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Dosing Sunitinib and Pazopanib in Renal Cell Carcinoma

Panelists:Carlos H. Barrios, MD, PUCRS School of Medicine; Daniel HEng, MD, MPH, FRCPC, Tom Baker Cancer Center; Paul Nathan, MBBS, PhD, FRCP, Mount Vernon Cancer Centre; Susanne Osanto, MD, PhD, Leiden University Medical Center; Nizar M. Tannir, MD, FACP, University of Texas MD Anderson Center
Published: Friday, Feb 12, 2016


Transcript:

Daniel Heng, MD, MPH, FRCPC:
Let’s go back to the sunitinib versus pazopanib. Since the COMPARZ and PISCES data came out, there are data about dose individualization of sunitinib. So giving sunitinib in a different way, not necessarily the 50 mg four weeks on, and two weeks off. So, for example, Dr. Bjarnason and his group looked at not dose reducing right away, but actually waiting for some sort of less than grade 2 toxicity.

So, having some sort of toxicity could potentially be an indicator for a proper dose, a proper dose being an indicator for having enough drug in your system causing enough efficacy and better PFS, overall survival, and response rate. And, so he’s done schedules of 50 mg, two weeks on, one week off, and they show really good response rates and progression-free survivals in a single arm setting. I know MD Anderson has done a study of schedule changes. Nizar, did you want to talk about that?

Nizar M. Tannir, MD, FACP: Yes, I was going to mention this at the previous exchange. Most people, now, who still use sunitinib at first-line therapy for patients with clear cell renal cell carcinoma (RCC), use the ultimate scheduling of two weeks on, one week off, instead of the standard four weeks on, two weeks off. And, this is the result of several retrospective studies including the one by Dr. Bjarnason.

We published our series of 180 patients or so, a couple of years ago, and came to the realization that the toxicity is less when we use the two weeks on, one week off, and efficacy is maintained or, in fact, was improved over the four weeks, two weeks. If you use the two weeks on, one week off, you do not have to interrupt, as often, and you do not have to reduce the dose of sunitinib from 50, down to 37.5, or 25. So patients can continue on therapy. I think there are now prospective data.

There was a recently published paper, from Korea, looking at the two schedules in a small randomized phase II trial where the two weeks on, one week off were certainly associated with fewer adverse events, compared to the four weeks on, two weeks off. And the efficacy was numerically better for the two weeks on, one week off schedule, although it was not statistically significant, again because of the small number of patients.

We are conducting a multi-institutional, single-arm study with sunitinib on the alternative schedule, the two weeks on, one week off with Cleveland, Fox Chase, UNC, and Stanford, where we are evaluating a 60-patient, phase II trial with the alternative schedule. So I think, yes, it is attractive. Now, there is a new way of prescribing sunitinib, which is the two weeks on, one week off schedule, although not with any comparison with pazopanib, I still feel that pazopanib is more tolerable even if you use a two weeks on, one week off schedule of sunitinib. That’s my experience.

Susanne Osanto, MD, PhD: But the 37.5 was also tested against the 50 mgs, four weeks on, two weeks off, presented by Bob Motzer, and although it may be better tolerated, the outcome is inferior. It’s not a huge difference. So we don’t use the 37.5 continuously. I think it’s been difficult to use other drug regimens that have not been tested in the formal large pivotal phase III trial.

Nizar M. Tannir, MD, FACP: And, there would be no phase III trial to look at a new schedule of sunitinib. But, as I said, the only prospective randomized trial is the Korean study looking at the two schedules, and that showed improved toxicity, or safety, or tolerability for the 2/1 schedule, and the efficacy was clearly numerically better, although statistically not. I agree with you.

Paul Nathan, MBBS, PhD, FRCP: The TKI pharmacodynamics is different in different ethnic subgroups.

Nizar M. Tannir, MD, FACP: Sure.

Daniel Heng, MD, MPH, FRCPC: But, what I do for sunitinib, though, is to start with 50 mg, four weeks on, two weeks off, and then, quickly reduce to 50 mg, two weeks on, one week off. So, technically, it’s not really a reduction before going to 37.5 mg to try to optimize the efficacy.

Carlos H. Barrios, MD: The challenge in this dose issue, that is extremely important, if you look back from the conceptual point of view, is that, in my opinion, we have not developed these agents looking at the ideal dose for most patients. We know if we look at TKIs, in general, not only in kidney cancer, but in all diseases where we are using them, dose has not been addressed in clinical trials as appropriately as we should.

The challenge of your colleague presenting this data is not necessarily the adjustment for toxicity bringing down the dose or changing the schedule, the challenge is increasing the dose in some patients to 62, and to 70 mg, or 75 mg. And, some patients actually do tolerate that kind of dose. There is some evidence, and that’s the challenge that I think we should try to address in future trials, that the dose needs to be adjusted to the pharmacogenetics or pharmacogenomics of the single patient.

We have not been developing drugs by paying attention to the metabolic aspects of the patients. We have, in the same arena, some evidence that in some situations, toxicity development that may probably relate to dose, may have a relation to efficacy. So, I think that with the speed of putting a drug in the market, sometimes we lack behind in generation information that is important in how to select the patient, according to how they to tolerate, metabolize some drugs.

Nizar M. Tannir, MD, FACP: I agree.

Daniel Heng, MD, MPH, FRCPC: Let’s move on.

Nizar M. Tannir, MD, FACP: Axitinib is where I was going to say is the drug that has been studied in a more scientific way, exactly what you’re talking about, based on pharmacokinetics, pharmacodynamics, targeting adverse events as a potential biomarker of response. Brian Rini led this way here and published the data in Lancet Oncology, last year, with the AGILE trial.

Daniel Heng, MD, MPH, FRCPC: Yeah. That’s very good discussion, so I think the dosing needs to be adjusted in a lot of our targeted therapies.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Daniel Heng, MD, MPH, FRCPC:
Let’s go back to the sunitinib versus pazopanib. Since the COMPARZ and PISCES data came out, there are data about dose individualization of sunitinib. So giving sunitinib in a different way, not necessarily the 50 mg four weeks on, and two weeks off. So, for example, Dr. Bjarnason and his group looked at not dose reducing right away, but actually waiting for some sort of less than grade 2 toxicity.

So, having some sort of toxicity could potentially be an indicator for a proper dose, a proper dose being an indicator for having enough drug in your system causing enough efficacy and better PFS, overall survival, and response rate. And, so he’s done schedules of 50 mg, two weeks on, one week off, and they show really good response rates and progression-free survivals in a single arm setting. I know MD Anderson has done a study of schedule changes. Nizar, did you want to talk about that?

Nizar M. Tannir, MD, FACP: Yes, I was going to mention this at the previous exchange. Most people, now, who still use sunitinib at first-line therapy for patients with clear cell renal cell carcinoma (RCC), use the ultimate scheduling of two weeks on, one week off, instead of the standard four weeks on, two weeks off. And, this is the result of several retrospective studies including the one by Dr. Bjarnason.

We published our series of 180 patients or so, a couple of years ago, and came to the realization that the toxicity is less when we use the two weeks on, one week off, and efficacy is maintained or, in fact, was improved over the four weeks, two weeks. If you use the two weeks on, one week off, you do not have to interrupt, as often, and you do not have to reduce the dose of sunitinib from 50, down to 37.5, or 25. So patients can continue on therapy. I think there are now prospective data.

There was a recently published paper, from Korea, looking at the two schedules in a small randomized phase II trial where the two weeks on, one week off were certainly associated with fewer adverse events, compared to the four weeks on, two weeks off. And the efficacy was numerically better for the two weeks on, one week off schedule, although it was not statistically significant, again because of the small number of patients.

We are conducting a multi-institutional, single-arm study with sunitinib on the alternative schedule, the two weeks on, one week off with Cleveland, Fox Chase, UNC, and Stanford, where we are evaluating a 60-patient, phase II trial with the alternative schedule. So I think, yes, it is attractive. Now, there is a new way of prescribing sunitinib, which is the two weeks on, one week off schedule, although not with any comparison with pazopanib, I still feel that pazopanib is more tolerable even if you use a two weeks on, one week off schedule of sunitinib. That’s my experience.

Susanne Osanto, MD, PhD: But the 37.5 was also tested against the 50 mgs, four weeks on, two weeks off, presented by Bob Motzer, and although it may be better tolerated, the outcome is inferior. It’s not a huge difference. So we don’t use the 37.5 continuously. I think it’s been difficult to use other drug regimens that have not been tested in the formal large pivotal phase III trial.

Nizar M. Tannir, MD, FACP: And, there would be no phase III trial to look at a new schedule of sunitinib. But, as I said, the only prospective randomized trial is the Korean study looking at the two schedules, and that showed improved toxicity, or safety, or tolerability for the 2/1 schedule, and the efficacy was clearly numerically better, although statistically not. I agree with you.

Paul Nathan, MBBS, PhD, FRCP: The TKI pharmacodynamics is different in different ethnic subgroups.

Nizar M. Tannir, MD, FACP: Sure.

Daniel Heng, MD, MPH, FRCPC: But, what I do for sunitinib, though, is to start with 50 mg, four weeks on, two weeks off, and then, quickly reduce to 50 mg, two weeks on, one week off. So, technically, it’s not really a reduction before going to 37.5 mg to try to optimize the efficacy.

Carlos H. Barrios, MD: The challenge in this dose issue, that is extremely important, if you look back from the conceptual point of view, is that, in my opinion, we have not developed these agents looking at the ideal dose for most patients. We know if we look at TKIs, in general, not only in kidney cancer, but in all diseases where we are using them, dose has not been addressed in clinical trials as appropriately as we should.

The challenge of your colleague presenting this data is not necessarily the adjustment for toxicity bringing down the dose or changing the schedule, the challenge is increasing the dose in some patients to 62, and to 70 mg, or 75 mg. And, some patients actually do tolerate that kind of dose. There is some evidence, and that’s the challenge that I think we should try to address in future trials, that the dose needs to be adjusted to the pharmacogenetics or pharmacogenomics of the single patient.

We have not been developing drugs by paying attention to the metabolic aspects of the patients. We have, in the same arena, some evidence that in some situations, toxicity development that may probably relate to dose, may have a relation to efficacy. So, I think that with the speed of putting a drug in the market, sometimes we lack behind in generation information that is important in how to select the patient, according to how they to tolerate, metabolize some drugs.

Nizar M. Tannir, MD, FACP: I agree.

Daniel Heng, MD, MPH, FRCPC: Let’s move on.

Nizar M. Tannir, MD, FACP: Axitinib is where I was going to say is the drug that has been studied in a more scientific way, exactly what you’re talking about, based on pharmacokinetics, pharmacodynamics, targeting adverse events as a potential biomarker of response. Brian Rini led this way here and published the data in Lancet Oncology, last year, with the AGILE trial.

Daniel Heng, MD, MPH, FRCPC: Yeah. That’s very good discussion, so I think the dosing needs to be adjusted in a lot of our targeted therapies.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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