Initial Phase III Data Shows Regorafenib's Efficacy in Pretreated HCC: Q&A with Ghassan Abou-Alfa, MD

Ghassan Abou-Alfa, MD

Regorafenib (Stivarga) may soon become another successful treatment for patients with unresectable hepatocellular carcinoma (HCC), following the demonstration of prolonged survival with the multikinase inhibitor versus best support care in the phase III RESORCE trial. 

In the study, the multikinase inhibitors safety profile was comparable to previous reports. Patients enrolled in the study were randomized 2:1 to a regorafenib plus best supportive care arm or placebo plus best supportive care arm. Patients received 160 mg of regorafenib once daily or placebo for 3 weeks followed by 1 week off, with 1 complete treatment cycle comprising 28 days. 

In a preceding 36-patient phase II study, which was the rationale for the larger RESORCE study, disease control was achieved in 26 patients (72%), including 1 patient with a partial response and 25 patients with stable disease. The median OS was 13.8 months and the median time to progression was 4.3 months.

In an interview withTargeted Oncology, Ghassan Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the trial and what it could mean for the HCC treatment paradigm.

Targeted Oncology:Can you tell us about some of the bigger news within the realm of HCC going on right now?

ABOU-ALFA:I think one of the biggest stories right now is a press release that came out from Bayer not that long ago in regard to the phase III trial of regorafenib versus placebo in the second line in HCC. First I would have to say that it is incredible that it’s already barely 10 years since the data on the SHARP trial, sorafenib versus placebo, came out, and now we’re already talking about the second line in HCC. That’s great news, after all.

Another interesting fact is that this press release comes at the point where after many trials in phase III settings have unfortunately failed in the second-line setting for HCC, now we’re seeing some possibly positive data, which of course we’re waiting for. The press release did not say anything other than this was a positive study.

Why this is important because our understanding is that this was what we called the “hiding fruit.” Patients are on sorafenib with a 10-month median survival, and usually they get the drug for about 5 months. So patients would be alive for about 5 months without therapy and this would be the “placebo arm.” 

As we know, many studies have already tried that approach with really great products that include brivanib among others. Unfortunately this data never panned out and, interestingly, in all those studies, the placebo arm performed better than what you’d think it might perform in regard to the historical control. There could be other variables that come along, but we’ll just have to wait.

The very interesting story, and which we are all eager to hear in regard to regorafenib, is that this is a multi-kinase inhibitor not that much different from sorafenib. It has some particularities, but they are subtle and not critically different. As such, it will be fascinating to see what the science is behind having a patient on sorafenib progress, and the move to regorafenib on the second line, and still get an improvement in overall survival.

How can this information make a significant impact in practices?

As I mentioned, the devil is in the details over here, because we really have to imagine how long these patients have been on sorafenib before they move to regorafenib. What kind of responses do you get, what kind of outcomes did we have, what are the differences between the 2 arms, and how significant and clinically significant those differences are? So really, it’s too early to decide any of this.

Nonetheless, it can certainly make us all pause after many attempts from innovative, different targets that really are highly valuable. Now we’re seeing another tyrosine kinase inhibitor not that different from sorafenib also showing an improvement in overall survival.

We have to put that in perspective. There is only 1 drug approved so far for the treatment of HCC in the United States, and pretty much most parts of the world. Now we’re talking about second line, and it’s not that different than what’s happening in the first line. I think this by itself is bringing a lot of scientific questions that we’ll just have to wait to ask until we see the data.

What are the optimal management techniques with regorafenib’s side effects?

Presuming where this will go after we see how the scientific community and the regulatory agencies react to the data that will be coming out is that regorafenib, like sorafenib, has an issue with hand-foot syndrome. That’s a very fascinating phenomenon that really has tried to be mitigated in many ways. Among them, support for a presumed hyperkeratosis that has already been published on by a Chinese group that will help tolerate the drug further. There’s another theory that this is a microcapillary phenomenon, which is a vascular phenomenon, and as such, you really have to mitigate it from that perspective.

With all this said, I think close observation, attention to patients, and reaction to the patient’s care on a very immediate basis is very critical. Patients on sorafenib, we like to check on them about three days after they start on therapy. Not really longer than that, and within a week’s time at least, have some pictures shared or see them in person to see what’s going on with that regard.

What are you looking forward to in the HCC space within the next few years?

This space is very exciting because there is so much going on. You have to really remember that before 2007, there was not a standard of care for this disease. Now there is a lot of interest in it, and those interests are going into different directions. One of them is still the tyrosine kinases and the different targeted therapies.