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Combination Therapies in Renal Cell Carcinoma

Panelists:Robert A. Figlin, MD, Cedars-Sinai Medical Center; Sandy Srinivas, MD, Stanford University Medical Center; Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Feb 22, 2016


Transcript:

Robert A. Figlin, MD:
Martin, for a long time over the last decade, we’ve thought about combining therapies. Really, the only therapy that has been combinable is the bevacizumab/interferon data that led to its approval. Have we put to rest kind of the story of combination therapy with targeted agents? I know we’ll circle back and talk about some novel agents that are not yet FDA-approved in this setting. But what are your thoughts about combining targeted VEGF therapies and TOR inhibitors? For the practicing physician, should they really be sequencing single agents, or should they be thinking about combinations in the current environment?

Martin H. Voss, MD: So it’s a very interesting question. Obviously, there’s an enormous amount of work that has gone into the concept of combining the two classes of agents that we know have efficacy in this disease. And it’s something that patients actually ask me all the time. The first time I meet with patients and I talk to them about the different medications we have in our armamentarium and I teach them about VEGF inhibition and I tell them about mTOR inhibitors, very frequently you get the question, why can’t we do the two together? They are two different things that treat the cancer. Wouldn’t it be more successful in combining the two? And obviously that’s been something that’s come up on clinical trials many times in the past.

And their current theme has been that of toxicity, specifically when combining VEGF TKI with other agents. So, there have been phase I trials of combining sunitinib, pazopanib, axitinib with mTOR inhibitors like everolimus and temsirolimus with no significant signal to increase efficacy, but definitely an increased toxicity signal. The exception being combinations with bevacizumab, so Avastin, as a VEGF A inhibitor, seems to pair better with mTOR inhibitors. And there is more data with Avastin combination than we have with TKI combinations that go all the way up to the phase III setting.

So we have randomized phase II trials and we have one phase III trial, the INTORACT trial which compared the combination of temsirolimus and intravenous mTOR inhibitor with bevacizumab and intravenous VEGF-A directed monoclonal antibody compared to bevacizumab in combination with interferon the way it is labeled. And everyone was sort of holding their breath to see the results of it. It was a decent sized trial, and Brian Rini published that in the JCO in 2013. Unfortunately, it did not meet its primary endpoint goal. The combination of an mTOR inhibitor with a VEGF inhibitor did not improve progression-free survival over that of bevacizumab with interferon.

Now, there are other combinations that have been tested unsuccessfully and back to your question, is this now the end of combination therapies? I think the chapter of combining VEGF-directed agent with mTOR-directed agents, those have largely closed, certainly for clear-cell kidney cancer. For non-clear-cell kidney cancer, there may actually be some interest in combining these agents. And, if you think about it, the success of VEGF-directed monotherapy in clear-cell kidney cancer, certainly to a large extent, owes to the fact that these cancers are uniquely similar in that the vast majority of these have lost VHL function, they’re VEGF-dependent. So those patients will do okay with just a VEGF inhibitor in the majority of cases.

For non-clear kidney cancer, we are seeing, like Nizar said, less favorable outcomes and that likely is due to the fact that they don’t all depend on VHL. And with that, combinations might be of more interest there and there is still some active investigation at that avenue. For the vast majority of patients who have clear-cell biology, there are now new combinations that are of interest because we have a new class of agents in the field and that is targeted immunotherapy with CTLA4 and PD-1, PD-L1 inhibitors.

So, over the last few years, the interest in combinations has been rejuvenated. We now have combinations of PD-1/PD-L1 inhibitors with both tyrosine kinase inhibitors, but also with bevacizumab. And those are showing promising results. Certainly, they have made it into the phase III setting. We have an ongoing phase III trial pairing atezolizumab which is a PD-L1-directed monoclonal antibody with bevacizumab in comparison to sunitinib as the standard of care in the first-line setting. And everyone is interested to see what that will show.

Robert A. Figlin, MD: Sandy, we had hoped that kidney cancer that’s resected without metastatic disease, when given some of these agents that we’ve tested in metastatic disease, would lead to an adjuvant therapy which heretofore does not exist for kidney cancer. Somewhat disappointed when Naomi Haas reported the results of the first trial and there’s other trials to be reported. Help our doctors understand the role of adjuvant therapy, what they should do in the high-risk resected patient, what constitutes a high-risk resected patient and how they should be followed, and when those patients should be thought about in terms of entering them on clinical trials.

Sandy Srinivas, MD: So the standard of care is to be watched. Unfortunately, as you mentioned, the large Intergroup trial led by ECOG with more than, I think the largest number to date with almost 1900 patients, which is blinded trial with one year of sunitinib, sorafenib, or placebo, unfortunately was negative for a disease-free survival and overall survival. In my view, it was a huge undertaking but there were dropouts, the side effects. It’s hard to do a blinded trial with drugs that have this level of toxicity, so I think there were dropouts. The toxicity was an issue. I also think that that trial included patients with T1 disease, and we know that that group of patients perhaps will have a high cure just with surgery alone.

Robert A. Figlin, MD: T1b.

Sandy Srinivas, MD: T1b.

Robert A. Figlin, MD: Right.

Sandy Srinivas, MD: So some of the ongoing trials are looking at a higher risk group. So there is a sunitinib trial with stage T3s and T4s versus placebo. There is an ongoing axitinib trial with patients with T3, T4, and node-positive disease. So, I think there is still hope that many of these adjuvant trials may turn out to be positive. There are also trials with everolimus. We certainly hope that there will be a role for adjuvant therapy in the future, but for now I think it is still standard of care for them to be watched. The high-risk patients include again those who are T3, T4, node-positive patients.

I tend to do scans on them every six months. Kidney cancer I think is one of those diseases where they can have recurrence much later. So the five year is not a golden rule in kidney cancer. People can relapse after a long time. There is a planned immunotherapy trial which is going to be led by ECOG, and hopefully that will have a better way to administer the drug with less side effects compared to some of the TKIs.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Martin, for a long time over the last decade, we’ve thought about combining therapies. Really, the only therapy that has been combinable is the bevacizumab/interferon data that led to its approval. Have we put to rest kind of the story of combination therapy with targeted agents? I know we’ll circle back and talk about some novel agents that are not yet FDA-approved in this setting. But what are your thoughts about combining targeted VEGF therapies and TOR inhibitors? For the practicing physician, should they really be sequencing single agents, or should they be thinking about combinations in the current environment?

Martin H. Voss, MD: So it’s a very interesting question. Obviously, there’s an enormous amount of work that has gone into the concept of combining the two classes of agents that we know have efficacy in this disease. And it’s something that patients actually ask me all the time. The first time I meet with patients and I talk to them about the different medications we have in our armamentarium and I teach them about VEGF inhibition and I tell them about mTOR inhibitors, very frequently you get the question, why can’t we do the two together? They are two different things that treat the cancer. Wouldn’t it be more successful in combining the two? And obviously that’s been something that’s come up on clinical trials many times in the past.

And their current theme has been that of toxicity, specifically when combining VEGF TKI with other agents. So, there have been phase I trials of combining sunitinib, pazopanib, axitinib with mTOR inhibitors like everolimus and temsirolimus with no significant signal to increase efficacy, but definitely an increased toxicity signal. The exception being combinations with bevacizumab, so Avastin, as a VEGF A inhibitor, seems to pair better with mTOR inhibitors. And there is more data with Avastin combination than we have with TKI combinations that go all the way up to the phase III setting.

So we have randomized phase II trials and we have one phase III trial, the INTORACT trial which compared the combination of temsirolimus and intravenous mTOR inhibitor with bevacizumab and intravenous VEGF-A directed monoclonal antibody compared to bevacizumab in combination with interferon the way it is labeled. And everyone was sort of holding their breath to see the results of it. It was a decent sized trial, and Brian Rini published that in the JCO in 2013. Unfortunately, it did not meet its primary endpoint goal. The combination of an mTOR inhibitor with a VEGF inhibitor did not improve progression-free survival over that of bevacizumab with interferon.

Now, there are other combinations that have been tested unsuccessfully and back to your question, is this now the end of combination therapies? I think the chapter of combining VEGF-directed agent with mTOR-directed agents, those have largely closed, certainly for clear-cell kidney cancer. For non-clear-cell kidney cancer, there may actually be some interest in combining these agents. And, if you think about it, the success of VEGF-directed monotherapy in clear-cell kidney cancer, certainly to a large extent, owes to the fact that these cancers are uniquely similar in that the vast majority of these have lost VHL function, they’re VEGF-dependent. So those patients will do okay with just a VEGF inhibitor in the majority of cases.

For non-clear kidney cancer, we are seeing, like Nizar said, less favorable outcomes and that likely is due to the fact that they don’t all depend on VHL. And with that, combinations might be of more interest there and there is still some active investigation at that avenue. For the vast majority of patients who have clear-cell biology, there are now new combinations that are of interest because we have a new class of agents in the field and that is targeted immunotherapy with CTLA4 and PD-1, PD-L1 inhibitors.

So, over the last few years, the interest in combinations has been rejuvenated. We now have combinations of PD-1/PD-L1 inhibitors with both tyrosine kinase inhibitors, but also with bevacizumab. And those are showing promising results. Certainly, they have made it into the phase III setting. We have an ongoing phase III trial pairing atezolizumab which is a PD-L1-directed monoclonal antibody with bevacizumab in comparison to sunitinib as the standard of care in the first-line setting. And everyone is interested to see what that will show.

Robert A. Figlin, MD: Sandy, we had hoped that kidney cancer that’s resected without metastatic disease, when given some of these agents that we’ve tested in metastatic disease, would lead to an adjuvant therapy which heretofore does not exist for kidney cancer. Somewhat disappointed when Naomi Haas reported the results of the first trial and there’s other trials to be reported. Help our doctors understand the role of adjuvant therapy, what they should do in the high-risk resected patient, what constitutes a high-risk resected patient and how they should be followed, and when those patients should be thought about in terms of entering them on clinical trials.

Sandy Srinivas, MD: So the standard of care is to be watched. Unfortunately, as you mentioned, the large Intergroup trial led by ECOG with more than, I think the largest number to date with almost 1900 patients, which is blinded trial with one year of sunitinib, sorafenib, or placebo, unfortunately was negative for a disease-free survival and overall survival. In my view, it was a huge undertaking but there were dropouts, the side effects. It’s hard to do a blinded trial with drugs that have this level of toxicity, so I think there were dropouts. The toxicity was an issue. I also think that that trial included patients with T1 disease, and we know that that group of patients perhaps will have a high cure just with surgery alone.

Robert A. Figlin, MD: T1b.

Sandy Srinivas, MD: T1b.

Robert A. Figlin, MD: Right.

Sandy Srinivas, MD: So some of the ongoing trials are looking at a higher risk group. So there is a sunitinib trial with stage T3s and T4s versus placebo. There is an ongoing axitinib trial with patients with T3, T4, and node-positive disease. So, I think there is still hope that many of these adjuvant trials may turn out to be positive. There are also trials with everolimus. We certainly hope that there will be a role for adjuvant therapy in the future, but for now I think it is still standard of care for them to be watched. The high-risk patients include again those who are T3, T4, node-positive patients.

I tend to do scans on them every six months. Kidney cancer I think is one of those diseases where they can have recurrence much later. So the five year is not a golden rule in kidney cancer. People can relapse after a long time. There is a planned immunotherapy trial which is going to be led by ECOG, and hopefully that will have a better way to administer the drug with less side effects compared to some of the TKIs.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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