Response and Outcomes With TKIs in HCC


Ghassan K. Abou-Alfa, MD: So, with this said, it brings me to the practices with regard to the treatment of advanced HCC. If anything, I jokingly say that all of us have an easy job. We had only to remember 1 drug, sorafenib. We’ve lived with 1 drug for almost 10 years. But tell us where it all started. What was the sorafenib story altogether to begin with?

A. Ruth He, MD, PhD: So, sorafenib is the first-ever approved systemic therapy for patients with advanced stage liver cancer. And it is an oral therapy, and it is approved because of its prolongation of overall survival. And the response rate actually is not that great. It can slow down the progression of the tumor and result in a survival benefit.

Ghassan K. Abou-Alfa, MD: Which I remember, this was 2007, and we had all heard this great story. And understandably, even though we say that there’s no response, no doubt that the drug works because it works a different way—it is a tyrosine kinase inhibitor—and not necessarily that it required that the tumor will shrink per se. And nonetheless, patients will come and ask you that question, “What do you mean it’s not going to shrink tumor?” Especially, remember, as you just mentioned a second ago, patients might have had a local therapy and are used to the interventional radiologist saying, “Oh great. We shrank it, it’s smaller, and now we’re going to give you a drug, you’re going to live longer, but it’s not going to shrink your tumor.” So, how do you explain that?

Anthony El-Khoueiry, MD: It’s certainly challenging because both physicians, or healthcare professionals in general, and patients like to see shrinkage of tumors. However, as you introduced, this is a psycho-static drug, and it is well known that it changes the behavior of the tumor. The exact mechanisms of an action are not necessarily clear, but as you said, slowing down the progression prolongs survival. I do explain to patients that, unfortunately, when they get to the treatment with sorafenib, they are in a stage where they’re not curable any more.

So, the goal of the therapy is to balance prolongation of life and preservation of quality. And that’s the intent of the therapy. And I think that’s the best way to help patients understand, what is the goal of the treatment. And the goal is life prolongation while preserving quality as much as possible.

The other relevancy in the discussion is that we do not know that response rate by itself is a great predictor of outcome in hepatocellular carcinoma all the time. It’s not always a predictive marker. Let’s say in a phase II study we may have a good response rate. That doesn’t always translate to overall survival in the phase III study. It’s a technical point, but it tells us that in this disease response is not everything and may not be always the most important marker.

Ghassan K. Abou-Alfa, MD: That’s great. And Catherine, from your standpoint—because remember, we have probably the most experience with regards to sorafenib—back to the point that you brought up about the liver functionality component per se, what are your concerns? Do you think we have no clue what we’re doing, or like, what are we supposed to do? But this is an important aspect. Like, how do you gauge between the liver functionality and sorafenib?

Catherine Frenette, MD: These patients have 2 diseases: They have liver cancer and they have endstage liver disease, by definition, with cirrhosis. It is really important to have a hepatologist and an oncologist working together on these patients and really communicating well. Even ideally, sometimes having the same clinic together where the patient can see both physicians at the same time. We do have to watch carefully for decompensation of their liver disease—development of ascites and encephalopathy, jaundice, coagulopathy—all of these issues that can happen because those are going to affect patient survival as well as the tolerability of any systemic therapy, either now or in the future.

Ghassan K. Abou-Alfa, MD: Fair, fair. And if anything, I recall that in the old days if patients were on sorafenib and sorafenib stopped working, we don’t know what to do other than probably a clinical trial. But as we just introduced the program, there are a lot of new data and among which, a drug called regorafenib. So, Ruth, tell us. What’s regorafenib and what do you know about it?

A. Ruth He, MD, PhD: Regorafenib is very much like sorafenib. It targets mainly similar genes, and it’s also an oral agent. But amazingly, when it’s tested in the randomized phase III trial, patients who have progressed on sorafenib have additional benefits, survival benefit, from this drug. So, now the randomized phase III study, the data, have supported its approval by the FDA in April of 2017, providing additional second-line options for those patients who have progressed on sorafenib.

Ghassan K. Abou-Alfa, MD: Yes, I know, I totally agree. If anything, regorafenib is probably a cousin, but I like to call it a distant cousin of sorafenib because admittedly, there are certain aspects—including type 2, including IGF, including the other markers and IC50 that are expressed—that differ from sorafenib. And more important, as you said correctly, is that patients who progress on sorafenib, they really actually did progress on sorafenib because of regorafenib and they get another improved survival for another 10 months. Actually, even I was happily surprised to see that actually the joined survival of sorafenib exposure, followed by the regorafenib exposure, is up to 24 months, which is incredible.

A. Ruth He, MD, PhD: Which is amazing.

Ghassan K. Abou-Alfa, MD: Incredible.

Transcript Edited for Clarity

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