Regorafenib Poised as Second-Line Standard of Care in HCC

Morris Sherman, MD, PhD

Despite numerous large studies over the past decade for patients with unresectable hepatocellular carcinoma (HCC), a second-line standard of care remained largely elusive following standard frontline therapy with sorafenib (Nexavar)—that is until findings from the phase III RESORCE trial exploring regorafenib (Stivarga) were reported earlier this year.

The phase III RESORCE trial, which was initially presented at the 2016 World Congress on Gastrointestinal Cancer, showed that regorafenib improved overall survival (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).

Findings from the study are being submitted to regulatory authorities for potential approval by the developer of the drug, Bayer Pharmaceuticals. Although regorafenib is not currently approved, Morris Sherman, MD, PhD, already views the agent as the standard second-line therapy, with hopes for moving the drug into the frontline setting.

To gain insight into regorafenib and other questions that remain in second-line treatment of HCC, OncLive interviewed Sherman, professor of Medicine at University of Toronto, at the 10th International Liver Cancer Association (ILCA) Annual Conference.

OncLive: You gave the opening and closing remarks on a session today about the present and future of HCC management—using evidence to guide treatment and optimize patient survival. Could you give me an overview of that talk?

Sherman: Basically, the question was, “Now that regorafenib is coming, where exactly does it fit”—obviously, it will be second-line to sorafenib. One of the things we see is that patients are treated with chemoembolization beyond what is known to be effective. The net result is that they get liver disease deterioration. When they're referred for first- or second-line treatment, the liver diseases is too advanced to allow treatment at all or, if it's not that advanced, the response to sorafenib will not be as good. Ideally, when you know that chemoembolization has failed, it's time to refer.

What does the entire treatment paradigm look like today for patients with liver cancer starting at diagnosis?

There have been some failures in the second-line setting—brivanib, everolimus, and ramucirumab, to name a few&mdash;why did these drugs fail?

They may have failed because they're not effective. That's the first reason. The second may have to do with trial design. One of the things that came from the brivanib trial was that the patients were the survivors. They were patients who had not deteriorated while on sorafenib and they had a relatively good phenotype of tumor. They were well enough to go into second-line treatment. And that wasn't taken into account. It means that even the placebo group would survive longer.

We're dealing with cirrhosis and the altered drug metabolism of cirrhosis. Just because something works in some other cancer where liver disease is not an issue, doesn't mean it's going to have the same metabolism as in patients with cirrhosis.

There is this question of what to do after sorafenib and it seems like you expect regorafenib to be approved in the second-line setting. Should it become standard of care then, after sorafenib?

Yes, it will be the standard second-line therapy. There are other study results expected later this year of other drugs that may become other second-line choices. And then, regorafenib should be looked at in first-line.

What else is important to think about with regard to second-line treatment?

I think it's crucial to recognize that this study was done in patients with good liver function. One of the issues that came up with sorafenib was that it was also done in patients with good liver function and physicians started using it in patients whose livers were not functioning well: Child-Pugh B or even C. I would not want to see regorafenib used under those circumstances—first of all, we don't have any safety data at the moment, but we also don't have any efficacy data in this population. Given that these patients are fragile with regard to their liver function and that there are risks with that, these patients should not be treated once their liver function has deteriorated.

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View more from the 2016 International Liver Cancer Association Annual Conference

It depends a lot on when the diagnosis is made and what stage of disease the diagnosis is made. Let's assume that the diagnosis is made early and it's a moderately aggressive cancer—that'll give us the whole spectrum. You start off with small tumors and radiofrequency ablation or some equivalent ablative procedure. Let's assume it recurs after two or three ablations and you can no longer ablate it. This patient may still be a candidate for surgery or may have been a candidate for surgery initially. This, or liver transplantation, may be curative. If they're not curative, they'll go on to chemoembolization. After that, it's sorafenib. Once there is progression of disease on sorafenib, at the moment, there's nothing. Once regorafenib is approved, that will be the next step.