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Future Directions in Renal Cell Carcinoma Management

Panelists: Sumanta Kumar Pal, MD, City of Hope; Neeraj Agarwal, MD, MS, Huntsman Cancer Institute; Bradley McGregor, MD, Dana-Farber Cancer Institute; Tian Zhang, MD, Duke Cancer Institute
Published: Monday, Apr 29, 2019



Transcript:

Sumanta Kumar Pal, MD:
Tian, I can sense you were itching to talk about some of the novel regimens that we have out there. One of those, of course, is the glutaminase inhibitors. We’ve heard a lot about that at recent meetings. So can you tell us first what a CANTATA is? No, I’m joking.

Tian Zhang, MD: The song we can start singing, that’s right. But we saw a phase I trial reported at GU ASCO [Genitourinary Cancers Symposium in 2019] of the glutaminase inhibitors really thinking about metabolomics and how that plays in the picture of cancer biology. And so we saw great disease control. So I think all except 1 patient had stable disease or better in that trial. And so we’re really thinking about, can we add this in to an immunotherapy regimen? Can that enhance the immunotherapy effect through a different mechanism, a novel mechanism? And so these ongoing trials are accruing patients in the later-line settings, and hopefully we’ll see ongoing responses from these patients.

Sumanta Kumar Pal, MD: It’s interesting. I like that signal. And on that same note, we’re seeing some compelling signals emerge from some of the NKTR studies that are coming about now. Neeraj, can you fill us in on those?

Neeraj Agarwal, MD: First of all, just taking a step back, the CANTATA trial is randomizing patients to cabozantinib versus cabozantinib with this glutaminase inhibitor. I think the earlier data were higher efficacy but really no increase in toxicity, which is a really exciting part of this combination. Now, coming to NKTR drug, interleukin-2 was my favorite for almost 10 years before ipilimumab-nivolumab arrived on the scene. And the only reason I used interleukin-2 for this long was the complete response rate, 10%. But then again, we were dealing with toxicities, and that remains the major issue as to why most of the patients are not eligible to receive high-dose interleukin-2, which is not the case with ipilimumab-nivolumab. Most of the patients can receive ipilimumab-nivolumab.

So how can we get all the benefits of high-dose interleukin-2 to the clinic and remove the toxicities? And I think that is going to be accomplished hopefully by this NKTR drug, which is pegylated interleukin-2. So it can be administered in the clinic on an outpatient basis, knowing the inpatient stay requirement. Other than slight hypotension, which is easily treated with intravenous saline on an outpatient basis in some patients, that remains the biggest attraction of this combination. Interleukin-2, which doesn’t require ICU admissions, is not associated with the toxicity but hopefully will have similar efficacy.

Sumanta Kumar Pal, MD: Interesting. Well, this has been a fantastic discussion, guys. I think we really have gone over the whole spectrum of what’s going on in renal cell carcinoma, ranging from some of the data that we had in years past to some of the studies that will emerge in the future. And I’d like to wrap up with a couple of closing thoughts from each of you. Maybe we’ll start with you, Tian.

Tian Zhang, MD: Well, I think it’s a really exciting time for our patients with kidney cancer and especially the patients with metastatic clear-cell kidney cancer. We’re really thinking about goals of treatment up front, complete responses, and if we can achieve a cure. We’re also thinking about layering sequences of treatment. And I’m really excited about our PEDIGREE trial, and hopefully we’ll improve outcomes even more on that trial.

Sumanta Kumar Pal, MD: PEDIGREE, PEDIGREE, PEDIGREE. Good point and well done. Good product placement there. Brad, what about you?

Bradley McGregor, MD: I think it’s a very exciting time, and we’re achieving more complete responses and we’re helping our patients. But there are still patients who aren’t responding to therapies we have. We have immunotherapy, and we have VEGF inhibition, but that’s not enough. There are patients who are refractory to that. So I think, as we look forward to the future, we really need to look at novel targets such as HIF-2 inhibition. Looking for these novel pathways for those patients who aren’t responding to what we have now to try to help all our patients is going to be really critical to advance the field.

Sumanta Kumar Pal, MD: Makes sense to me. Neeraj?

Neeraj Agarwal, MD: So it is great to see so many drug combinations appearing on the scene for our patients. There are more options than ever, but I think none of these are going to cure most of the patients. We’re still seeing a minority of patients getting complete responses. Given that, I think the first summary of my discussion is that all these regimens are probably good for a select group of patients.

No one regimen is best for all. So I believe in the ipilimumab-nivolumab combination, but there is a room for sequencing of monotherapies and there are some patients who are going to need combinations. But given that most of these regimens are not going to cure most of the patients, referral for clinical trials and clinical trial accrual remains the most important aspect of my job, I think. And based on that, I will pick up 2 trials, the PEDIGREE trial and CANTATA trial. I think those are the 2 first-line and second-line trials I can think of that are most exciting right now.

Sumanta Kumar Pal, MD: Great way to summarize: CANTATA and PEDIGREE. I like that. Well, thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us, and we hope you found this OncLive Peer Exchange® to be useful and informative.


Transcript Edited for Clarity

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Transcript:

Sumanta Kumar Pal, MD:
Tian, I can sense you were itching to talk about some of the novel regimens that we have out there. One of those, of course, is the glutaminase inhibitors. We’ve heard a lot about that at recent meetings. So can you tell us first what a CANTATA is? No, I’m joking.

Tian Zhang, MD: The song we can start singing, that’s right. But we saw a phase I trial reported at GU ASCO [Genitourinary Cancers Symposium in 2019] of the glutaminase inhibitors really thinking about metabolomics and how that plays in the picture of cancer biology. And so we saw great disease control. So I think all except 1 patient had stable disease or better in that trial. And so we’re really thinking about, can we add this in to an immunotherapy regimen? Can that enhance the immunotherapy effect through a different mechanism, a novel mechanism? And so these ongoing trials are accruing patients in the later-line settings, and hopefully we’ll see ongoing responses from these patients.

Sumanta Kumar Pal, MD: It’s interesting. I like that signal. And on that same note, we’re seeing some compelling signals emerge from some of the NKTR studies that are coming about now. Neeraj, can you fill us in on those?

Neeraj Agarwal, MD: First of all, just taking a step back, the CANTATA trial is randomizing patients to cabozantinib versus cabozantinib with this glutaminase inhibitor. I think the earlier data were higher efficacy but really no increase in toxicity, which is a really exciting part of this combination. Now, coming to NKTR drug, interleukin-2 was my favorite for almost 10 years before ipilimumab-nivolumab arrived on the scene. And the only reason I used interleukin-2 for this long was the complete response rate, 10%. But then again, we were dealing with toxicities, and that remains the major issue as to why most of the patients are not eligible to receive high-dose interleukin-2, which is not the case with ipilimumab-nivolumab. Most of the patients can receive ipilimumab-nivolumab.

So how can we get all the benefits of high-dose interleukin-2 to the clinic and remove the toxicities? And I think that is going to be accomplished hopefully by this NKTR drug, which is pegylated interleukin-2. So it can be administered in the clinic on an outpatient basis, knowing the inpatient stay requirement. Other than slight hypotension, which is easily treated with intravenous saline on an outpatient basis in some patients, that remains the biggest attraction of this combination. Interleukin-2, which doesn’t require ICU admissions, is not associated with the toxicity but hopefully will have similar efficacy.

Sumanta Kumar Pal, MD: Interesting. Well, this has been a fantastic discussion, guys. I think we really have gone over the whole spectrum of what’s going on in renal cell carcinoma, ranging from some of the data that we had in years past to some of the studies that will emerge in the future. And I’d like to wrap up with a couple of closing thoughts from each of you. Maybe we’ll start with you, Tian.

Tian Zhang, MD: Well, I think it’s a really exciting time for our patients with kidney cancer and especially the patients with metastatic clear-cell kidney cancer. We’re really thinking about goals of treatment up front, complete responses, and if we can achieve a cure. We’re also thinking about layering sequences of treatment. And I’m really excited about our PEDIGREE trial, and hopefully we’ll improve outcomes even more on that trial.

Sumanta Kumar Pal, MD: PEDIGREE, PEDIGREE, PEDIGREE. Good point and well done. Good product placement there. Brad, what about you?

Bradley McGregor, MD: I think it’s a very exciting time, and we’re achieving more complete responses and we’re helping our patients. But there are still patients who aren’t responding to therapies we have. We have immunotherapy, and we have VEGF inhibition, but that’s not enough. There are patients who are refractory to that. So I think, as we look forward to the future, we really need to look at novel targets such as HIF-2 inhibition. Looking for these novel pathways for those patients who aren’t responding to what we have now to try to help all our patients is going to be really critical to advance the field.

Sumanta Kumar Pal, MD: Makes sense to me. Neeraj?

Neeraj Agarwal, MD: So it is great to see so many drug combinations appearing on the scene for our patients. There are more options than ever, but I think none of these are going to cure most of the patients. We’re still seeing a minority of patients getting complete responses. Given that, I think the first summary of my discussion is that all these regimens are probably good for a select group of patients.

No one regimen is best for all. So I believe in the ipilimumab-nivolumab combination, but there is a room for sequencing of monotherapies and there are some patients who are going to need combinations. But given that most of these regimens are not going to cure most of the patients, referral for clinical trials and clinical trial accrual remains the most important aspect of my job, I think. And based on that, I will pick up 2 trials, the PEDIGREE trial and CANTATA trial. I think those are the 2 first-line and second-line trials I can think of that are most exciting right now.

Sumanta Kumar Pal, MD: Great way to summarize: CANTATA and PEDIGREE. I like that. Well, thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us, and we hope you found this OncLive Peer Exchange® to be useful and informative.


Transcript Edited for Clarity
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