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First-Line Therapy in Advanced HCC

Insights From: Catherine T. Frenette, MD, Scripps Green Hospital; Darren S. Sigal, MD, Scripps Green Hospital
Published: Wednesday, May 16, 2018



Transcript: 

Catherine T. Frenette, MD: So, let’s now talk about first-line treatment options in advanced HCC. Darren, give us an idea of the role of systemic therapies in advanced liver cancer.

Darren S. Sigal, MD: The frontline therapy of advanced hepatocellular carcinoma has really undergone some significant advances over the past 6 or 7 years. And the pivotal study that led to these changes was the SHARP study. The SHARP study was a large randomized study of 602 patients randomized to sorafenib or placebo for advanced HCC. And so, what the primary endpoint showed was that the median overall survival was improved from 7.9 months to 10.7 months. That’s important because that’s a significant number in oncology, and it’s also important to remember that that median number is half the people did better than that median. And there certainly are a group of patients who can live much longer, even multiple years, with sorafenib alone. Sorafenib is generally a well-tolerated oral tyrosine kinase inhibitor. It targets multiple pathways, probably most significantly for our discussion is the VEGF [vascular endothelial growth factor] pathway. And some of the important adverse effects are hand-foot skin reaction, diarrhea, fatigue, and liver function abnormalities. Those are the most common adverse effects that had been reported.

Another study that validated sorafenib in the frontline setting was the Asia-Pacific trial. And the Asia-Pacific trial came after SHARP and it was about 276 patients in the Asia-Pacific region, and it also confirmed that sorafenib in the frontline setting improved overall survival. That improvement in overall survival was a little bit less of 6.5 versus 4.2 months. And the significance of that is probably because of the high percentage of patients with viral hepatitis B in the Asia-Pacific trial. As you’re aware, viral hepatitis B is a poor-risk feature anyway for HCC. And if you look at the SHARP trial, there was a much smaller percentage of patients with viral hepatitis B.

More recently, there’s another promising clinical trial that has been presented using a medication called lenvatinib, and lenvatinib is like sorafenib, an oral tyrosine kinase inhibitor that also targets multiple pathways. Again, the VEGF pathway is important in its mechanism of action. And in what’s called the REFLECT trial or Study 304, lenvatinib was compared to sorafenib in a 1:1 randomization in the frontline setting. And this was a very large study of 954 patients. What it showed was that there was a numerical improvement in overall survival, although not statistically significant. There was also a higher response rate of about 24% versus 9%. Now, that 9% response rate for sorafenib was higher than reported in the SHARP study, which was only a few percent. But the other point of interest is that that response rate, I think, is clinically important because often when patients come to me, they may be having pain, pressure feelings. And one of the goals of therapy is not just improvement in overall survival, which is always a primary goal of therapy, but it’s also producing a response, and that response can also have palliative benefits.

Catherine T. Frenette, MD: What are your thoughts on the patients who get sorafenib, or lenvatinib, or any of the tyrosine kinase inhibitors and maybe they don’t get a response but they have stable disease? Is that considered a win?

Darren S. Sigal, MD: In medical oncology, stable disease is always considered a win. It’s always nice to see tumor shrinkage for sure. But, again, if we go back to the SHARP study and sorafenib, the response rates were less than 5%. And so, what that shows is that the improvement in overall survival was not because of tumor shrinkage, it was because of stable disease. So, your point highlights the dilemma treating oncologists are going to face whether they prescribe sorafenib or lenvatinib, when it gets approved at some point in the near future, because there’s no difference in survival endpoints. There was a difference in response rate.

Catherine T. Frenette, MD: Do you use sorafenib in Child-Pugh B patients?

Darren S. Sigal, MD: That’s an excellent question. In the SHARP study, Child-Pugh B patients were excluded. However, about 5% of the SHARP study were Child-Pugh B patients. So, I’m willing to and I have treated patients with sorafenib with Child-Pugh B, and I believe subsequent data have shown that there still can be benefits in that population. Subsequent studies have also actually included Child-Pugh B7 patients in the inclusion criteria.

Catherine T. Frenette, MD: I think that that highlights the importance of liver function. Especially with clinical trials, many times they exclude patients with Child-Pugh B because they don’t want the competing mortality of the liver disease. But I think you’re right, with select Child-Pugh B patients, it has been shown that these medicines can be used safely and sometimes effectively. But, again, that depends on the patient and the clinical situation.

Darren S. Sigal, MD: Correct.

Catherine T. Frenette, MD: So, do you use chemotherapy in patients with advanced HCC?

Darren S. Sigal, MD: Up until the past few years, chemotherapy was something that was considered in hepatocellular carcinoma—most classically, Adriamycin-based therapies. I think today, those therapies are really becoming obsolete. There may be some rare examples or rare scenarios where cytotoxic chemotherapy may be important, and, in those scenarios, my preference is to use either single-agent Xeloda [capecitabine] or FOLFOX. FOLFOX has been shown in other GI [gastrointestinal] settings to be safe in patients with significant liver dysfunction. And there are some data to suggest there could be a response rate and a benefit, but I want to emphasize that would not be a standard of care in this modern setting.

Catherine T. Frenette, MD: Can you combine sorafenib with locoregional therapies?

Darren S. Sigal, MD: So, there have been several studies looking at that. I believe at least 3 different studies have looked at that. The largest and probably the most well-known is called the SPACE trial. And the idea behind using sorafenib with locoregional therapies is that when you ablate or embolize a tumor, you’re going to induce a significant amount of vascular growth factors. Sorafenib, as we had alluded to already, blocks the VEGF pathway. And so, mechanistically, it was very satisfying to look in to these combinations, but, to date, there really is no consistent findings showing that there is a significant improvement in survival or response rates.

Catherine T. Frenette, MD: Tell us about the TACTICS trial.

Darren S. Sigal, MD: Thank you for asking about the TACTICS trial. That was recently presented at the ASCO [American Society of Clinical Oncology] GI meeting in January in San Francisco. And that trial is a little bit different than the others in that it actually did show a statistical improvement in progression-free survival. It was a study in Asia, and it randomized 156 patients to either TACE [transarterial chemoembolization] or TACE plus sorafenib. The study design was somewhat similar, but there were some important differences as well in terms of when patients were given or recommended to get TACE. But nevertheless, there was nearly a doubling of progression-free survival from about 13 to about 25 months, and so that certainly is something that might have an impact on future study design and standard of care. I think that it’s going to be important to understand what were the differences in this study versus previous studies that were negative. So, I think it’s certainly an area that should be under active investigation.

Transcript Edited for Clarity 
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Transcript: 

Catherine T. Frenette, MD: So, let’s now talk about first-line treatment options in advanced HCC. Darren, give us an idea of the role of systemic therapies in advanced liver cancer.

Darren S. Sigal, MD: The frontline therapy of advanced hepatocellular carcinoma has really undergone some significant advances over the past 6 or 7 years. And the pivotal study that led to these changes was the SHARP study. The SHARP study was a large randomized study of 602 patients randomized to sorafenib or placebo for advanced HCC. And so, what the primary endpoint showed was that the median overall survival was improved from 7.9 months to 10.7 months. That’s important because that’s a significant number in oncology, and it’s also important to remember that that median number is half the people did better than that median. And there certainly are a group of patients who can live much longer, even multiple years, with sorafenib alone. Sorafenib is generally a well-tolerated oral tyrosine kinase inhibitor. It targets multiple pathways, probably most significantly for our discussion is the VEGF [vascular endothelial growth factor] pathway. And some of the important adverse effects are hand-foot skin reaction, diarrhea, fatigue, and liver function abnormalities. Those are the most common adverse effects that had been reported.

Another study that validated sorafenib in the frontline setting was the Asia-Pacific trial. And the Asia-Pacific trial came after SHARP and it was about 276 patients in the Asia-Pacific region, and it also confirmed that sorafenib in the frontline setting improved overall survival. That improvement in overall survival was a little bit less of 6.5 versus 4.2 months. And the significance of that is probably because of the high percentage of patients with viral hepatitis B in the Asia-Pacific trial. As you’re aware, viral hepatitis B is a poor-risk feature anyway for HCC. And if you look at the SHARP trial, there was a much smaller percentage of patients with viral hepatitis B.

More recently, there’s another promising clinical trial that has been presented using a medication called lenvatinib, and lenvatinib is like sorafenib, an oral tyrosine kinase inhibitor that also targets multiple pathways. Again, the VEGF pathway is important in its mechanism of action. And in what’s called the REFLECT trial or Study 304, lenvatinib was compared to sorafenib in a 1:1 randomization in the frontline setting. And this was a very large study of 954 patients. What it showed was that there was a numerical improvement in overall survival, although not statistically significant. There was also a higher response rate of about 24% versus 9%. Now, that 9% response rate for sorafenib was higher than reported in the SHARP study, which was only a few percent. But the other point of interest is that that response rate, I think, is clinically important because often when patients come to me, they may be having pain, pressure feelings. And one of the goals of therapy is not just improvement in overall survival, which is always a primary goal of therapy, but it’s also producing a response, and that response can also have palliative benefits.

Catherine T. Frenette, MD: What are your thoughts on the patients who get sorafenib, or lenvatinib, or any of the tyrosine kinase inhibitors and maybe they don’t get a response but they have stable disease? Is that considered a win?

Darren S. Sigal, MD: In medical oncology, stable disease is always considered a win. It’s always nice to see tumor shrinkage for sure. But, again, if we go back to the SHARP study and sorafenib, the response rates were less than 5%. And so, what that shows is that the improvement in overall survival was not because of tumor shrinkage, it was because of stable disease. So, your point highlights the dilemma treating oncologists are going to face whether they prescribe sorafenib or lenvatinib, when it gets approved at some point in the near future, because there’s no difference in survival endpoints. There was a difference in response rate.

Catherine T. Frenette, MD: Do you use sorafenib in Child-Pugh B patients?

Darren S. Sigal, MD: That’s an excellent question. In the SHARP study, Child-Pugh B patients were excluded. However, about 5% of the SHARP study were Child-Pugh B patients. So, I’m willing to and I have treated patients with sorafenib with Child-Pugh B, and I believe subsequent data have shown that there still can be benefits in that population. Subsequent studies have also actually included Child-Pugh B7 patients in the inclusion criteria.

Catherine T. Frenette, MD: I think that that highlights the importance of liver function. Especially with clinical trials, many times they exclude patients with Child-Pugh B because they don’t want the competing mortality of the liver disease. But I think you’re right, with select Child-Pugh B patients, it has been shown that these medicines can be used safely and sometimes effectively. But, again, that depends on the patient and the clinical situation.

Darren S. Sigal, MD: Correct.

Catherine T. Frenette, MD: So, do you use chemotherapy in patients with advanced HCC?

Darren S. Sigal, MD: Up until the past few years, chemotherapy was something that was considered in hepatocellular carcinoma—most classically, Adriamycin-based therapies. I think today, those therapies are really becoming obsolete. There may be some rare examples or rare scenarios where cytotoxic chemotherapy may be important, and, in those scenarios, my preference is to use either single-agent Xeloda [capecitabine] or FOLFOX. FOLFOX has been shown in other GI [gastrointestinal] settings to be safe in patients with significant liver dysfunction. And there are some data to suggest there could be a response rate and a benefit, but I want to emphasize that would not be a standard of care in this modern setting.

Catherine T. Frenette, MD: Can you combine sorafenib with locoregional therapies?

Darren S. Sigal, MD: So, there have been several studies looking at that. I believe at least 3 different studies have looked at that. The largest and probably the most well-known is called the SPACE trial. And the idea behind using sorafenib with locoregional therapies is that when you ablate or embolize a tumor, you’re going to induce a significant amount of vascular growth factors. Sorafenib, as we had alluded to already, blocks the VEGF pathway. And so, mechanistically, it was very satisfying to look in to these combinations, but, to date, there really is no consistent findings showing that there is a significant improvement in survival or response rates.

Catherine T. Frenette, MD: Tell us about the TACTICS trial.

Darren S. Sigal, MD: Thank you for asking about the TACTICS trial. That was recently presented at the ASCO [American Society of Clinical Oncology] GI meeting in January in San Francisco. And that trial is a little bit different than the others in that it actually did show a statistical improvement in progression-free survival. It was a study in Asia, and it randomized 156 patients to either TACE [transarterial chemoembolization] or TACE plus sorafenib. The study design was somewhat similar, but there were some important differences as well in terms of when patients were given or recommended to get TACE. But nevertheless, there was nearly a doubling of progression-free survival from about 13 to about 25 months, and so that certainly is something that might have an impact on future study design and standard of care. I think that it’s going to be important to understand what were the differences in this study versus previous studies that were negative. So, I think it’s certainly an area that should be under active investigation.

Transcript Edited for Clarity 
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