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VEGF TKI Therapy in the Adjuvant Setting of RCC

Panelists: Robert A. Figlin, MD, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center; Eric Jonasch, MD, University of Texas MD Anderson Cancer Center; Toni K. Choueiri, MD, Dana-Farber Cancer Institute; Michael R. Harrison, MD, Duke Cancer Institute; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published Online: Wednesday, Apr 26, 2017



Transcript:

Robert A. Figlin, MD:
Michael, one of the remarkable pieces of information that has come out in the last 3 to 6 months is that while we’ve spent the last decade studying many molecules in the advanced disease setting, we continue to recognize that there’s this group of patients called “high-risk resected.” Many of us see those patients where they’ve undergone their surgical procedure. They don’t have measurable metastatic disease on imaging. But we know that based upon work that I did at UCLA with Arie Belldegrun and others, there’s a real risk of this disease coming back and threatening their life. And then, we had the first introduction of the adjuvant world in what’s called the ASSURE trial, with Naomi Haas telling us that when one looked at placebo versus sorafenib versus sunitinib, there really wasn’t any benefit to the use of adjuvant therapy in that population of patients. And most recently, Alain Ravaud had an article in JCO that looked at sunitinib, not exactly the same, but in a group of patients with high-risk resected disease. Are we ready in prime time, in the adjuvant setting, to use a TKI?

Michael R. Harrison, MD: That’s a good question. So, these data are quite confusing. I think it’s potentially good news for our patients because, like you said, we know that there are certain groups that are very high risk, and we haven’t really been able to do anything, based on any data, to reduce their risk. In terms of looking at several trials and thinking about why there were differences, I think it’s really important to go a little bit into the weeds. Thinking about the S-TRAC study, which was the positive trial of adjuvant sunitinib versus placebo, that was a trial that looked at about 600 patients with high-risk disease, and it’s important how that was defined. That was defined as, at least, a T3 tumor-positive and/or node-positive disease. Those patients were treated with sunitinib, again at the standard 50-mg daily dose on the 4/2 schedule. Importantly, patients were started at that dose and not reduced. That study did show a 24% reduction in their risk of disease progression, as defined by radiographic evidence of disease or death. Side effects were comparable with what is the known side effect profile of sunitinib.

I think to really understand why this trial might have been positive versus ASSURE, let’s say, you really have to think about some of those differences. ASSURE enrolled lower-risk patients, so they did allow some patients who were not T3- or node-positive. They did allow patients who had non–clear cell RCC. They also had an amendment whereby they decreased the starting dose of both drugs. Again, this was an adjuvant trial of sorafenib, sunitinib, or placebo. They were not starting and maintaining that dose intensity. When you take those factors into account, it could explain, in part, why S-TRAC was positive while ASSURE was negative. Another thing, though, that has raised controversy is in S-TRAC, the benefit was seen in terms of independent radiographic review in terms of the primary endpoint. It was really not seen, barely though, by investigator-assessed review. So, that’s also a little bit confusing.

We’ve also heard by press release that the PROTECT study, which was a study of pazopanib or placebo, again, in high-risk patients still defined a little bit differently, was also negative. That study also reduced the starting dose after a time period.

In summary, I would argue that sunitinib is ready for prime time. Again, as we were talking about some of the other drugs, sunitinib is not a drug that has just come on to the scene. This is a drug we’ve been using for 10+ years. We know the side effect profile. We know how to use it. I think it’s very critical, though, that we identify those high-risk patients as they were identified in the trial—those T3- and/or N-positive patients—and that we start at the dose of 50 mg daily on that 4/2 schedule. So, in other words, if you’re extrapolating to a little bit lower risk—you’re including non–clear cell—you’re reducing the dose, you’re probably not going to get that benefit. I also think you have to think about the patients’ goals of care. There are some patients who may not be appropriate to put through 1 year of sunitinib based on their goals of care. I think it has to be a motivated patient that understands the risks, that’s going to work with you, in tandem or in the group, to manage the side effect profile to maintain that dose intensity.

Robert A. Figlin, MD: Toni, you want to weigh in?

Toni K. Choueiri, MD: I have to be provocative here for Michael. What Michael said, his interpretation is, overall, correct. But in an adjuvant setting in genitourinary malignancies in general, I would like to see survival benefit. There was absolutely no survival benefit after 5.4 years’ median follow-up on S-TRAC or at least a trend toward that. Because, now, what we started the conversation with, Bob, is active surveillance. So, all those patients that recurred because there was a median disease-free survival, disease-free survival on S-TRAC was prolonged by 1 year, delayed by 1 year. When these recurrences are done on modern day scans in the lung, few spots like this, where folks could have waited a bit to start the treatment or where these recurrences in terms of brain metastases, liver metastases, and bone metastases need something immediate, there was absolutely no overall survival benefit. Going back to Dr. Haas’s study, which was really an almost 2000-patient study, it’s true that it did enroll non–clear cell, it did enroll lower-risk patients up to T1b. But this study also had a significant amount of patients who were really high-risk, N-positive, T4, T3, grade 3, grade 4, Fuhrman grade 3, 4. And when you look at the subgroup analysis, there is no signal in terms of disease-free survival or overall survival, not even a hazard ratio lower than 0.9, for example.

Now we know, in the public domain, that the pazopanib study didn’t meet its primary endpoint. So, I’m not sure that we accept the adjuvant paradigm now. And having said so, there are a lot of ongoing studies where we’re still considering disease-free survival, perhaps to have a powering issue in terms of sample size. But I think it’s important, in those patients that are cured after nephrectomy, to see if we can cure them more with an adjuvant therapy rather than delaying a treatment that may not kill them.

Transcript Edited for Clarity

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Transcript:

Robert A. Figlin, MD:
Michael, one of the remarkable pieces of information that has come out in the last 3 to 6 months is that while we’ve spent the last decade studying many molecules in the advanced disease setting, we continue to recognize that there’s this group of patients called “high-risk resected.” Many of us see those patients where they’ve undergone their surgical procedure. They don’t have measurable metastatic disease on imaging. But we know that based upon work that I did at UCLA with Arie Belldegrun and others, there’s a real risk of this disease coming back and threatening their life. And then, we had the first introduction of the adjuvant world in what’s called the ASSURE trial, with Naomi Haas telling us that when one looked at placebo versus sorafenib versus sunitinib, there really wasn’t any benefit to the use of adjuvant therapy in that population of patients. And most recently, Alain Ravaud had an article in JCO that looked at sunitinib, not exactly the same, but in a group of patients with high-risk resected disease. Are we ready in prime time, in the adjuvant setting, to use a TKI?

Michael R. Harrison, MD: That’s a good question. So, these data are quite confusing. I think it’s potentially good news for our patients because, like you said, we know that there are certain groups that are very high risk, and we haven’t really been able to do anything, based on any data, to reduce their risk. In terms of looking at several trials and thinking about why there were differences, I think it’s really important to go a little bit into the weeds. Thinking about the S-TRAC study, which was the positive trial of adjuvant sunitinib versus placebo, that was a trial that looked at about 600 patients with high-risk disease, and it’s important how that was defined. That was defined as, at least, a T3 tumor-positive and/or node-positive disease. Those patients were treated with sunitinib, again at the standard 50-mg daily dose on the 4/2 schedule. Importantly, patients were started at that dose and not reduced. That study did show a 24% reduction in their risk of disease progression, as defined by radiographic evidence of disease or death. Side effects were comparable with what is the known side effect profile of sunitinib.

I think to really understand why this trial might have been positive versus ASSURE, let’s say, you really have to think about some of those differences. ASSURE enrolled lower-risk patients, so they did allow some patients who were not T3- or node-positive. They did allow patients who had non–clear cell RCC. They also had an amendment whereby they decreased the starting dose of both drugs. Again, this was an adjuvant trial of sorafenib, sunitinib, or placebo. They were not starting and maintaining that dose intensity. When you take those factors into account, it could explain, in part, why S-TRAC was positive while ASSURE was negative. Another thing, though, that has raised controversy is in S-TRAC, the benefit was seen in terms of independent radiographic review in terms of the primary endpoint. It was really not seen, barely though, by investigator-assessed review. So, that’s also a little bit confusing.

We’ve also heard by press release that the PROTECT study, which was a study of pazopanib or placebo, again, in high-risk patients still defined a little bit differently, was also negative. That study also reduced the starting dose after a time period.

In summary, I would argue that sunitinib is ready for prime time. Again, as we were talking about some of the other drugs, sunitinib is not a drug that has just come on to the scene. This is a drug we’ve been using for 10+ years. We know the side effect profile. We know how to use it. I think it’s very critical, though, that we identify those high-risk patients as they were identified in the trial—those T3- and/or N-positive patients—and that we start at the dose of 50 mg daily on that 4/2 schedule. So, in other words, if you’re extrapolating to a little bit lower risk—you’re including non–clear cell—you’re reducing the dose, you’re probably not going to get that benefit. I also think you have to think about the patients’ goals of care. There are some patients who may not be appropriate to put through 1 year of sunitinib based on their goals of care. I think it has to be a motivated patient that understands the risks, that’s going to work with you, in tandem or in the group, to manage the side effect profile to maintain that dose intensity.

Robert A. Figlin, MD: Toni, you want to weigh in?

Toni K. Choueiri, MD: I have to be provocative here for Michael. What Michael said, his interpretation is, overall, correct. But in an adjuvant setting in genitourinary malignancies in general, I would like to see survival benefit. There was absolutely no survival benefit after 5.4 years’ median follow-up on S-TRAC or at least a trend toward that. Because, now, what we started the conversation with, Bob, is active surveillance. So, all those patients that recurred because there was a median disease-free survival, disease-free survival on S-TRAC was prolonged by 1 year, delayed by 1 year. When these recurrences are done on modern day scans in the lung, few spots like this, where folks could have waited a bit to start the treatment or where these recurrences in terms of brain metastases, liver metastases, and bone metastases need something immediate, there was absolutely no overall survival benefit. Going back to Dr. Haas’s study, which was really an almost 2000-patient study, it’s true that it did enroll non–clear cell, it did enroll lower-risk patients up to T1b. But this study also had a significant amount of patients who were really high-risk, N-positive, T4, T3, grade 3, grade 4, Fuhrman grade 3, 4. And when you look at the subgroup analysis, there is no signal in terms of disease-free survival or overall survival, not even a hazard ratio lower than 0.9, for example.

Now we know, in the public domain, that the pazopanib study didn’t meet its primary endpoint. So, I’m not sure that we accept the adjuvant paradigm now. And having said so, there are a lot of ongoing studies where we’re still considering disease-free survival, perhaps to have a powering issue in terms of sample size. But I think it’s important, in those patients that are cured after nephrectomy, to see if we can cure them more with an adjuvant therapy rather than delaying a treatment that may not kill them.

Transcript Edited for Clarity
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