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Choosing Among TKIs in Advanced RCC

Panelists:Robert A. Figlin, MD, FACP, Cedars-Sinai Medical Center;Daniel J. George, MD, Duke University Medical Center;Thomas Hutson, DO, PharmD, Baylor Charles A. Sammons Cancer Center;David F. McDermott, MD, Dana Farber Harvard Cancer Center;Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center;Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center
Published: Monday, Jul 18, 2016


Transcript:

Robert A. Figlin, MD:
Tom, it’s important for us because the oncology world talks about predicting outcomes with biomarkers. We have trials in the frontline setting that were comparative trials; the COMPARZ trial, for example. So, when you have two TKIs that have been shown to be commercially available—with comparable levels of activity, possibly a different toxicity profile—how do you think about that when you approach the patient, and what does that discussion sound like?

Thomas Hutson, DO, PharmD: Yes, that’s a very good and meaningful question. I think you know to just take a step back as we’re unlaying this, asking what our goals of therapy for the patient are. I want to give my patient and their family a sense of what the natural history of the disease is going to be like, in that we do have now 9 therapies at our disposal to utilize—and patients often have come in, because of media, thinking they’re going to get X, Y, Z therapy first—and understanding that our goal, as Dan and others have suggested, is that we want to maximize the benefit on the current therapy. They will get these other therapies, in due time, sequentially along the way. And so what we try to bring to bear is evidence-based medicine.

We’ve got standard options that we consider to be really global standards of care in the frontline setting, with most patients receiving one of two VEGF TKIs—sunitinib, pazopanib—and up until 2 or 3 years ago, we didn’t have any trial that compared the two. But we’re fortunate now that we have a trial, the COMPARZ trial, which was designed not as a true head-to-head comparison, but a noninferiority study. We have now a trial with almost 1200 patients in it, which gives us some idea of the nuances between the agents, and from that trial, we know that both agents seem to be similar in efficacy and outcome. Slight nuances there.

Toxicity is shades of gray, difference between the two. And really enough that when I’ve interacted with community oncologists, they haven’t been swayed one way or the other based on toxicity for it. So, what we’ve been really trying to instill upon the community oncologist is that they get familiar with the drug, one of them. You know there are two here that are equally efficacious or similar in efficacy. Know how to use that well in your patients. If that is sunitinib, know that. Know that you can do dose modifications and how they work, how to manage toxicity, and know about the 2/1 alternative dosing schedule with that. If it’s Votrient, know about that drug and the need to monitoring liver function tests. And I think, at the end of the day, as long as the patients has had either one of those therapies and they’ve been delivered well by the treating doctor, managed well with toxicity control, then I think we’ve done justice to our patients for that.

Your other question was, as a field, are we at a point where we can start picking and choosing between one drug or another, based upon biomarkers, or take another step into patient or tumor characteristics? And the answer is, no. But we have certainly identified a phenotype of patient that we think does well with VEGF inhibitors. We haven’t really been able to connect the dots between that and a biomarker test. And I’m encouraged by what we’re seeing at meetings like ASCO about, for instance, mTOR inhibitors, about finding different mutations in PTEN (phosphatase and tensin homolog) and others that predict that that group of drugs may work better in a patient population.

The interesting thing that we’ve had with VEGF inhibitors, to be honest with you, is they work in 80% of our people. So, we know that the development of hypertension while on therapy predicts response to therapy, and that they’re going to do better when they have that or other side effects. But most of them will have that because it works in most patients. What we really want is to be able to get that blood test, that simple blood test to be able to look at the tumor specimen and be able to predict that way, and we’re just not quite there yet.

Robert A. Figlin, MD: Nizar, Tom brought up changing dose and schedule. A couple of years ago, we didn’t have that option, where we’re using sunitinib; it was the four-entry schedule because that’s what we had; that was what the package insert said. We now have some retrospective studies that have suggested that you can maintain dose area under the curve with a different schedule. How do you incorporate that into your practice when choosing drugs?

Nizar M. Tannir, MD: Yes, I think it is an important area because I think the goal is to keep the patient on therapy as long as possible and not stop therapy and change to a different agent because of toxicity—if they are benefiting from the therapy in terms of efficacy. At MD Anderson and other investigators, other institutions also looked at it, and just talking to the patient when they were taking the sunitinib for 4 weeks in a row, their adverse events peaked towards the third, fourth week. So, it was intuitive to say, “Well, what about switching to 2 weeks on, 1 week off?”, and then still in a 6-week block, they’re going to get the same number of doses, but can we do that to get the adverse events?

And when we started going to the 2/1 schedule—and we published this a couple of years ago—in about 180 patients, we saw that patients who received sunitinib with a 2/1 schedule stayed on therapy longer. And there was a suggestion that those patients had a better outcome in terms of survival. So, obviously this is retrospective data and all the data published with this—except for one randomized phase II trial from Korea, I believe. There is the possibility of the patient selection bias. But one trial was a randomized phase II trial looking at 4/2 versus 2/1 schedule and showed that for adverse events, the 2/1 schedule was better. Better tolerated, less toxicity, but the efficacy endpoints or outcome were similar.

I agree with Tom, I think it’s more about what you’re comfortable with. If you’re a community oncologist and you see fewer patients with kidney cancer per year—and you’ve already been used to treating them with one agent, and you’re comfortable with that agent—I think that’s fine, just continue. But now we have an alternative. If you are comfortable with sunitinib because it came out many years prior, then I think the 2/1 schedule does make sense.

I have to say, though, we have now at MD Anderson—actually it’s a multicenter trial with Betsy, your group is participating in that trial, and Cleveland Clinic and other sites—where we’re doing a single-arm study on the 2/1 schedule. And when we go to a prospective study, unfortunately, I’m still seeing a lot of hand/foot and a lot of fatigue, a lot of myelosuppression, even on the 2/1 schedule. So, I am of the position that—and I think there is data to support that from PISCES and COMPARZ—in general, pazopanib is better tolerated of the two agents, even, I would say, when you go to 2/1 schedule.

The 2/1 schedule is better tolerated than the 4/2 schedule, but I believe when you look at pazopanib versus sunitinib, overall, even if you use a 2/1 schedule, pazopanib, in my opinion, is the better-tolerated agent, except for the liver toxicity where you have to be careful. I think the feet are shifting so fast that sunitinib/pazopanib are probably, in the next 2 years, not going to be the first-line therapy, which I’m sure you’re going to lead us to the next segment of what will be the future. I believe the future is going to be with possibly combining an immunotherapy agent, such as a PD-1 or PD-L1, plus a better-tolerated VEGF-directed therapy, such as axitinib or bevacizumab. Obviously no data yet for the practicing oncologist, but I think this is where the future is going.

Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Tom, it’s important for us because the oncology world talks about predicting outcomes with biomarkers. We have trials in the frontline setting that were comparative trials; the COMPARZ trial, for example. So, when you have two TKIs that have been shown to be commercially available—with comparable levels of activity, possibly a different toxicity profile—how do you think about that when you approach the patient, and what does that discussion sound like?

Thomas Hutson, DO, PharmD: Yes, that’s a very good and meaningful question. I think you know to just take a step back as we’re unlaying this, asking what our goals of therapy for the patient are. I want to give my patient and their family a sense of what the natural history of the disease is going to be like, in that we do have now 9 therapies at our disposal to utilize—and patients often have come in, because of media, thinking they’re going to get X, Y, Z therapy first—and understanding that our goal, as Dan and others have suggested, is that we want to maximize the benefit on the current therapy. They will get these other therapies, in due time, sequentially along the way. And so what we try to bring to bear is evidence-based medicine.

We’ve got standard options that we consider to be really global standards of care in the frontline setting, with most patients receiving one of two VEGF TKIs—sunitinib, pazopanib—and up until 2 or 3 years ago, we didn’t have any trial that compared the two. But we’re fortunate now that we have a trial, the COMPARZ trial, which was designed not as a true head-to-head comparison, but a noninferiority study. We have now a trial with almost 1200 patients in it, which gives us some idea of the nuances between the agents, and from that trial, we know that both agents seem to be similar in efficacy and outcome. Slight nuances there.

Toxicity is shades of gray, difference between the two. And really enough that when I’ve interacted with community oncologists, they haven’t been swayed one way or the other based on toxicity for it. So, what we’ve been really trying to instill upon the community oncologist is that they get familiar with the drug, one of them. You know there are two here that are equally efficacious or similar in efficacy. Know how to use that well in your patients. If that is sunitinib, know that. Know that you can do dose modifications and how they work, how to manage toxicity, and know about the 2/1 alternative dosing schedule with that. If it’s Votrient, know about that drug and the need to monitoring liver function tests. And I think, at the end of the day, as long as the patients has had either one of those therapies and they’ve been delivered well by the treating doctor, managed well with toxicity control, then I think we’ve done justice to our patients for that.

Your other question was, as a field, are we at a point where we can start picking and choosing between one drug or another, based upon biomarkers, or take another step into patient or tumor characteristics? And the answer is, no. But we have certainly identified a phenotype of patient that we think does well with VEGF inhibitors. We haven’t really been able to connect the dots between that and a biomarker test. And I’m encouraged by what we’re seeing at meetings like ASCO about, for instance, mTOR inhibitors, about finding different mutations in PTEN (phosphatase and tensin homolog) and others that predict that that group of drugs may work better in a patient population.

The interesting thing that we’ve had with VEGF inhibitors, to be honest with you, is they work in 80% of our people. So, we know that the development of hypertension while on therapy predicts response to therapy, and that they’re going to do better when they have that or other side effects. But most of them will have that because it works in most patients. What we really want is to be able to get that blood test, that simple blood test to be able to look at the tumor specimen and be able to predict that way, and we’re just not quite there yet.

Robert A. Figlin, MD: Nizar, Tom brought up changing dose and schedule. A couple of years ago, we didn’t have that option, where we’re using sunitinib; it was the four-entry schedule because that’s what we had; that was what the package insert said. We now have some retrospective studies that have suggested that you can maintain dose area under the curve with a different schedule. How do you incorporate that into your practice when choosing drugs?

Nizar M. Tannir, MD: Yes, I think it is an important area because I think the goal is to keep the patient on therapy as long as possible and not stop therapy and change to a different agent because of toxicity—if they are benefiting from the therapy in terms of efficacy. At MD Anderson and other investigators, other institutions also looked at it, and just talking to the patient when they were taking the sunitinib for 4 weeks in a row, their adverse events peaked towards the third, fourth week. So, it was intuitive to say, “Well, what about switching to 2 weeks on, 1 week off?”, and then still in a 6-week block, they’re going to get the same number of doses, but can we do that to get the adverse events?

And when we started going to the 2/1 schedule—and we published this a couple of years ago—in about 180 patients, we saw that patients who received sunitinib with a 2/1 schedule stayed on therapy longer. And there was a suggestion that those patients had a better outcome in terms of survival. So, obviously this is retrospective data and all the data published with this—except for one randomized phase II trial from Korea, I believe. There is the possibility of the patient selection bias. But one trial was a randomized phase II trial looking at 4/2 versus 2/1 schedule and showed that for adverse events, the 2/1 schedule was better. Better tolerated, less toxicity, but the efficacy endpoints or outcome were similar.

I agree with Tom, I think it’s more about what you’re comfortable with. If you’re a community oncologist and you see fewer patients with kidney cancer per year—and you’ve already been used to treating them with one agent, and you’re comfortable with that agent—I think that’s fine, just continue. But now we have an alternative. If you are comfortable with sunitinib because it came out many years prior, then I think the 2/1 schedule does make sense.

I have to say, though, we have now at MD Anderson—actually it’s a multicenter trial with Betsy, your group is participating in that trial, and Cleveland Clinic and other sites—where we’re doing a single-arm study on the 2/1 schedule. And when we go to a prospective study, unfortunately, I’m still seeing a lot of hand/foot and a lot of fatigue, a lot of myelosuppression, even on the 2/1 schedule. So, I am of the position that—and I think there is data to support that from PISCES and COMPARZ—in general, pazopanib is better tolerated of the two agents, even, I would say, when you go to 2/1 schedule.

The 2/1 schedule is better tolerated than the 4/2 schedule, but I believe when you look at pazopanib versus sunitinib, overall, even if you use a 2/1 schedule, pazopanib, in my opinion, is the better-tolerated agent, except for the liver toxicity where you have to be careful. I think the feet are shifting so fast that sunitinib/pazopanib are probably, in the next 2 years, not going to be the first-line therapy, which I’m sure you’re going to lead us to the next segment of what will be the future. I believe the future is going to be with possibly combining an immunotherapy agent, such as a PD-1 or PD-L1, plus a better-tolerated VEGF-directed therapy, such as axitinib or bevacizumab. Obviously no data yet for the practicing oncologist, but I think this is where the future is going.

Transcript Edited for Clarity
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