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Emerging Therapies in Advanced HCC

Insights From: Richard S. Finn, MD, Geffen School of Medicine;Arndt Vogel, MD, Hannover Medical School
Published: Wednesday, Dec 28, 2016


Transcript:

Richard Finn, MD:
This is a very exciting time in HCC drug development. While we’ve been disappointed with some of the phase III studies completed to date, we recently had a positive phase III study. So, that gives us hope that we can make a difference in this disease. There are several ongoing phase III studies that we’re waiting to read out with novel mechanisms. Tivantinib targets the hepatocyte growth factor receptor. This will be perhaps one of the first studies evaluated in a biomarker-selected population. The feeling is that high c-Met in tumors is a bad prognostic sign, and that patients who get tivantinib who have high c-Met, might get a benefit. That’s based on a phase II study that was done a few years ago that showed that in a retrospective analysis, patients who had high c-Met were the ones who really got a benefit with tivantinib.

Cabozantinib is a c-Met-plus inhibitor I would say. It hit several kinases. It’s been evaluated in second line, but, unlike tivantinib, it is not in a biomarker-selected population. It was initially evaluated in a mixed population of both sorafenib-naïve and sorafenib-progressing patients. That study has completed accrual and we’ll have to wait to see the results. There is another biomarker-selected population being evaluated, and that is with ramucirumab. Here, the biomarker is elevated alpha-fetoprotein (AFP), and that, again, was based on a retrospective review from the initial phase III study with ramucirumab, targeting vascular endothelial growth factor. That was negative, but, in retrospective review, the patients who had a high AFP had a poor natural history, but they also were the ones who got a benefit from ramucirumab.

Arndt Vogel, MD: What are the most promising targeted therapies in HCC? That is a good and important question. As mentioned before, we had a couple of negative trials not only in first line, but also in second line. But, out of these negative trials, we have learned that there might be some subgroup of patients who might benefit from, specifically, 2 drugs. One is ramucirumab. So, the REACH-1 study was a negative study. In the overall population, we were not able to achieve a significant survival benefit in second line. But, what we have learned is that AFP is a very interesting clinical biomarker. When we look at the overall survival data in the placebo group of patients with a high AFP level, it was very short, only 4.2 months. In comparison, patients who had lower AFP levels below 400 ng/ml, overall survival was much better, around 11 months. So, higher AFP levels are a prognostic marker in HCC.

Interestingly, it’s not only prognostic, but it appears also to be predictive. Because in the group with a poor prognosis, (patients with high AFP level and a short survival in the placebo group), ramucirumab significantly almost doubled the median survival. So, these data were quite promising, and, based on these data, a second study is now underway—the REACH-2 study—in which specifically ramucirumab is investigated in patients with high AFP levels.

And, the second drug is tivantinib. Tivantinib is most likely a c-MET inhibitor. Also, in this case, a phase II was a negative study in the overall population. There was no significant improvement in overall survival. But, what the investigators have done in the study, they have looked to which patient could benefit from the c-MET inhibitors. And what they found is that patients who had high c-MET expression, similar to patients with high AFP levels, are patients with a poor prognosis. And, in this poor prognosis group, again, tivantinib significantly improved overall survival compared to patients with a low c-MET expression in which tivantinib was not as active. Based on these data, similar to the REACH-2 study, a second, larger phase III study has been undertaken for tivantinib in which specifically patients with high c-MET levels are included. And the study has finished recruitment, and I think we will see the survival data probably next year.

Richard Finn, MD: Perhaps the area that has the highest interest is with the monoclonal antibodies against PD-1. There have been very intriguing data presented at ASCO for the past 2 years with nivolumab in a single-arm phase II study. In the population of liver cancer patients whom they evaluated, there was a fairly high response rate. Again, response isn’t something we usually see with liver cancer, but it’s in the range of 15% to 20%. And those responses were typically very durable. There were a few complete responses. And if we look at the role of immunotherapy in other diseases we treat, it’s clearly having a big impact. So, there’s a lot of excitement with 2 ongoing phase III studies. There’s a frontline study of nivolumab versus sorafenib for newly diagnosed advanced liver cancer, and there’s a second-line study for patients who progress on sorafenib looking at pembrolizumab versus placebo.

Arndt Vogel, MD: Checkpoint inhibitors are currently used in all indications, and there’s no cancer in which they have not been tried. Similarly, we have also first data in HCC for PD-1/PD-L1 inhibitors, and also for CTLA4 inhibitors. The question is, what is the best time to use these drugs? We have a small study, which has been published this year or last year at ASCO, in which the CTLA4 inhibitor has been combined with local therapies, RFA and TACE. And what we have seen here, it was a small study, is that it’s safe, and that we can most likely combine these systemic therapies with local therapies. And, I think, this is a very promising approach to really combine systemic therapy and local therapy in our patients with HCC.

Larger studies have been undertaken with nivolumab in HCC. At the beginning, there was the question, of course, whether patients with HCC can be treated with checkpoint inhibitors, because one of the frequently observed side effects is hepatitis, or autoimmune hepatitis, which we can see with checkpoint inhibitors. So, can we keep patients, who have already hepatitis, with a drug that might induce hepatitis? And, there were some safety concerns. There were first some dose-escalation studies which luckily confirmed that it is safe to use these drugs in patients with liver disease, independent of whether they had viral liver disease or not, whether they have received sorafenib before, or were naïve for sorafenib. So, there’s no safety concern. Now, we have the first data with the expansion cohort, which are quite promising. We do see some responses, and we see, in a couple of patients, a disease stabilization for more than 6 months. These data are very early and they have to mature, and we, of course, have to wait for the larger phase III studies that compare the outcome to sorafenib in first line, maybe, or to best supportive care in second line.

Transcript Edited for Clarity
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Transcript:

Richard Finn, MD:
This is a very exciting time in HCC drug development. While we’ve been disappointed with some of the phase III studies completed to date, we recently had a positive phase III study. So, that gives us hope that we can make a difference in this disease. There are several ongoing phase III studies that we’re waiting to read out with novel mechanisms. Tivantinib targets the hepatocyte growth factor receptor. This will be perhaps one of the first studies evaluated in a biomarker-selected population. The feeling is that high c-Met in tumors is a bad prognostic sign, and that patients who get tivantinib who have high c-Met, might get a benefit. That’s based on a phase II study that was done a few years ago that showed that in a retrospective analysis, patients who had high c-Met were the ones who really got a benefit with tivantinib.

Cabozantinib is a c-Met-plus inhibitor I would say. It hit several kinases. It’s been evaluated in second line, but, unlike tivantinib, it is not in a biomarker-selected population. It was initially evaluated in a mixed population of both sorafenib-naïve and sorafenib-progressing patients. That study has completed accrual and we’ll have to wait to see the results. There is another biomarker-selected population being evaluated, and that is with ramucirumab. Here, the biomarker is elevated alpha-fetoprotein (AFP), and that, again, was based on a retrospective review from the initial phase III study with ramucirumab, targeting vascular endothelial growth factor. That was negative, but, in retrospective review, the patients who had a high AFP had a poor natural history, but they also were the ones who got a benefit from ramucirumab.

Arndt Vogel, MD: What are the most promising targeted therapies in HCC? That is a good and important question. As mentioned before, we had a couple of negative trials not only in first line, but also in second line. But, out of these negative trials, we have learned that there might be some subgroup of patients who might benefit from, specifically, 2 drugs. One is ramucirumab. So, the REACH-1 study was a negative study. In the overall population, we were not able to achieve a significant survival benefit in second line. But, what we have learned is that AFP is a very interesting clinical biomarker. When we look at the overall survival data in the placebo group of patients with a high AFP level, it was very short, only 4.2 months. In comparison, patients who had lower AFP levels below 400 ng/ml, overall survival was much better, around 11 months. So, higher AFP levels are a prognostic marker in HCC.

Interestingly, it’s not only prognostic, but it appears also to be predictive. Because in the group with a poor prognosis, (patients with high AFP level and a short survival in the placebo group), ramucirumab significantly almost doubled the median survival. So, these data were quite promising, and, based on these data, a second study is now underway—the REACH-2 study—in which specifically ramucirumab is investigated in patients with high AFP levels.

And, the second drug is tivantinib. Tivantinib is most likely a c-MET inhibitor. Also, in this case, a phase II was a negative study in the overall population. There was no significant improvement in overall survival. But, what the investigators have done in the study, they have looked to which patient could benefit from the c-MET inhibitors. And what they found is that patients who had high c-MET expression, similar to patients with high AFP levels, are patients with a poor prognosis. And, in this poor prognosis group, again, tivantinib significantly improved overall survival compared to patients with a low c-MET expression in which tivantinib was not as active. Based on these data, similar to the REACH-2 study, a second, larger phase III study has been undertaken for tivantinib in which specifically patients with high c-MET levels are included. And the study has finished recruitment, and I think we will see the survival data probably next year.

Richard Finn, MD: Perhaps the area that has the highest interest is with the monoclonal antibodies against PD-1. There have been very intriguing data presented at ASCO for the past 2 years with nivolumab in a single-arm phase II study. In the population of liver cancer patients whom they evaluated, there was a fairly high response rate. Again, response isn’t something we usually see with liver cancer, but it’s in the range of 15% to 20%. And those responses were typically very durable. There were a few complete responses. And if we look at the role of immunotherapy in other diseases we treat, it’s clearly having a big impact. So, there’s a lot of excitement with 2 ongoing phase III studies. There’s a frontline study of nivolumab versus sorafenib for newly diagnosed advanced liver cancer, and there’s a second-line study for patients who progress on sorafenib looking at pembrolizumab versus placebo.

Arndt Vogel, MD: Checkpoint inhibitors are currently used in all indications, and there’s no cancer in which they have not been tried. Similarly, we have also first data in HCC for PD-1/PD-L1 inhibitors, and also for CTLA4 inhibitors. The question is, what is the best time to use these drugs? We have a small study, which has been published this year or last year at ASCO, in which the CTLA4 inhibitor has been combined with local therapies, RFA and TACE. And what we have seen here, it was a small study, is that it’s safe, and that we can most likely combine these systemic therapies with local therapies. And, I think, this is a very promising approach to really combine systemic therapy and local therapy in our patients with HCC.

Larger studies have been undertaken with nivolumab in HCC. At the beginning, there was the question, of course, whether patients with HCC can be treated with checkpoint inhibitors, because one of the frequently observed side effects is hepatitis, or autoimmune hepatitis, which we can see with checkpoint inhibitors. So, can we keep patients, who have already hepatitis, with a drug that might induce hepatitis? And, there were some safety concerns. There were first some dose-escalation studies which luckily confirmed that it is safe to use these drugs in patients with liver disease, independent of whether they had viral liver disease or not, whether they have received sorafenib before, or were naïve for sorafenib. So, there’s no safety concern. Now, we have the first data with the expansion cohort, which are quite promising. We do see some responses, and we see, in a couple of patients, a disease stabilization for more than 6 months. These data are very early and they have to mature, and we, of course, have to wait for the larger phase III studies that compare the outcome to sorafenib in first line, maybe, or to best supportive care in second line.

Transcript Edited for Clarity
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