Hepatocellular Carcinoma Update, Issue 1, 2017 (Video Program)Available research data and ongoing trials in the second-line setting for HCC
7:50 minutes.
TRANSCRIPTION:
DR LLOVET: We just published the trial January in Lancet, comparing regorafenib versus placebo in patients progressing to sorafenib. And the results were very appealing in the sense that the patients improved survival, again, for 3 months. So if you were allocated to the regorafenib arm you were surviving around 10.6 months as opposed to placebo, 7.8 months. So this was a breakthrough, again, in the management of the disease This will be the only second-line treatment in patients progressing to sorafenib in the front line. There are other trials, though, that are active at this point or have completed recruitment that may have appealing drugs. One of these trials, for instance, is comparing ramucirumab, a monoclonal antibody, against VEGF receptor 2 versus placebo. There is another trial with checkpoint inhibitors, pembro, versus placebo in the second line. And there is another trial that compares cabozantinib — that is a MET inhibitor, VEGF receptor inhibitor — versus placebo, also in the second line. And there is, finally, another trial that has completed recruitment. That is tivantinib versus placebo, a cytotoxic drug and a tubulin inhibitor and potentially a MET inhibitor compared to placebo. In this case the trial is enriched for only MET-positive patients. So we have all these options in the second line. They are all in Phase III. There are also plenty of trials in Phase II. Here you have the list of the trials and the drugs that have been tested in HCC during the last 10 years after the success of sorafenib in 2007. You can see in the adjuvant setting we’re comparing sorafenib versus placebo. The trial was negative. Retinoid versus placebo, the trial is negative. Then, in intermediate stage, we were testing radiofrequency plus doxo versus radiofrequency. We were comparing TACE alone versus TACE plus sorafenib, or TACE alone versus TACE plus brivanib. The trials were negative. In the front line: sorafenib plus-minus erlotinib, sorafenib versus brivanib. All these are multikinase inhibitors. Sorafenib versus sunitinib versus linifanib and plus-minus doxorubicin. These 5 trials in the front line were negative. So at this point we have 3 trials still ongoing or waiting for results in the front line. Those are sorafenib versus yttrium-90 that I mentioned to you, also sorafenib versus lenvatinib. That is also a multikinase inhibitor that has been approved for thyroid cancer, for instance. And sorafenib versus nivolumab. That has been approved for several indications, in melanoma, colorectal and renal, and so on. In the second line we have these 3 trials already published: brivanib versus placebo, everolimus — that is an mTOR inhibitor — versus placebo and ramucirumab versus placebo. All of them have been negative. And at this point we have rego versus placebo that I will mention to you. This is the trial that has been positive, so is the most important option for a patient progressing to sorafenib. And then we have tivantinib versus placebo, cabozantinib and pembro versus placebo. This is the spectrum of the trials that are currently ongoing for regulatory approval. Of course, in the front line and second line you may have 50 trials in Phase II looking for a signal of efficacy. But these ones I’m showing here are the trials that can make a difference in terms of decision-making and regulatory approval. DR LOVE: Can you remind us what we know about bevacizumab in HCC? DR LLOVET: Yes. Bevacizumab has never been tested in Phase III, has been tested in Phase II in small single-arm studies including 40 patients. And the median survival and the objective response was not appealing with bevacizumab. Median survival was around 10 months, with objective responses less than 10%. So bevacizumab has not been tested and has not moved the concept forward in Phase III ever in HCC. DR LOVE: Any comments about this issue of why so few of these randomized trials have actually been positive? DR LLOVET: Yes. I am summarizing this in this slide, but point number 5 is the most important one. In fact the drugs are not powerful enough. So brivanib, linifanib, erlotinib, everolimus, ramucirumab, doxorubicin — these drugs do not have potent antitumoral effects. There are other reasons, though. For instance, we have 2 cases in which we already have identified — and it has been published — toxicity. For instance, with sunitinib: Sunitinib is a very potent multikinase inhibitor that is inducing an antitumoral effect, but the downside is that you have toxicity. So you may have liver dysfunction and even treatment-related death in up to 3% to 4% of the patients. Linifanib also, the trial was stopped for lack of efficacy and also for toxicity. So in some instances, these drugs, for instance, sunitinib that is very potent in renal cancer and is not toxic in these patients — in HCC we have 2 diseases, liver cancer and cirrhosis. And sunitinib is toxic for the cirrhotic liver, and the patients do not tolerate that. These are the main reasons. Then there are other reasons. None of the trials in Phase III that have been reported was enriched for any biomarker. And some of them, for instance, everolimus, an mTOR inhibitor, could have been enriched. Or, as I’m showing now, there are some trials in Phase III now enriched for biomarkers. So the main strategies are these 2 strategies on how are we moving forward with systemic therapies in HCC. Either we get more effective drugs for what we call all comers — means all the patients — and this can be multikinase inhibitors, regorafenib — and I will show you the results — lenvatinib or immunotherapies, for instance, nivolumab. Or we are moving to what is called precision medicine, so identifying small pockets of patients with a potent onco-driver that we can block with drugs. This can be the case of FGF19, insulin growth factor 2 and others. |