so a liver biopsy is not necessary to confirm diagnosis in most patients. Patients should be told this, he continued.

So Far, Only Sorafenib

In his overview of new agents being investigated for liver cancer, Dr. Abou-Alfa noted that to date, much of the research effort has been directed at the antiangiogenic approach because of the success of sorafenib (Nexavar, Bayer Healthcare). This was the first targeted agent to be approved for use in HCC, in 2006.

So far, however, it remains the only one, he added.

Despite intense efforts with similar compounds, none have been successful. A phase 3 trial of sunitinib vs sorafenib was negative, and recently there was an announcement that an ongoing phase 3 trial of linifanib vs sorafenib was discontinued for lack of benefit, Dr. Abou-Alfa reported. Recently reported results from a phase 2 trial of brivanib in second-line treatment were negative, although a phase 3 trial of brivanib vs sorafenib is ongoing. Results of that study are eagerly awaited.

"There has been a big effort from the pharmaceutical companies, but so far nothing has improved on sorafenib," he commented.

"With antiangiogenic therapy, it may be that a ceiling has been reached," he said. The future may need a combination therapy approach, he added.

This is being explored in ongoing trials, which include studies pitching sorafenib against a combination of erlotinib with bevacizumab, sorafenib vs sorafenib with erlotinib, and doxorubicin with sorafenib vs doxorubicin alone.

Need for New Therapies

Several speakers stressed the need for new therapies in liver cancer. Despite other therapeutic options, including resection, radiofrequency ablation, percutaneous ethanol injection, and ultimately liver transplantation, there is a pressing need for therapeutic advances.

Liver cancer is the sixth most common cancer in the world, with 750,000 new cases diagnosed each year. There is a preponderance of cases (470,000) in Eastern Asia. But even in the United States, liver cancer is a problem, commented Joseph Llovet, MD, PhD, director of HCC Research at Mount Sinai School of Medicine. In the United States, the liver cancer death rate is increasing at a rate faster than that of any other cancer. The only other cancers that are increasing are esophageal cancer and melanoma; the cancer death rates for other types are all decreasing, he said.

14th World Congress on Gastrointestinal Cancer (WCGC): Abstract 0-0009. Presented June 28, 2012.

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