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Improving Survival in HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, UCLA; Laura M. Kulik, MD, Northwestern University Feinberg School of Medicine; R. Kate Kelley, MD, University of California-San Francisco; Riad Salem, MD, Northwestern University Feinberg School of Medicine
Published: Thursday, Mar 09, 2017



Transcript:

Ghassan K. Abou-Alfa, MD:
This brings me to an important point. As you can imagine, Laura, in oncology, it’s all about shrinkage, tumor markers, etc, and sometimes we struggle at explaining survival. From your standpoint, especially if we’re going to try to include that cirrhotic component, how can we reach to the patient and make sure that the message about improvement in survival is there?

Laura M. Kulik, MD: Well, it can be difficult because, as Rich had originally said, we’re dealing with 2 diseases. Explain to the patients that both those diseases are competing with each other to cause them harm and decrease their overall survival, and letting them know that they do not have a curative option is very important so that their expectations are not that this tumor is going to go away. And from there, I think telling patients that this drug is the only drug that is currently available at this point in time that has shown survival is very important. Because a lot of times we’re trying to get patients on drugs and they show up and they’re the ones who don’t want to start it. They hear the side effects. You tell them about manageability. They don’t want to come back in 10 days to be seen again. They’re traveling far. I found, as a hepatologist treating people, that if I set them up with an oncologist closer to home in the community, that that has worked very well. Patients are a lot more amenable to saying, “Okay, well, I’ll go see this guy who lives 5 miles away from me in 2 weeks and follow up.” I don’t feel comfortable saying, “Okay, come back in 3 months after you’ve just started them on a biological agent.” I think that telling them that this is not going to cure them, but the hope that they’re going to have improved not only length of time but hopefully quality of life by decreasing some of their symptoms, such as pain, can drive that point home to patients.

Ghassan K. Abou-Alfa, MD: Sure. So, with sorafenib on board, I think Richard mentioned that there was a lot of, to be fair, genuine and serious attempts to see if we can improve on the surviving beyond the 10.7 months that we just heard from Katie. Interestingly, we were all involved in those very noble efforts and really nothing worked. I have to say this is hot off the press. The Lancet, just literally on January 7, just a few days ago, published the study on regorafenib for a patient with HCC who progressed on sorafenib. It was a randomized double-blind, placebo-controlled phase III trial. So, you were part of that study. Tell us first about the results and let’s discuss it.

Richard S. Finn, MD: Well, I think the RESORCE study is the light at the end of the tunnel for us in liver cancer, given that we’ve had about 10 years without a new drug, without a positive phase III study. And you allude to the fact that maybe this was a dark horse in the race, but in retrospective, maybe it wasn’t. Regorafenib, like sorafenib, is a multi-targeted therapy. It hits several kinases, but differentiates itself a little bit. It’s a very potent pan-VEGF inhibitor, including VEGFR2 as well as the TI-2 receptor, which plays a role in angiogenesis.

Ghassan K. Abou-Alfa, MD: And if I may add here, it was actually designed to do that. In other words, the intent when the regorafenib was designed was to actually improve or catch on more targets than sorafenib.

Richard S. Finn, MD: Correct. I think we need to be humble when we approach drugs like this. We might not know exactly what they’re doing. Regorafenib was approved already and shown to be an anti-cancer drug in colon cancer and also in GI stromal tumors, where it hits the c-KIT receptor. There was a phase II study led by Jordi Bruix out of Barcelona, a very well conducted study defining patients who had progressed on sorafenib, with a clear definition of that—excluding patients who were intolerant. And then there was a very provocative median survival, not looking at response rates per se, although those were reported and they were higher than with sorafenib. But needless to say, the survival is in the 13- or 14-month range. And we know now, from many of the negative phase III studies in second-line, that median survival for this population was about 8 months. If we look at the development of sorafenib, your work in a large phase II study showed a survival of about 9 to 10 months, and that was the signal to move that drug ahead in frontline.

The regorafenib study, I think besides taking a new molecule into second-line, also learned from some of the clinical trial design errors that maybe occurred in some of the other phase III studies. They had a benchmark for what to expect in second-line; that 8 months—which I think surprised a lot of people when we looked at the brivanib, the first drug to read out in the post sorafenib era being around 9 months—no one really expected that. But we’re also dealing with all the other prognostic factors in second-line HCC that are important to stratify for and control for, such as high alpha-fetoprotein. We saw that in the ramucirumab data that that’s an important prognostic factor. And maybe we should be separating macrovascular invasion and extrahepatic spread instead of lumping them together, as we saw in the brivanib and the everolimus experience.

Needless to say, this was a well-conducted, randomized phase III double-blind, placebo-controlled study of regorafenib; 160 mg orally daily on a 3 weeks on, 1 week off regimen versus a placebo on the same regimen. And this was a positive study for overall survival, improving overall survival by about 3 months. We saw an improvement from about 8 months to just under 11 months, a hazard ratio of 0.63, which is a 37% decrease in the risk of death. A lot of this was managed similar to sorafenib, with prolonging stabilized disease. But interesting enough, the response rate was higher with this drug. Clearly, this is a different drug than sorafenib. And what is progression on sorafenib? That is something we’ve wrestled with for a while for a drug, as Katie pointed out, that has no response rate really. When do we say patients are progressing? And in this study, we said RECIST progression, so more than a 20% increase and, at that point, randomizing them to the 2 control arms. We saw that there was a real response rate, by RECIST, of 10% with regorafenib. So, taken together, its mechanism of action, which is differentiated from sorafenib and the response rate, I think we can confidently say that this is establishing, potentially, a new standard of care in second-line once the drug receives regulatory approval.

Ghassan K. Abou-Alfa, MD: Fascinating story. If anything, I would say that we’re all doctors, we’re not really early adopters; sometimes we question things. But it was really an interesting paper from Dr. Bruix in The Lancet, and it’s fascinating because one of the questions that was raised, how long patients who have been on sorafenib, could you be like just kind of passing from sorafenib to regorafenib? Believe it or not, actually patients were on sorafenib for at least 7 months before they progressed and moved to regorafenib. The second question was maybe these are highly selected patients with really great outcomes, and maybe there was a long delay between the stop of the sorafenib and start of regorafenib. This was only 28 days. This is a real story. It was not a really appropriately designed analysis, but nonetheless is bringing quite an intriguing point that the sorafenib followed by the regorafenib together will clump something close to 24-month median survival. It’s a quite fascinating story, which obviously we’re trying to understand from the biologic standpoint. What is really the set up over here that led to the improvement in outcome? Is it really just different biology? Is it the prepping in the field? Is the sequence important? These are all questions that we are all looking into and raising.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD:
This brings me to an important point. As you can imagine, Laura, in oncology, it’s all about shrinkage, tumor markers, etc, and sometimes we struggle at explaining survival. From your standpoint, especially if we’re going to try to include that cirrhotic component, how can we reach to the patient and make sure that the message about improvement in survival is there?

Laura M. Kulik, MD: Well, it can be difficult because, as Rich had originally said, we’re dealing with 2 diseases. Explain to the patients that both those diseases are competing with each other to cause them harm and decrease their overall survival, and letting them know that they do not have a curative option is very important so that their expectations are not that this tumor is going to go away. And from there, I think telling patients that this drug is the only drug that is currently available at this point in time that has shown survival is very important. Because a lot of times we’re trying to get patients on drugs and they show up and they’re the ones who don’t want to start it. They hear the side effects. You tell them about manageability. They don’t want to come back in 10 days to be seen again. They’re traveling far. I found, as a hepatologist treating people, that if I set them up with an oncologist closer to home in the community, that that has worked very well. Patients are a lot more amenable to saying, “Okay, well, I’ll go see this guy who lives 5 miles away from me in 2 weeks and follow up.” I don’t feel comfortable saying, “Okay, come back in 3 months after you’ve just started them on a biological agent.” I think that telling them that this is not going to cure them, but the hope that they’re going to have improved not only length of time but hopefully quality of life by decreasing some of their symptoms, such as pain, can drive that point home to patients.

Ghassan K. Abou-Alfa, MD: Sure. So, with sorafenib on board, I think Richard mentioned that there was a lot of, to be fair, genuine and serious attempts to see if we can improve on the surviving beyond the 10.7 months that we just heard from Katie. Interestingly, we were all involved in those very noble efforts and really nothing worked. I have to say this is hot off the press. The Lancet, just literally on January 7, just a few days ago, published the study on regorafenib for a patient with HCC who progressed on sorafenib. It was a randomized double-blind, placebo-controlled phase III trial. So, you were part of that study. Tell us first about the results and let’s discuss it.

Richard S. Finn, MD: Well, I think the RESORCE study is the light at the end of the tunnel for us in liver cancer, given that we’ve had about 10 years without a new drug, without a positive phase III study. And you allude to the fact that maybe this was a dark horse in the race, but in retrospective, maybe it wasn’t. Regorafenib, like sorafenib, is a multi-targeted therapy. It hits several kinases, but differentiates itself a little bit. It’s a very potent pan-VEGF inhibitor, including VEGFR2 as well as the TI-2 receptor, which plays a role in angiogenesis.

Ghassan K. Abou-Alfa, MD: And if I may add here, it was actually designed to do that. In other words, the intent when the regorafenib was designed was to actually improve or catch on more targets than sorafenib.

Richard S. Finn, MD: Correct. I think we need to be humble when we approach drugs like this. We might not know exactly what they’re doing. Regorafenib was approved already and shown to be an anti-cancer drug in colon cancer and also in GI stromal tumors, where it hits the c-KIT receptor. There was a phase II study led by Jordi Bruix out of Barcelona, a very well conducted study defining patients who had progressed on sorafenib, with a clear definition of that—excluding patients who were intolerant. And then there was a very provocative median survival, not looking at response rates per se, although those were reported and they were higher than with sorafenib. But needless to say, the survival is in the 13- or 14-month range. And we know now, from many of the negative phase III studies in second-line, that median survival for this population was about 8 months. If we look at the development of sorafenib, your work in a large phase II study showed a survival of about 9 to 10 months, and that was the signal to move that drug ahead in frontline.

The regorafenib study, I think besides taking a new molecule into second-line, also learned from some of the clinical trial design errors that maybe occurred in some of the other phase III studies. They had a benchmark for what to expect in second-line; that 8 months—which I think surprised a lot of people when we looked at the brivanib, the first drug to read out in the post sorafenib era being around 9 months—no one really expected that. But we’re also dealing with all the other prognostic factors in second-line HCC that are important to stratify for and control for, such as high alpha-fetoprotein. We saw that in the ramucirumab data that that’s an important prognostic factor. And maybe we should be separating macrovascular invasion and extrahepatic spread instead of lumping them together, as we saw in the brivanib and the everolimus experience.

Needless to say, this was a well-conducted, randomized phase III double-blind, placebo-controlled study of regorafenib; 160 mg orally daily on a 3 weeks on, 1 week off regimen versus a placebo on the same regimen. And this was a positive study for overall survival, improving overall survival by about 3 months. We saw an improvement from about 8 months to just under 11 months, a hazard ratio of 0.63, which is a 37% decrease in the risk of death. A lot of this was managed similar to sorafenib, with prolonging stabilized disease. But interesting enough, the response rate was higher with this drug. Clearly, this is a different drug than sorafenib. And what is progression on sorafenib? That is something we’ve wrestled with for a while for a drug, as Katie pointed out, that has no response rate really. When do we say patients are progressing? And in this study, we said RECIST progression, so more than a 20% increase and, at that point, randomizing them to the 2 control arms. We saw that there was a real response rate, by RECIST, of 10% with regorafenib. So, taken together, its mechanism of action, which is differentiated from sorafenib and the response rate, I think we can confidently say that this is establishing, potentially, a new standard of care in second-line once the drug receives regulatory approval.

Ghassan K. Abou-Alfa, MD: Fascinating story. If anything, I would say that we’re all doctors, we’re not really early adopters; sometimes we question things. But it was really an interesting paper from Dr. Bruix in The Lancet, and it’s fascinating because one of the questions that was raised, how long patients who have been on sorafenib, could you be like just kind of passing from sorafenib to regorafenib? Believe it or not, actually patients were on sorafenib for at least 7 months before they progressed and moved to regorafenib. The second question was maybe these are highly selected patients with really great outcomes, and maybe there was a long delay between the stop of the sorafenib and start of regorafenib. This was only 28 days. This is a real story. It was not a really appropriately designed analysis, but nonetheless is bringing quite an intriguing point that the sorafenib followed by the regorafenib together will clump something close to 24-month median survival. It’s a quite fascinating story, which obviously we’re trying to understand from the biologic standpoint. What is really the set up over here that led to the improvement in outcome? Is it really just different biology? Is it the prepping in the field? Is the sequence important? These are all questions that we are all looking into and raising.

Transcript Edited for Clarity
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