World Congress on Gastrointestinal Cancer 14, Barcelona, Spain

Tivantinib first drug to have overall survival benefit as second-line hepatocellular carcinoma treatment

Dr Camillo Porta – Fondazione IRCCS Policlinico Universitario San Matteo, Pavia, Italy

HCC is an active area of research. Why is that? Why are new agents needed?

It’s an extremely active area because until a few years ago no systemic treatment ever proved to be able to impact on the natural history of this disease. Then came sorafenib, the one and only registered drug for the treatment of HCC, and unfortunately now after the failure of sorafenib no active treatments are available. So many companies, pharmaceutical companies, and many academic institutions are working hard to find further treatments for these patients.

You presented data on a phase II trial with tivantinib. Can you tell us about the drug?

Tivantinib is a novel oral drug that targets the MET proto-oncogene that is a key driver of hepatic carcinogenesis and has been proved also to be responsible for the carcinogenic process in many other tumour types. Therefore, this is a very targeted agent, touching and inactivating a key pathway in the development of HCC.

Can you tell us about the study and the top-line efficacy results?

This was a phase II placebo-controlled study of tivantinib or placebo in pre-treated HCC patients. The primary endpoint of the study was time to progression and indeed tivantinib was able to significantly prolong time to progression in the intention to treat population. Notably enough, those patients who had a higher MET expression at immunohistochemistry received the larger benefit from tivantinib treatment and, furthermore, they achieved also a significant overall survival advantage as compared to placebo. Not only did we establish MET inhibition as a rational strategy to target HCC but also we were able to identify MET expression as both a prognostic and predictive factor in HCC.

Are there any tolerability issues with tivantinib?

The drug was quite well tolerated; the safety profile did not include any unexpected adverse event. The main toxicity was haematological but notably, when at the middle of the study we observed too many cases of grade 3 or more neutropenia, we decided to dose reduce the drug and, indeed, after dose reduction the percentage of patients experiencing neutropenia fell to almost 6%. Definitely a well-tolerated drug with no unexpected toxicities.

Results have already been released at ASCO 2012. What’s new here?

We were able to define in a better way, because we accumulated data in the meantime, on the outcome of the MET high and MET low populations, allowing for a better definition of results in terms of TTP and overall survival.

Does that mean using c-MET expression could be a way of selecting patients?

We have already planned to perform a randomised controlled phase III trial that hopefully will be the registry trial for tivantinib in HCC and we are going to enrich the population, selecting just MET high patients.

After their presentation at this morning’s session, one of the session co-chairs described the results as “”thrilling”. What do you think prompted him to say that?

Basically for three reasons. The first one is that it’s a proof of principle that targeting MET we can achieve a benefit in HCC. Second is this is an unmet needs situation because presently no active treatments were available for patients failing the first line systemic treatment, that is sorafenib. Third, because we were able to identify a biomarker that could really help us to select patients potentially able to achieve the maximum benefit from the drug.

Aside from HCC, could tivantinib be used in other tumour types?

Absolutely, yes. A phase III trial in non-small cell lung cancer in combination has been already performed, the data are not available but we are waiting for the preliminary results. If one considers the importance of MET in several tumour types we can foresee a bright future for the drug, at least hopefully.

Are there any other trials or research you are doing with this drug or other agents you’d like to mention?

We are especially working on the pre-clinic because we badly need to understand more the carcinogenic processes. For example, one of the questions that Dr Lovett (?) asked me today is are you sure that the previous treatment had not induced the expression of MET? So a lot of translational experiments will be performed to really catch up the best mechanisms of this drug and potentially of combinations of similar drugs.

What’s your take home message from the study?

We probably will have second line treatment for HCC if the phase II data will translate into a benefit in phase III. We have identified a predictive and prognostic factor for HCC, that is MET expression by immunohistochemistry. And finally, tivantinib is a really promising drug in the field of HCC and not only.

Would this drug ever be used in the first-line setting?

Of course we do not know but it is probable that the future development will try to move tivantinib into an earlier treatment setting but it’s the future. For now we have to concentrate on the validation of the phase II data in our phase III setting to register the drug.