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Treating Non-Clear Cell Histologies of RCC

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: Tuesday, Feb 16, 2016


Transcript:

Robert A. Figlin, MD:
So, Nizar, to build this out, we finally have data on the non-clear-cell histologies. We have data that you’ve reported. We have the ASPEN trial that just was reported at ASCO last year. So turn our attention to choosing frontline therapy in the non-clear-cell histologies—papillary, chromophobe, translocation tumors, undifferentiated— kind of a basket of lots of different diseases. But what did these trials help us decide about how to approach those patients?

Nizar M. Tannir, MD, FACP: I believe this diverse group of non-clear-cell histologies, as you alluded to, is the most challenging to treat, and I think some of the challenges are based on our understanding or insights into the biology. We know far more about the biology of clear-cell and you led the field many years ago studying clear-cell, and so the role of VHL there. So I think biology is still, I think, the key to really understanding our discoveries to find more effective therapies.

Now, there have been some retrospective studies looking at the role of the approved agents, the sunitinib and the everolimus and others in non-clear-cell histologies, suggesting that these agents are active. The approval actually of the VEGFR TKIs of sorafenib, sunitinib, and others, actually in the US, at least, did not limit to clear-cell histology, although the studies were done mostly in clear-cell histology except for the temsirolimus Global ARCC Trial where 20% of the patients recruited on that trial have non-clear-cell histology.

So, based on the retrospective data suggesting there is some activity with a VEGFR TKI, based on the temsirolimus data in the Global ARCC Trial in poor-risk patients, I think it was really natural to lead to a prospective trial comparing sunitinib, which Sandy mentioned has been on the market now 10 years, with an mTOR class representative, everolimus.

So that led to the conception of the two randomized trials, randomized phase II trials, the ESPN that we led at MD Anderson with the Harvard Consortium and the ASPEN trial which was led by the Duke. And both these trials showed similar findings, but there were some differences. What we hypothesized was everolimus for non-clear-cell based on the temsirolimus Global ARCC Trial would be perhaps more effective than sunitinib.

We were disappointed with the activity of sunitinib in non-clear-cell based on our own data in a single arm phase II trial, which we published in European Urology in 2012, where the response rate was 5% with sunitinib in non-clear-cell. And this was a 60-patient trial, and the median PFS was disappointingly very short of three months. So we built that hypothesis that maybe the mTOR inhibitors would be better, but we were actually surprised and disappointed that everolimus actually was not superior, in fact numerically led to a shorter PFS of four months versus six months with sunitinib in non-clear-cell.

Now, what the ASPEN trial showed, they included some poor-risk patients. They showed that for poor-risk patients, everolimus actually was better than sunitinib. In the ESPN trial, most of the patients were good-risk and intermediate-risk. So these two trials, what they have informed us was that the two agents have modest activity. The patients with non-clear-cell RCCs should still be considered for enrollment on clinical trials. And that’s my take on the non-clear-cell field. We still need better agents, better therapies. The currently approved target therapies are not that effective.

I’ll say there is a caveat here about chromophobe tumors. Chromophobe, as we all know, is a more indolent tumor than papillary type 2, for example, and that tumor can respond, in our experience. In the first trial we did, the single arm phase II trial with sunitinib as well as ESPN, patients with chromophobe did respond actually to sunitinib in our experience. But they do also respond to everolimus because frequently these chromophobe tumors have mutations in the TSC1-TSC2 complex as well as the mTOR gene pathways complex.

So patients with chromophobe histology do respond to either agent, but, again, overall, the effectiveness of the currently approved agents is not high as we see in clear-cell. And so there is dire need, in my opinion, to look at these tumors now separately instead of a basket with all of the histologies grouped in a basket. But understand the biology of each papillary chromophobe, the translocation. And I think, now, there are efforts that have started, collaborative efforts across academic institutions. And finally we’re getting industry also engaged to try to conduct trials in specific tumors such as papillary, for example, or translocation, or medullary carcinoma.

And, so I think it behooves us, and I think this is my message to the oncologists in the community, when they see a patient with non-clear-cell histology, please refer them to institutions where there are trials for these tumors because these are rare tumors. Unless we collaborate and have trials and we all refer patients to those trials, we’re not going to have really a headway and make an impact to improve the lives of these patients.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
So, Nizar, to build this out, we finally have data on the non-clear-cell histologies. We have data that you’ve reported. We have the ASPEN trial that just was reported at ASCO last year. So turn our attention to choosing frontline therapy in the non-clear-cell histologies—papillary, chromophobe, translocation tumors, undifferentiated— kind of a basket of lots of different diseases. But what did these trials help us decide about how to approach those patients?

Nizar M. Tannir, MD, FACP: I believe this diverse group of non-clear-cell histologies, as you alluded to, is the most challenging to treat, and I think some of the challenges are based on our understanding or insights into the biology. We know far more about the biology of clear-cell and you led the field many years ago studying clear-cell, and so the role of VHL there. So I think biology is still, I think, the key to really understanding our discoveries to find more effective therapies.

Now, there have been some retrospective studies looking at the role of the approved agents, the sunitinib and the everolimus and others in non-clear-cell histologies, suggesting that these agents are active. The approval actually of the VEGFR TKIs of sorafenib, sunitinib, and others, actually in the US, at least, did not limit to clear-cell histology, although the studies were done mostly in clear-cell histology except for the temsirolimus Global ARCC Trial where 20% of the patients recruited on that trial have non-clear-cell histology.

So, based on the retrospective data suggesting there is some activity with a VEGFR TKI, based on the temsirolimus data in the Global ARCC Trial in poor-risk patients, I think it was really natural to lead to a prospective trial comparing sunitinib, which Sandy mentioned has been on the market now 10 years, with an mTOR class representative, everolimus.

So that led to the conception of the two randomized trials, randomized phase II trials, the ESPN that we led at MD Anderson with the Harvard Consortium and the ASPEN trial which was led by the Duke. And both these trials showed similar findings, but there were some differences. What we hypothesized was everolimus for non-clear-cell based on the temsirolimus Global ARCC Trial would be perhaps more effective than sunitinib.

We were disappointed with the activity of sunitinib in non-clear-cell based on our own data in a single arm phase II trial, which we published in European Urology in 2012, where the response rate was 5% with sunitinib in non-clear-cell. And this was a 60-patient trial, and the median PFS was disappointingly very short of three months. So we built that hypothesis that maybe the mTOR inhibitors would be better, but we were actually surprised and disappointed that everolimus actually was not superior, in fact numerically led to a shorter PFS of four months versus six months with sunitinib in non-clear-cell.

Now, what the ASPEN trial showed, they included some poor-risk patients. They showed that for poor-risk patients, everolimus actually was better than sunitinib. In the ESPN trial, most of the patients were good-risk and intermediate-risk. So these two trials, what they have informed us was that the two agents have modest activity. The patients with non-clear-cell RCCs should still be considered for enrollment on clinical trials. And that’s my take on the non-clear-cell field. We still need better agents, better therapies. The currently approved target therapies are not that effective.

I’ll say there is a caveat here about chromophobe tumors. Chromophobe, as we all know, is a more indolent tumor than papillary type 2, for example, and that tumor can respond, in our experience. In the first trial we did, the single arm phase II trial with sunitinib as well as ESPN, patients with chromophobe did respond actually to sunitinib in our experience. But they do also respond to everolimus because frequently these chromophobe tumors have mutations in the TSC1-TSC2 complex as well as the mTOR gene pathways complex.

So patients with chromophobe histology do respond to either agent, but, again, overall, the effectiveness of the currently approved agents is not high as we see in clear-cell. And so there is dire need, in my opinion, to look at these tumors now separately instead of a basket with all of the histologies grouped in a basket. But understand the biology of each papillary chromophobe, the translocation. And I think, now, there are efforts that have started, collaborative efforts across academic institutions. And finally we’re getting industry also engaged to try to conduct trials in specific tumors such as papillary, for example, or translocation, or medullary carcinoma.

And, so I think it behooves us, and I think this is my message to the oncologists in the community, when they see a patient with non-clear-cell histology, please refer them to institutions where there are trials for these tumors because these are rare tumors. Unless we collaborate and have trials and we all refer patients to those trials, we’re not going to have really a headway and make an impact to improve the lives of these patients.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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