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Optimizing Sequencing of Therapies in HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, University of California Los Angeles; R. Kate Kelley, MD, University of California San Francisco; Andrew X. Zhu, MD, PhD, Harvard Medical School; Tony Saab, MD, Mayo Clinic
Published: Monday, Mar 04, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD: Andrew, to move on from the first-line therapy, we spoke about sorafenib and we spoke about lenvatinib, move to second-line therapy. One of the things, exactly as Rich mentioned to us in the beginning, was the rather surprising outcome that was positive for regorafenib after exposure to sorafenib. Tell us a little bit more about that.

Andrew X. Zhu, MD, PhD: I think you mean the RESORCE trial, which has really addressed the value of regorafenib for patients who tolerate the sorafenib but eventually progress. And they get randomized to receive either regorafenib or placebo. I think the trial definitively demonstrated it improved survival. I think with that data, the drug was approved very quickly. And it was surprising for the following reason. I think if we really look at the structure of both molecules, they’re actually incredibly similar. And I think we feel like, how can a drug with just very subtle change actually behave this way? But, on the other hand, a subtle change does not necessarily mean the drug doesn’t have any other unique mechanism of action. So regorafenib definitely inhibits other important pathways, for example, the TIE2 pathway.

In the end, a positive study coming from the RESORCE trial really lend the patients for the first time a second-line treatment option. So I think for that reason, the trial definitely has its merit. And also as Richard already published the data, if you look at the selected population, patient getting the sorafenib, and when they fail, they get sequenced down to the regorafenib. In the selected population, granted, the survival can be up to 26 months, which I think for the first time we realize the availability of multiple drugs is really changing the life expectancy of our patients. We’re going to discuss a little bit how do we optimize the sequencing. But I think with the availability of more than 1 drug, you’re actually changing the natural history of the disease.

And the safety profile of this drug is very much known to the oncology folks because the drug has been approved in colorectal cancer, in gastrointestinal stromal tumor. So, as oncologists, we know the safety profile very well. And I have to say that the safety profile for the HCC population, in my experience, and also based on the data, it’s manageable. I think you just need to be incredibly vigilant. I think you have to know how to deal with a similar safety profile that we encounter with sorafenib; the hand and foot skin reaction, the diarrhea. But, on the other hand, if you’re actually very much on top of things, I think these patients can actually get the treatment and also get the benefit.

Ghassan K. Abou-Alfa, MD: Katie, after REGO [regorafenib], clearly there was a lot of enthusiasm about many other drugs. And one of them that yourself, myself have been involved in is cabozantinib. Tell us about cabozantinib. What is it? And, at the same time, tell us about the phase II data that you started with.

R. Kate Kelley, MD: So cabozantinib, as you know quite well, is another multikinase inhibitor whose targets are similar to sorafenib and regorafenib, including the VEGF receptor, isoforms 2 and 3 predominantly, but also includes MET, the hepatocyte growth factor receptor, as well as AXL and a couple other targets for inhibition that distinguishes it somewhat from the other multikinase inhibitors. And so cabozantinib was first studied in a large basket trial, a randomized discontinuation trial that included HCC as one of the tumor cohorts. And, in the single-arm uncontrolled phase II data, it did show promising survival approaching the 14- to 15-month range in the predominantly second-line population. And that prompted the development of the phase III randomized CELESTIAL trial to study cabozantinib versus placebo in both second- and third-line HCC patients after first-line sorafenib.

Ghassan K. Abou-Alfa, MD: Rich, as an outsider to this all cabozantinib data that Katie, and myself, and many others were involved in, give us your perspective. What do you see that [differentiates] CABO [cabozantinib] from other TKIs [tyrosine kinase inhibitors]?

Richard S. Finn, MD: I’ve got to say that even what has changed in the past 2 years, they were all of a sudden having all these positive studies with TKIs. And, initially, I thought when we saw the REGO data, as Andy alluded to, it’s a similar drug to sorafenib structurally, though biochemically it’s a little different. The RESORCE study was very well designed in that there were stratification factors that we learned from other studies. It required documented progression on sorafenib, so it’s a very homogenous population. And it required patients to have tolerated a minimum dose of sorafenib. When that study read out positive, the feeling was, well, it’s a good study design. And maybe the others failed because they were just bad study designs. But then we look and see the control arm in that study behave the same as other second-line studies, and that makes you think that it was a good study design but also a good drug.

And then CABO study was launched using fewer stratification factors, did not require documented progression on sorafenib. It was somewhat of the old design. Yet it read out positive, and it was as positive I think as REGO or any other second-line study. And I think it’s very satisfying. I think it’s another option. It’s hard for me to differentiate the clinical activity of that drug from regorafenib. The data look very similar as far as its tumor control, PFS [progression-free survival], [adverse] effect profile. But the two drugs biochemically are very different. Both of them have that common VEGF stream. I’m interested to know the importance of hitting AXL and MET in second-line liver cancer.

Ghassan K. Abou-Alfa, MD: If we recall all of us, there was another c-MET inhibitor. It’s a multitargeted c-MET inhibitor. It’s not really specific for c-MET only, which was tivantinib. And that trial, tivantinib versus placebo, was negative while the one with the cabozantinib versus placebo, as we just heard, was positive. The intriguing difference was that the tivantinib required the patient have c-MET expression, which was measured at that time based on some data from the phase II as being 50%, 3 to 4+ expression on immunostaining, that would allow patients to get on the study. The smart thing that collectively we did in regard to the cabozantinib, we were agnostic in regard to the expression of the c-MET.

And this really brings into play how much of c-MET is needed for the expression versus not. And, remember, for example, in breast cancer, ER-positivity, even a whiff of ER [estrogen receptor] would be enough to use hormone therapy. And number 2 is of course, we’re very clear in understanding that this is a multikinase inhibitor. It’s not only specifically c-MET, per se. Actually, that … might at least allude to some of that positive outcome that the cabozantinib study had.

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Transcript: 

Ghassan K. Abou-Alfa, MD: Andrew, to move on from the first-line therapy, we spoke about sorafenib and we spoke about lenvatinib, move to second-line therapy. One of the things, exactly as Rich mentioned to us in the beginning, was the rather surprising outcome that was positive for regorafenib after exposure to sorafenib. Tell us a little bit more about that.

Andrew X. Zhu, MD, PhD: I think you mean the RESORCE trial, which has really addressed the value of regorafenib for patients who tolerate the sorafenib but eventually progress. And they get randomized to receive either regorafenib or placebo. I think the trial definitively demonstrated it improved survival. I think with that data, the drug was approved very quickly. And it was surprising for the following reason. I think if we really look at the structure of both molecules, they’re actually incredibly similar. And I think we feel like, how can a drug with just very subtle change actually behave this way? But, on the other hand, a subtle change does not necessarily mean the drug doesn’t have any other unique mechanism of action. So regorafenib definitely inhibits other important pathways, for example, the TIE2 pathway.

In the end, a positive study coming from the RESORCE trial really lend the patients for the first time a second-line treatment option. So I think for that reason, the trial definitely has its merit. And also as Richard already published the data, if you look at the selected population, patient getting the sorafenib, and when they fail, they get sequenced down to the regorafenib. In the selected population, granted, the survival can be up to 26 months, which I think for the first time we realize the availability of multiple drugs is really changing the life expectancy of our patients. We’re going to discuss a little bit how do we optimize the sequencing. But I think with the availability of more than 1 drug, you’re actually changing the natural history of the disease.

And the safety profile of this drug is very much known to the oncology folks because the drug has been approved in colorectal cancer, in gastrointestinal stromal tumor. So, as oncologists, we know the safety profile very well. And I have to say that the safety profile for the HCC population, in my experience, and also based on the data, it’s manageable. I think you just need to be incredibly vigilant. I think you have to know how to deal with a similar safety profile that we encounter with sorafenib; the hand and foot skin reaction, the diarrhea. But, on the other hand, if you’re actually very much on top of things, I think these patients can actually get the treatment and also get the benefit.

Ghassan K. Abou-Alfa, MD: Katie, after REGO [regorafenib], clearly there was a lot of enthusiasm about many other drugs. And one of them that yourself, myself have been involved in is cabozantinib. Tell us about cabozantinib. What is it? And, at the same time, tell us about the phase II data that you started with.

R. Kate Kelley, MD: So cabozantinib, as you know quite well, is another multikinase inhibitor whose targets are similar to sorafenib and regorafenib, including the VEGF receptor, isoforms 2 and 3 predominantly, but also includes MET, the hepatocyte growth factor receptor, as well as AXL and a couple other targets for inhibition that distinguishes it somewhat from the other multikinase inhibitors. And so cabozantinib was first studied in a large basket trial, a randomized discontinuation trial that included HCC as one of the tumor cohorts. And, in the single-arm uncontrolled phase II data, it did show promising survival approaching the 14- to 15-month range in the predominantly second-line population. And that prompted the development of the phase III randomized CELESTIAL trial to study cabozantinib versus placebo in both second- and third-line HCC patients after first-line sorafenib.

Ghassan K. Abou-Alfa, MD: Rich, as an outsider to this all cabozantinib data that Katie, and myself, and many others were involved in, give us your perspective. What do you see that [differentiates] CABO [cabozantinib] from other TKIs [tyrosine kinase inhibitors]?

Richard S. Finn, MD: I’ve got to say that even what has changed in the past 2 years, they were all of a sudden having all these positive studies with TKIs. And, initially, I thought when we saw the REGO data, as Andy alluded to, it’s a similar drug to sorafenib structurally, though biochemically it’s a little different. The RESORCE study was very well designed in that there were stratification factors that we learned from other studies. It required documented progression on sorafenib, so it’s a very homogenous population. And it required patients to have tolerated a minimum dose of sorafenib. When that study read out positive, the feeling was, well, it’s a good study design. And maybe the others failed because they were just bad study designs. But then we look and see the control arm in that study behave the same as other second-line studies, and that makes you think that it was a good study design but also a good drug.

And then CABO study was launched using fewer stratification factors, did not require documented progression on sorafenib. It was somewhat of the old design. Yet it read out positive, and it was as positive I think as REGO or any other second-line study. And I think it’s very satisfying. I think it’s another option. It’s hard for me to differentiate the clinical activity of that drug from regorafenib. The data look very similar as far as its tumor control, PFS [progression-free survival], [adverse] effect profile. But the two drugs biochemically are very different. Both of them have that common VEGF stream. I’m interested to know the importance of hitting AXL and MET in second-line liver cancer.

Ghassan K. Abou-Alfa, MD: If we recall all of us, there was another c-MET inhibitor. It’s a multitargeted c-MET inhibitor. It’s not really specific for c-MET only, which was tivantinib. And that trial, tivantinib versus placebo, was negative while the one with the cabozantinib versus placebo, as we just heard, was positive. The intriguing difference was that the tivantinib required the patient have c-MET expression, which was measured at that time based on some data from the phase II as being 50%, 3 to 4+ expression on immunostaining, that would allow patients to get on the study. The smart thing that collectively we did in regard to the cabozantinib, we were agnostic in regard to the expression of the c-MET.

And this really brings into play how much of c-MET is needed for the expression versus not. And, remember, for example, in breast cancer, ER-positivity, even a whiff of ER [estrogen receptor] would be enough to use hormone therapy. And number 2 is of course, we’re very clear in understanding that this is a multikinase inhibitor. It’s not only specifically c-MET, per se. Actually, that … might at least allude to some of that positive outcome that the cabozantinib study had.

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