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Reviewing Results from COMPARZ and PISCES Clinical Trials

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 05, 2016


Transcript:

Daniel Heng, MD, MPH, FRCPC:
So, we’re left with sunitinib and pazopanib as first-line treatment agents for clinical trials that looked at that. Carlos, what did you think were some of the top-line results, and what you took away from the COMPARZ and the PISCES clinical trials?

Carlos H. Barrios, MD: Well, after the revolution we had in the treatment of renal cell cancer in the decade of the 2000s, we lacked direct evidence of comparisons amongst these different agents that were brought into clinical practice. And, the COMPARZ trial is an important trial just because of that, among other reasons, but, essentially, put face to face, head to head, the comparisons with sunitinib and pazopanib.

It was a large trial with over 1,000 patients that used standard doses of 800 mg of pazopanib and the 50 mg of sunitinib in the schedule of four weeks, two weeks off on the sunitinib and, essentially, showed noninferiority with the two treatment arms with a PFS that was around seven, eight months for both agents and with an overall survival that also was around 28, 29 months for both agents, which obviously it’s one of the important aspects of this trial, that for the first time with these agents in the following decade after they were introduced into clinical practice, we got survivals approaching 30 months, which is obviously something extremely important for us to consider in the management of these patients.

What was clearly different in the analysis of this trial is that the toxicities were different. The usual toxicities with sunitinib were the ones that were seen in this trial with fatigue, diarrhea, hand-foot syndrome, and pazopanib was associated more with laboratory abnormalities as the most frequent toxicity, particularly liver function enzyme elevation. So this trial essentially pointed out to a noninferiority of the two agents in first-line management of these patients, and with a toxicity profile that would tend to favor the pazopanib in that regard.

The PISCES trial that was led by Dr. Escudier was a very interesting trial that used a very particular design. Actually, what they did is they randomized a number of patients to receive a period of about two-and-a-half months, 10 weeks of either sunitinib or pazopanib. After those first 10 weeks, patients were put on hold on the treatment for a period of about two weeks, and then the opposite treatment was given for the same period of time.

So, after completion of that period of time of treatment, patients were given a questionnaire trying to address which of the two treatments that they have all received in sequence they would prefer. And the results were very clearly in favor of the pazopanib arm with approximately 70% of the patients preferring the pazopanib. Obviously, the patients were blinded for the treatments, and about 20, 22% of the patients preferring the sunitinib, and the rest of the patients were actually indifferent for that.

Very interesting also in the analysis of this trial, the same questionnaire was presented to the doctors who were taking care of the patients and they were also blinded to the treatments, and doctors also as well, in about 60% of the cases, preferred the pazopanib treatment in that regard. So pointing out in this small, but very elegant study that toxicity is an important aspect of the treatment of these patients and particularly when we’re dealing with tyrosine kinase inhibitors (TKIs), that even though they targeted specific TKIs, they also target a number of other enzymes that may be associated with a lot of the toxicity we associate with these kind of treatments.

Daniel Heng, MD, MPH, FRCPC: That’s excellent. So, Paul, going to the other side of the ocean, what is your interpretation of this and how do you apply it to your practice?

Paul Nathan, MBBS, PhD, FRCP: I have a very similar interpretation to that which we just heard. I think in the palliative setting, patient quality of life and patient experience really are as key, as efficacy, and we shouldn’t lose sight of that. And I think having a trial design that allowed a patient reported outcome as a primary endpoint was really, in some ways, practice changing. I think it’s much more attractive to have that sort of information influence practice that comes directly from patient preference, rather than a doctor interpreting what a patient is going through.

And I think having patients describing, themselves, what they are experiencing, is much more powerful. Because of the equivalence in efficacy, we were very involved with the COMPARZ study, and from our local experience and our patients’ experience, we moved pretty much to using pazopanib as our main first-line TKI. And that’s been the case since those studies.

There are subgroups of patients whom I tend to prefer treating with sunitinib first, and those are generally in those data gap areas where we have a little bit less robust evidence with pazopanib. So, I more likely use sunitinib in non-clear cell cancers or indeed with brain disease. There is a little bit of data with pazopanib, but not as much with sunitinib. But for most of our patients, we’ll be starting off on pazopanib. I should say, those are the patients outside clinical trials because I still think clinical trials are the standard-of-care option for patients with incurable disease.

Carlos H. Barrios, MD: An important aspect of this is the consistency of the data. Different trials showed information in the same direction, and I know there are some people who actually, even before the clinical data was available, had the perception that the toxicity was lower with the pazopanib, and we’re already utilizing pazopanib in that setting.

Nizar M. Tannir, MD, FACP: So, to follow up on that point that Carlos is mentioning, at MD Anderson, we did embrace pazopanib as first-line therapy for the appropriate patient who’s a candidate for a VEGFR TKI. So we had launched a randomized trial that you’re aware of, Danny, the STAR trial, the sequential to agent assessment in renal cell carcinoma (RCC) therapy, comparing three different classes of agents for VEGFR TKI, which was pazopanib instead of sunitinib, and we compared that with everolimus as a representative of the mTOR inhibitor class, and bevacizumab single agent without the interferon, as Susanne mentioned, because we felt that we needed a randomized trial using bevacizumab without the interferon because we were comfortable with using bevacizumab alone because of its toxicity profile being very manageable.

And, we published on our experience in the real world, so to speak, of pazopanib in the salvage setting post sorafenib, sunitinib. We published that a couple of years ago in European Journal of Cancer where we had safety and also efficacy using pazopanib as salvage. But, we also recently published a retrospective study off 88 patients with clear-cell RCC using pazopanib in the real world as first-line therapy. And the results were almost identical to the COMPARZ data in terms of survival.

The median OS in patients treated with pazopanib in that retrospective real world experience where we used people, where we enrolled patients, we treated patients in the real world who had brain metastasis or laboratory abnormalities that would not have made them eligible to participate in COMPARZ or other trials. And the median OS with pazopanib was 29.1 months, so exactly the median OS with sunitinib and pazopanib. And the response rate was 39% and the median PFS was 13 months. And, we had a very similar adverse-events profile that was compared, published in the trial. So, off protocol, I think there is data from MD Anderson that puts pazopanib as the preferred agent for first-line therapy.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Daniel Heng, MD, MPH, FRCPC:
So, we’re left with sunitinib and pazopanib as first-line treatment agents for clinical trials that looked at that. Carlos, what did you think were some of the top-line results, and what you took away from the COMPARZ and the PISCES clinical trials?

Carlos H. Barrios, MD: Well, after the revolution we had in the treatment of renal cell cancer in the decade of the 2000s, we lacked direct evidence of comparisons amongst these different agents that were brought into clinical practice. And, the COMPARZ trial is an important trial just because of that, among other reasons, but, essentially, put face to face, head to head, the comparisons with sunitinib and pazopanib.

It was a large trial with over 1,000 patients that used standard doses of 800 mg of pazopanib and the 50 mg of sunitinib in the schedule of four weeks, two weeks off on the sunitinib and, essentially, showed noninferiority with the two treatment arms with a PFS that was around seven, eight months for both agents and with an overall survival that also was around 28, 29 months for both agents, which obviously it’s one of the important aspects of this trial, that for the first time with these agents in the following decade after they were introduced into clinical practice, we got survivals approaching 30 months, which is obviously something extremely important for us to consider in the management of these patients.

What was clearly different in the analysis of this trial is that the toxicities were different. The usual toxicities with sunitinib were the ones that were seen in this trial with fatigue, diarrhea, hand-foot syndrome, and pazopanib was associated more with laboratory abnormalities as the most frequent toxicity, particularly liver function enzyme elevation. So this trial essentially pointed out to a noninferiority of the two agents in first-line management of these patients, and with a toxicity profile that would tend to favor the pazopanib in that regard.

The PISCES trial that was led by Dr. Escudier was a very interesting trial that used a very particular design. Actually, what they did is they randomized a number of patients to receive a period of about two-and-a-half months, 10 weeks of either sunitinib or pazopanib. After those first 10 weeks, patients were put on hold on the treatment for a period of about two weeks, and then the opposite treatment was given for the same period of time.

So, after completion of that period of time of treatment, patients were given a questionnaire trying to address which of the two treatments that they have all received in sequence they would prefer. And the results were very clearly in favor of the pazopanib arm with approximately 70% of the patients preferring the pazopanib. Obviously, the patients were blinded for the treatments, and about 20, 22% of the patients preferring the sunitinib, and the rest of the patients were actually indifferent for that.

Very interesting also in the analysis of this trial, the same questionnaire was presented to the doctors who were taking care of the patients and they were also blinded to the treatments, and doctors also as well, in about 60% of the cases, preferred the pazopanib treatment in that regard. So pointing out in this small, but very elegant study that toxicity is an important aspect of the treatment of these patients and particularly when we’re dealing with tyrosine kinase inhibitors (TKIs), that even though they targeted specific TKIs, they also target a number of other enzymes that may be associated with a lot of the toxicity we associate with these kind of treatments.

Daniel Heng, MD, MPH, FRCPC: That’s excellent. So, Paul, going to the other side of the ocean, what is your interpretation of this and how do you apply it to your practice?

Paul Nathan, MBBS, PhD, FRCP: I have a very similar interpretation to that which we just heard. I think in the palliative setting, patient quality of life and patient experience really are as key, as efficacy, and we shouldn’t lose sight of that. And I think having a trial design that allowed a patient reported outcome as a primary endpoint was really, in some ways, practice changing. I think it’s much more attractive to have that sort of information influence practice that comes directly from patient preference, rather than a doctor interpreting what a patient is going through.

And I think having patients describing, themselves, what they are experiencing, is much more powerful. Because of the equivalence in efficacy, we were very involved with the COMPARZ study, and from our local experience and our patients’ experience, we moved pretty much to using pazopanib as our main first-line TKI. And that’s been the case since those studies.

There are subgroups of patients whom I tend to prefer treating with sunitinib first, and those are generally in those data gap areas where we have a little bit less robust evidence with pazopanib. So, I more likely use sunitinib in non-clear cell cancers or indeed with brain disease. There is a little bit of data with pazopanib, but not as much with sunitinib. But for most of our patients, we’ll be starting off on pazopanib. I should say, those are the patients outside clinical trials because I still think clinical trials are the standard-of-care option for patients with incurable disease.

Carlos H. Barrios, MD: An important aspect of this is the consistency of the data. Different trials showed information in the same direction, and I know there are some people who actually, even before the clinical data was available, had the perception that the toxicity was lower with the pazopanib, and we’re already utilizing pazopanib in that setting.

Nizar M. Tannir, MD, FACP: So, to follow up on that point that Carlos is mentioning, at MD Anderson, we did embrace pazopanib as first-line therapy for the appropriate patient who’s a candidate for a VEGFR TKI. So we had launched a randomized trial that you’re aware of, Danny, the STAR trial, the sequential to agent assessment in renal cell carcinoma (RCC) therapy, comparing three different classes of agents for VEGFR TKI, which was pazopanib instead of sunitinib, and we compared that with everolimus as a representative of the mTOR inhibitor class, and bevacizumab single agent without the interferon, as Susanne mentioned, because we felt that we needed a randomized trial using bevacizumab without the interferon because we were comfortable with using bevacizumab alone because of its toxicity profile being very manageable.

And, we published on our experience in the real world, so to speak, of pazopanib in the salvage setting post sorafenib, sunitinib. We published that a couple of years ago in European Journal of Cancer where we had safety and also efficacy using pazopanib as salvage. But, we also recently published a retrospective study off 88 patients with clear-cell RCC using pazopanib in the real world as first-line therapy. And the results were almost identical to the COMPARZ data in terms of survival.

The median OS in patients treated with pazopanib in that retrospective real world experience where we used people, where we enrolled patients, we treated patients in the real world who had brain metastasis or laboratory abnormalities that would not have made them eligible to participate in COMPARZ or other trials. And the median OS with pazopanib was 29.1 months, so exactly the median OS with sunitinib and pazopanib. And the response rate was 39% and the median PFS was 13 months. And, we had a very similar adverse-events profile that was compared, published in the trial. So, off protocol, I think there is data from MD Anderson that puts pazopanib as the preferred agent for first-line therapy.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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