Hepatocellular Carcinoma: A Changing Treatment Landscape


Josep Llovet, MD: During the last 10 years, there have been a lot of trials, testing several drugs, trying to improve the benefits of sorafenib. All of these trials have been negative until recently. We have several studies testing sunitinib, erlotinib, lenvatinib, and other types of drugs in the frontline and in second-line settings that have been negative. Very recently, during the last year-and-a-half, luckily enough we have 3 trials showing positive results. The first one is lenvatinib. That is a multikinase inhibitor. It was compared head-to-head with sorafenib, with positive results in noninferiority. So, we have a new tool, a new treatment, for patients in frontline advanced HCC.

Then, in those patients progressing on sorafenib—that was the other scenario for which we did not have any drugs—there are 2 drugs that emerged with positive trials. One is regorafenib versus placebo. The second one, precisely in this meeting, is cabozantinib versus placebo. Beyond that, we also had the approval of a checkpoint inhibitor, nivolumab, that was approved based on data from a phase II single-arm study of 280 patients with a good signal of efficacy.

The current unmet needs in HCC are as follows. In terms of adjuvant treatments, we don’t have any effective adjuvant therapy despite that there have been 15 randomized controlled trials testing all types of drugs. This is an unmet need because 70% of the patients undergoing resectional local ablation present recurrence at 5 years. Therefore, we need drugs in this scenario. The second unmet need is in intermediate HCC: patients with liver-only disease. We only have chemoembolization that has shown to improve survival. So, we need alternatives to chemoembolization or combinations of systemic therapies plus chemoembolization. Certainly, in advanced stages of the disease, despite these new drugs that have recently emerged as effective, we still need to try to achieve long-lasting responses and, ideally, some percentage of cure. We are far from that at this point. So, these are the most important unmet needs.

The most important unmet need in the frontline is to improve the outcome of sorafenib. Sorafenib is providing very efficacious effect in terms of improving survival, from an 8-month median survival for the patients at that stage to 11 months. But this result, despite being encouraging, needs to be thoroughly improved. So, the first unmet need is to try to improve the outcomes of these patients and to achieve higher survival rates. The second is to try to identify drugs that are also well tolerated, where some adverse events are manageable. With sorafenib, luckily enough, the adverse events are quite manageable. But there are still 15% to 20%, in some instances, of patients who do not tolerate the drug, and therefore we need for an alternative to that.

The predictors of response of sorafenib and lenvatinib are not extremely well defined. But for sorafenib, we already know some clinical predictors of response. We recently reported the meta-analysis of 2 randomized controlled trials testing sorafenib versus placebo. In these studies, we identified the patients with hepatitis-C virus infection—related HCC, and those patients with liver-only disease without metastases are the ones who achieved better outcomes with sorafenib. Just to say, the median survival for patients with hepatitis C treated with sorafenib in the trials was a 14-month median survival as opposed to the expected 11 months.

In lenvatinib, the data are more recent and we only know the subgroup analysis of the trial that was presented. We can sense that those patients with more aggressive tumors—for instance, patients with high AFP levels or patients with microvascular invasion—are those responding better to lenvatinib. So, we are in the scenario in which we have 2 drugs for frontline, and despite that they are efficacious in all populations, some of the patients may be treated more with sorafenib and eventually, others may be treated more with lenvatinib.

Transcript Edited for Clarity

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