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Multitargeted TKI Therapy in Metastatic HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; A. Ruth He, MD, PhD, Georgetown University Medical Center; Mark W. Karwal, MD, University of Iowa Health Care; Mark H. OHara, MD, Hospital of the University of Pennsylvania; Manish R. Sharma, MD, University of Chicago; Amit Singal, MD, UT Southwestern Medical Center
Published: Thursday, Oct 11, 2018



Transcript:

Ghassan K. Abou-Alfa, MD:
I would like to revert back to the TKIs. There is another important story, that I proudly reported on, on behalf of all other colleagues, at the ASCO Gastrointestinal Cancers Symposium. A phase III trial of cabozantinib versus placebo actually showed an improvement in survival in the patients who received cabozantinib. Understandably, this was a new event for this drug, which is a c-MET inhibitor plus a multi-TKI. Ruth, did the data surprise you?

A. Ruth He, MD, PhD: Cabozantinib is a very interesting drug. Comparing the targets of the other TKIs, it targets MET and AXL. These are important molecules in HCC, not only for the cancer but maybe also for the immune environment. There’s a lot of speculation regarding how this drug actually works. It has been proven to be quite a strong drug. In the second-line setting, when compared with placebo, it shows a survival benefit. This study is a little different from the other second-line study. A quarter of the patients actually had 2 lines of therapy. The signal is still very strong. I think that has proven that cabozantinib is a good, strong second-line, or even third-line option for patients.

Ghassan K. Abou-Alfa, MD: Fair enough. We were very thrilled about that positive data. Manish, there was this trial of a c-MET inhibitor, as well as a TKI, tivantinib. It was negative. Tell us more.

Manish R. Sharma, MD: We are still trying to understand the role of MET in this disease. I think that tivantinib—there was a lot of excitement about that. There was even biomarker selection in that study. We were actually looking for MET expression and were picking those patients to try to give tivantinib to. Maybe we got a bit ahead of ourselves in the science, but the thought was that we had a target and a drug, so we should hit it to see the fruits of that labor. That turned out to be a negative study, as you have already said. And so, maybe going after MET, specifically, is not the answer.

Cabozantinib may have been successful because it doesn’t only go after MET. It actually has other targets as well. What has always intrigued me with tyrosine kinase inhibitors is that some are more specific; and some are more, if you will, dirty, or promiscuous. They hit a lot of different targets. In some diseases, it’s actually advantageous to have one that’s a bit more dirty, so that it hits many different kinases. That seems to be the case here with cabozantinib. Like you said, there may even be an immunologic modulation component to how cabozantinib is working. We’re not really sure what it’s doing. The fact that it’s multitargeted may be advantageous, as compared to lenvatinib, or a monoclonal antibody. In some diseases, we’ve been very successful in hitting the target very specifically with either a small molecule or a monoclonal antibody. HCC seems to have this broad scope. Hitting a lot of different targets with these kinase inhibitors has been more successful.

Ghassan K. Abou-Alfa, MD: I fully agree with you. If anything, at the time when they did other phase II data, they found that if the c-MET was high, patients would not do great. And, if anything, giving anti–c-MET, tivantinib, at that time, definitely could improve outcomes. As such, they elected that they would only allow patients who had c-MET–positivity (50%, 3 to 4-plus expression in immunostaining) to go on the study, which was negative.      
      
Interestingly, when we started working on cabozantinib, I remember that the same question was brought up. However, I said to use it for all patients. What was the science behind that? I’m not the only one who would think that way. We now understand that multi-TKIs are not valued based on one specific target. At the same time, we don’t know how much of that target is going to be important, one way or the other. That’s why I would say that the cabozantinib data were positive. It really showed an improvement in survival that was quite impressive compared to placebo. I have had hands-on experience, but I’m sure many others have done that as well. Mark, have you used cabozantinib at all?

Mark H. O’Hara, MD: We, unfortunately, didn’t have the trial open in our center. So, in the HCC world, until it’s approved, I haven’t used it very much. I have used it a little in renal cell carcinoma....

Ghassan K. Abou-Alfa, MD: What’s your experience?

Mark H. O’Hara, MD: It seems to be pretty well-tolerated, with similar side effects to what we’ve seen with the other TKIs—the fatigue, the diarrhea, some hypertension. But overall, I think it’s pretty well-tolerated.

Transcript Edited for Clarity.

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Transcript:

Ghassan K. Abou-Alfa, MD:
I would like to revert back to the TKIs. There is another important story, that I proudly reported on, on behalf of all other colleagues, at the ASCO Gastrointestinal Cancers Symposium. A phase III trial of cabozantinib versus placebo actually showed an improvement in survival in the patients who received cabozantinib. Understandably, this was a new event for this drug, which is a c-MET inhibitor plus a multi-TKI. Ruth, did the data surprise you?

A. Ruth He, MD, PhD: Cabozantinib is a very interesting drug. Comparing the targets of the other TKIs, it targets MET and AXL. These are important molecules in HCC, not only for the cancer but maybe also for the immune environment. There’s a lot of speculation regarding how this drug actually works. It has been proven to be quite a strong drug. In the second-line setting, when compared with placebo, it shows a survival benefit. This study is a little different from the other second-line study. A quarter of the patients actually had 2 lines of therapy. The signal is still very strong. I think that has proven that cabozantinib is a good, strong second-line, or even third-line option for patients.

Ghassan K. Abou-Alfa, MD: Fair enough. We were very thrilled about that positive data. Manish, there was this trial of a c-MET inhibitor, as well as a TKI, tivantinib. It was negative. Tell us more.

Manish R. Sharma, MD: We are still trying to understand the role of MET in this disease. I think that tivantinib—there was a lot of excitement about that. There was even biomarker selection in that study. We were actually looking for MET expression and were picking those patients to try to give tivantinib to. Maybe we got a bit ahead of ourselves in the science, but the thought was that we had a target and a drug, so we should hit it to see the fruits of that labor. That turned out to be a negative study, as you have already said. And so, maybe going after MET, specifically, is not the answer.

Cabozantinib may have been successful because it doesn’t only go after MET. It actually has other targets as well. What has always intrigued me with tyrosine kinase inhibitors is that some are more specific; and some are more, if you will, dirty, or promiscuous. They hit a lot of different targets. In some diseases, it’s actually advantageous to have one that’s a bit more dirty, so that it hits many different kinases. That seems to be the case here with cabozantinib. Like you said, there may even be an immunologic modulation component to how cabozantinib is working. We’re not really sure what it’s doing. The fact that it’s multitargeted may be advantageous, as compared to lenvatinib, or a monoclonal antibody. In some diseases, we’ve been very successful in hitting the target very specifically with either a small molecule or a monoclonal antibody. HCC seems to have this broad scope. Hitting a lot of different targets with these kinase inhibitors has been more successful.

Ghassan K. Abou-Alfa, MD: I fully agree with you. If anything, at the time when they did other phase II data, they found that if the c-MET was high, patients would not do great. And, if anything, giving anti–c-MET, tivantinib, at that time, definitely could improve outcomes. As such, they elected that they would only allow patients who had c-MET–positivity (50%, 3 to 4-plus expression in immunostaining) to go on the study, which was negative.      
      
Interestingly, when we started working on cabozantinib, I remember that the same question was brought up. However, I said to use it for all patients. What was the science behind that? I’m not the only one who would think that way. We now understand that multi-TKIs are not valued based on one specific target. At the same time, we don’t know how much of that target is going to be important, one way or the other. That’s why I would say that the cabozantinib data were positive. It really showed an improvement in survival that was quite impressive compared to placebo. I have had hands-on experience, but I’m sure many others have done that as well. Mark, have you used cabozantinib at all?

Mark H. O’Hara, MD: We, unfortunately, didn’t have the trial open in our center. So, in the HCC world, until it’s approved, I haven’t used it very much. I have used it a little in renal cell carcinoma....

Ghassan K. Abou-Alfa, MD: What’s your experience?

Mark H. O’Hara, MD: It seems to be pretty well-tolerated, with similar side effects to what we’ve seen with the other TKIs—the fatigue, the diarrhea, some hypertension. But overall, I think it’s pretty well-tolerated.

Transcript Edited for Clarity.
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