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HCC: Emerging Therapies

Insights From: Catherine T. Frenette, MD, Scripps Green Hospital; Darren S. Sigal, MD, Scripps Green Hospital
Published: Friday, Jun 01, 2018



Transcript: 

Catherine T. Frenette, MD: Now let’s talk about some of the emerging therapies for liver cancer. Dr. Sigal, can you give us an idea of other targeted therapies that are currently being studied?

Darren S. Sigal, MD: I’m sure if you search clinicaltrials.gov, there are many, many options that are under active investigation. There are several that I think are of interest. The first is an agent called enzalutamide, which is approved for prostate cancer but is being looked at currently in an ongoing study in hepatocellular carcinoma. Another agent that is very promising is an agent called cabozantinib. Cabozantinib is an oral tyrosine kinase inhibitor that interferes with multiple cell signaling pathways, including VEGF pathways that have been important in the other oral tyrosine kinases approved already for hepatocellular carcinoma.

In the CELESTIAL trial, cabozantinib was shown to improve overall survival from 8 to 10.2 months versus placebo. There was almost a tripling of the progression-free survival. There are several important points to remember about this study. It allowed up to 2 prior lines of therapy; patients had to have progressed on at least 1. So, for some patients in the study, actually, this would have been the third-line therapy—and it still had an improvement in overall survival. There were also some other poor-risk features of these patients. Nearly 40% of patients were viral hepatitis B–positive, and a significant number of patients either had extrahepatic spread or macrovascular invasion. So, this is an important agent that will become more important in the future, hopefully when it gains approval.

The third agent is called lenvatinib. Lenvatinib was looked at in a phase III study in the frontline setting, randomizing patients to lenvatinib versus sorafenib, which is the benchmark frontline standard of care. And what this study showed is that there was no statistical difference in survival endpoints, although, numerically, lenvatinib had an improvement in overall survival. There was also an improvement in response rate from 9% to 24%.

Catherine T. Frenette, MD: Dr. Sigal, we know that nivolumab has FDA accelerated approval for second-line treatment of advanced HCC. Are there other immunotherapies that are being looked at in this setting?

Darren S. Sigal, MD: Yes. So, other immune checkpoint inhibitors are being looked at, and there’s an agent, pembrolizumab, that has been studied in a phase II trial of 105 patients in the second-line setting. In a very similar manner to the KEYNOTE-040 trial, this study reported a response rate of about 16%, with the median survival not yet reached at approximately 9 months. And so, this is in an ongoing phase III study as well right now.

Another approach to immune therapy in HCC is combination immune checkpoint inhibitors. And there’s a phase I/II trial that has been reported combining durvalumab, which is a PD-L1–blocking agent, to tremelimumab, which is a CTLA4-blocking agent. And in this study, there were 40 patients accrued. There was a phase I dose escalation, and patients could have either been treated with sorafenib, refused sorafenib, or been intolerant to sorafenib. And what was shown, there was a confirmed overall response rate of about 30%. So, that is a very high, maybe the highest reported, response rate in systemic therapy for hepatocellular carcinoma. And this is being looked at now in an ongoing phase III study called the HIMALAYA trial.

Catherine T. Frenette, MD: Any concerns about toxicity with combinations of multiple immune therapies?

Darren S. Sigal, MD: So, combination checkpoint inhibitor therapies can be toxic, and there were toxicities reported in the phase I/II trial. But most data related to combination checkpoint inhibitors come from the melanoma literature and, more recent, the renal cell carcinoma literature. And so, there certainly can be increased risk for autoimmunity and specifically colitis.

Catherine T. Frenette, MD: Well, we certainly have reviewed a lot of interesting information about the treatment of HCC, in first-line, second-line advanced, and locoregional therapies. We thank you very much for joining us for today’s discussion.

Transcript Edited for Clarity
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Transcript: 

Catherine T. Frenette, MD: Now let’s talk about some of the emerging therapies for liver cancer. Dr. Sigal, can you give us an idea of other targeted therapies that are currently being studied?

Darren S. Sigal, MD: I’m sure if you search clinicaltrials.gov, there are many, many options that are under active investigation. There are several that I think are of interest. The first is an agent called enzalutamide, which is approved for prostate cancer but is being looked at currently in an ongoing study in hepatocellular carcinoma. Another agent that is very promising is an agent called cabozantinib. Cabozantinib is an oral tyrosine kinase inhibitor that interferes with multiple cell signaling pathways, including VEGF pathways that have been important in the other oral tyrosine kinases approved already for hepatocellular carcinoma.

In the CELESTIAL trial, cabozantinib was shown to improve overall survival from 8 to 10.2 months versus placebo. There was almost a tripling of the progression-free survival. There are several important points to remember about this study. It allowed up to 2 prior lines of therapy; patients had to have progressed on at least 1. So, for some patients in the study, actually, this would have been the third-line therapy—and it still had an improvement in overall survival. There were also some other poor-risk features of these patients. Nearly 40% of patients were viral hepatitis B–positive, and a significant number of patients either had extrahepatic spread or macrovascular invasion. So, this is an important agent that will become more important in the future, hopefully when it gains approval.

The third agent is called lenvatinib. Lenvatinib was looked at in a phase III study in the frontline setting, randomizing patients to lenvatinib versus sorafenib, which is the benchmark frontline standard of care. And what this study showed is that there was no statistical difference in survival endpoints, although, numerically, lenvatinib had an improvement in overall survival. There was also an improvement in response rate from 9% to 24%.

Catherine T. Frenette, MD: Dr. Sigal, we know that nivolumab has FDA accelerated approval for second-line treatment of advanced HCC. Are there other immunotherapies that are being looked at in this setting?

Darren S. Sigal, MD: Yes. So, other immune checkpoint inhibitors are being looked at, and there’s an agent, pembrolizumab, that has been studied in a phase II trial of 105 patients in the second-line setting. In a very similar manner to the KEYNOTE-040 trial, this study reported a response rate of about 16%, with the median survival not yet reached at approximately 9 months. And so, this is in an ongoing phase III study as well right now.

Another approach to immune therapy in HCC is combination immune checkpoint inhibitors. And there’s a phase I/II trial that has been reported combining durvalumab, which is a PD-L1–blocking agent, to tremelimumab, which is a CTLA4-blocking agent. And in this study, there were 40 patients accrued. There was a phase I dose escalation, and patients could have either been treated with sorafenib, refused sorafenib, or been intolerant to sorafenib. And what was shown, there was a confirmed overall response rate of about 30%. So, that is a very high, maybe the highest reported, response rate in systemic therapy for hepatocellular carcinoma. And this is being looked at now in an ongoing phase III study called the HIMALAYA trial.

Catherine T. Frenette, MD: Any concerns about toxicity with combinations of multiple immune therapies?

Darren S. Sigal, MD: So, combination checkpoint inhibitor therapies can be toxic, and there were toxicities reported in the phase I/II trial. But most data related to combination checkpoint inhibitors come from the melanoma literature and, more recent, the renal cell carcinoma literature. And so, there certainly can be increased risk for autoimmunity and specifically colitis.

Catherine T. Frenette, MD: Well, we certainly have reviewed a lot of interesting information about the treatment of HCC, in first-line, second-line advanced, and locoregional therapies. We thank you very much for joining us for today’s discussion.

Transcript Edited for Clarity
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