Update on Immunotherapy Advances in Renal and Bladder Cancer - Cora Sternberg

(Length of interview: 17 min)

Cora Sternberg and Alicia Morgans provide a review of immunotherapy advances in both renal cell and bladder cancer.  They review past and current trials providing insights into potential clinical and treatment applications.

Biographies:

Cora Sternberg MD, FACP Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Former Chief of the Department of Medical Oncology at the San Camillo-Forlanini Hospital in Rome, Italy


Read the Full Video Transcript

Dr. Alicia Morgans: Hi and welcome to continued coverage of ESMO 2018 in Munich. I am so delighted to have here with me today, Dr. Cora Sternberg. Lovely to talk to you actually right before you start your new position at Cornell. 

Dr. Cora Sternberg: I'm thrilled to be going back to New York after so many years and my position will be the clinical director of the Israel Englander Institute for Precision Medicine at Cornell. 

Dr. Alicia Morgans: Fantastic. 

Dr. Cora Sternberg: I'll also be working in GU oncology with the group there, so I'm very excited about it. 

Dr. Alicia Morgans: Very good. You will be very busy there just like you are very busy here at ESMO. Already today, and it's only Saturday, you've had multiple presentations at this year's ESMO. And I would love to hear your thoughts on those. You gave a great update on immunotherapy in kidney cancer and in bladder cancer. Will you share with us some of the highlights? 

Dr. Cora Sternberg: Well, there's been so much going on over the last 10 to 15 years, both in kidney cancer and in bladder cancer.  Yesterday, I gave a summary in the educational session, and I was surprised at how many people were there, the room was really quite full, it was nice. 

Kidney cancer: we started out with cytokines back in the nineties with IL2,   from there, we went on for the last decade to have the TKI's VEGF receptor inhibitors, and now we're back to immunotherapy again. And the few trials that I highlighted yesterday, the first one was the trial of nivolumab compared to everolimus, CheckMate 025, comparing after patients have received VEGF inhibitor therapy such as sunitinib or pazopanib, for example. This was a randomized trial of immunotherapy with an anti PD-1 inhibitor versus an MTOR inhibitor, everolimus, that had been standard of care.

What was seen was that patients who got nivolumab had a much longer overall survival, and this has honestly become a standard of care in second-line therapy now. Fewer and fewer people are using everolimus ever since that study, so that's been quite an important study, I would say. Progression-free survival was not that different in that study. I think the main important thing was that the overall survival was different. 

Dr. Alicia Morgans: True. Agreed. 

Dr. Cora Sternberg: The other study that I highlighted, that's been really talked about quite a lot lately, is the study in first-line renal cancer. And it was a study of ipilimumab and nivolumab versus sunitinib in the first line. It was first presented by Bernard Escudier at last year’s ESMO meeting. What was found there, particularly in patients with intermediate and poor risk patients ... an important increase in progression-free survival and an important increase in overall survival, and it seemed that the patients who had PD-L1 positive, as measured by the way that they measured it for that study, were the ones who did much, much better. And the patients who had what we call favorable risk, according to the IDMC category by Heng, those patients actually did better with sunitinib in terms of response rate. Progression-free survival was better with sunitinib. 

So, in the ESMO new guidelines that should be coming out just today, they recommend in first line to give the combination of ipilimumab and nivolumab. Now, the renal doses for that study were nivolumab three and ipilimumab one. What's happened though is if you look at the whole ITT population, there is an advantage for the combination of immunotherapy, as opposed to sunitinib. So, there are some guidelines and some people who are actually giving immunotherapy also in the favorable risk patients. But I would say from this study, it's clear that the intermediate and poor risk patients are the ones who benefit the most. 

Dr. Alicia Morgans: Absolutely. And that was certainly practice changing. 

Dr. Cora Sternberg: Definitely practice changing. The problem is that in Europe thus far, this has not been accepted. They say that we should probably have done a randomized trial in which there was a third arm with nivolumab alone. They don't know what ipilimumab is adding. And I'm not sure what's going to happen with that, and in the United States, this has become the first line of therapy in America for sure. 

Dr. Alicia Morgans: Absolutely, well maybe someone will design that trial. But in the meantime, practice has changed, particularly as you said, for the higher or poor risk patients and intermediate patients. Great update on these advances. And what about bladder cancer?

Dr. Cora Sternberg: I also discussed yesterday the IMmotion 151 trial.

Dr. Alicia Morgans: Yes, can't forget that.

Dr. Cora Sternberg: That trial was atezolizumab and bevacizumab as compared again to sunitinib. There's been quite a number of trials that have been compared to sunitinib, which had ... for years, has been the number one treatment in first line therapy. And the different thing about this was also, it was first line, but they also allowed patients with sarcomatoid features and histology to enter the trial. In this trial, there was a clear advantage for progression-free survival, advantage for those patients who are PD-L1 positive. Again, we don't have overall survival data that's mature enough yet. But it seems that, especially in the PD-L1 data that were presented at the ESMO and SITC, that perhaps that's a very interesting combination as well.

That hasn't made it into the guidelines as yet, but it seems that the combination of a VEGF inhibitor and a PD-1 inhibitor could also be a very interesting first line option. I think we're going to have more and more first line options in renal cancer. We had a press release yesterday about the combination of axitinib and pembrolizumab. I believe it was McDermott last year, presented that data and just phase two data. There were really exciting response rates, overall response rates, in like the 70 percent range in patients who were really doing very, very well. So, we're waiting to hear those phase three data too. That was kidney cancer. 

Dr. Alicia Morgans: So before we move on to bladder, how are you thinking about making decisions with your patients and choosing between all of these agents, particularly in the first line setting? Are there some key tenants to the decisions that you're going make? 

Dr. Cora Sternberg: I think it really depends upon where you live and I think it really depends on what region you live in and it depends on what is accepted. If EMA in Europe doesn't accept the combination of ipi/nivo, you can't give that in first line, whereas that has been given to everyone in the United States now. So, I think a lot of it in Europe with socialized medicine has to do with reimbursement and what's available.  I think that, in studies, it's very important that they stratify patients by region because there are different drugs that are available in different regions. I think things will definitely change and we're going to be moving away from sunitinib in first line now.

Dr. Alicia Morgans: I always appreciate your unique perspective as being someone who's had time in New York as well as time in Italy and now back to New York. You have such a perspective on how geography and policy really affects the decisions that our patients and we make in the day to day practice. 

Dr. Alicia Morgans: What do you feel are the highlights of bladder cancer and immunotherapy that you discussed in your talk? 

Dr. Cora Sternberg: Again, bladder cancer had not changed for the last 30 years really since the MVAC chemotherapy and then the high dose MVAC therapy which is used in gemcitabine/platinum. Chemotherapy is effective in bladder cancer, although we reached a plateau, and in second line, we never had anything that really worked very well. In the United States, there's nothing really approved. Whereas in Europe, vinflunine is approved on data that are not really that convincing and not curing anyone. So having the checkpoint inhibitors in second line for bladder cancer has been extremely exciting. Five of them have been approved by the FDA. They're not all available in Europe, again, because of reimbursement.

And they're not all based on phase three trials either. Some are phase two trials, some are phase l, phase Ib trials. So that was some of the excuses that had been used by countries such as Italy to not reimburse some of these drugs. But they have been all accepted in the United States and they're all being used in the United States. They've all been tested in different ways with PD-L1 testing done in different ways, with different assays, which makes it very complicated to understand the importance of PD-L1 because there's different interpretations on whether they're measuring in just the immune cells or in the tumor cells or in both. 

So, even pathologists among themselves discuss this at length. But we've had one phase three trial that was clearly positive in the second line setting,  the pembrolizumab trial published by Belmont first in the New England Journal of Medicine.  That was pembrolizumab, after patients had one to two lines of cisplatin therapy and they were randomized against what we call investigator's choice, either docetaxel, paclitaxel or vinflunine. There was a clear 27 percent reduction in the risk of death, which held out over time in the second line setting in favor of pembrolizumab. So that is something that has been accepted in America and in Europe that, because it's a phase three trial, it's very interesting. And those data have held out over time. Interestingly enough, in the second line setting, it seems that the PDL-1 status is not predictive because all patients did better with pembrolizumab then with chemotherapy. 

The other phase three study was a study with atezolizumab. And when atezolizumab was actually the first to be developed, it was developed in phase two, Jonathan Rosenberg had presented that a long time ago when it was accepted the United States. At the time, when they first worked on that, they thought that patients had to have immunohistochemical by their assay, which was called VENTANTA assay, positive being two or three positive, looking at the immune cells. They designed their study so their patients, looking at the two, three positive cells, they had to be positive. So, without this kind of a hierarchical design on a phase three very large study, again, against investigators choice in second line, they did not show that atezolizumab was better than chemotherapy. So that drug, in Europe, was not accepted, although it's still used very widely in the United States. 

So, those are the two phase three trials. The rest of the trials, there's avelumab phase two trial which, again, that's used in the United States, but not accepted in most parts of Europe because it's a phase two trial. And other trials are phase two trials, it's the ones with the avelumab and durvalumab. 

Today, Jonathan Rosenberg presented, we call it, CheckMate-032, which is part of a very large thousand patient trial with many different solid tumors....There were three different arms, but it's not a randomized trial. It's kind of a randomized allocation because the first part of the trial was randomized and it was nivolumab compared to nivolumab and ipilimumab. But the dosage there was  nivolumab three and ipilimumab one. Now, there's a third cohort that they added on, not randomized, it was nivolumab one and ipilimumab three. When those data were originally presented, the nivolumab one ipilimumab three, by Hammers and others, it seemed that this would perhaps be a more toxic regimen. 

But he presented the data today on 92 patients, and I think that the data were actually really exciting and encouraging. I can't compare them to the other data because it's not a randomized trial. But he really did show a 38 percent response rate and a 58 percent response rate in those patients who were PD-L1.  There were a lot of patients who also had stable disease. The drugs were slightly more toxic but not very much more toxic than having nivolumab three ipi one. So, I think it's a regimen that is tolerable and can be given. It's efficacious, and I think that it really warrants a phase three study. And there is a phase three study that's ongoing with that combination, comparing it to chemotherapy. 

Dr. Alicia Morgans: So, I absolutely agree, and I look forward to the phase three data because like you said, really, there was no comparator arm. This is a single arm, although it was done sort of in conjunction with these other arms. It's really not something we can do to compare across arms, but hypothesis generating and intriguing and very encouraging to know that it's tolerable. Because I think in the community and in conversations that I have, thinking about ipilimumab and nivolumab, in combination, in patients who have been pre-treated and who may have a poor performance status or comorbidities or other complications from prior therapy that still affect their daily lives, we need to make sure we keep them safe as we treat them effectively. And so that's very, very encouraging.

Dr. Cora Sternberg: Absolutely, I agree with you. 

Dr. Alicia Morgans: So, we look forward to that phase three data. So, what are your closing thoughts and final thoughts for the audience to think about as they consider all of the immunotherapy advances in kidney cancer and bladder cancer that we're learning about and thinking about here at ESMO? 

Dr. Cora Sternberg: Well, I think it's really great to be a GU oncologist, it's a great time. Things have been really exciting and we're all learning a lot about immunotherapy. We need to learn a lot more about immunotherapy. We need to learn more about which patients will respond better to immunotherapy, which patients have more of a signature that's an angiogenic signature and perhaps can be treated with a VEGF inhibitor for kidney cancer, and which ones don't have an angiogenic signature and need to be treated with immunotherapy, and which are the ones that perhaps need to be treated with the combination?

And they looked at that and they did a biomarker study based on IMmotion 150, then this was validated in the 151 study this morning, by Brian Rini, showing that you can separate patients out into different groups and try to understand which are the best patients based on biomarkers to give immunotherapy to.  I think that's really going to be the wave of the future. 

Also, with bladder cancer, I think that we have really come a long way. I mean, I have patients who, in the past, when they had ... after MVAC chemotherapy and they have liver and lung and bladder disease, I've never seen CR's. But now I have long-lasting CR's years after they've stopped therapy. I mean, that's, really exciting, and we need to learn how to manage the drugs and we need to learn how to give these drugs. But I think that the future is looking a lot better. Unfortunately, these drugs are not for everybody. 

If patients have an inflammatory disease or their own high dose corticosteroids, they're not patients that are eligible for immunotherapy. But I think that, in general, those patients who can receive it and who do well, the future is brighter for them. 

Dr. Alicia Morgans: Absolutely. We need to continue to move our advances into phase three, practice changing studies. We need to continue to think about the selection of patients and developing biomarkers that can actually help us choose a therapy that's going to be effective for a given individual. We need to think about options for patients who have these inflammatory diseases, something beyond immunotherapy in some cases, I think. The other thing that you alluded to, that we need to think about as a field, is thinking about the duration of treatment. How long do we actually need to treat these patients before we can give them some time off of therapy and feel confident that they will have complete stabilization of their disease or continue to have their CR? So there are many things that we still need to do. And I appreciate you bringing them all to our attention and I so appreciate, and what an honor to talk with, someone who's given such an update-

Dr. Cora Sternberg: It's an honor to speak with you too. 

Dr. Alicia Morgans: Thank you, Cora.
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