In this podcast, Dr. Brian Rini discusses some of the research on kidney cancer presented at ASCO’s 2015 Annual Meeting.
ASCO: You're listening to a podcast from Cancer.Net.
In today's podcast we'll discuss some of the research on kidney cancer presented at ASCO's 2015 Annual Meeting. This podcast will be led by Dr. Brian Rini, who is a professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and a staff member of the Department of Solid Tumor Oncology at Cleveland Clinic Taussig Cancer Institute. Dr. Rini is also an Associate Editor for Cancer.Net.
The ASCO Annual Meeting is the premier educational and scientific event where physicians, researchers, and other healthcare professionals gather to discuss the latest in cancer care and treatment. This Cancer.Net podcast helps put new research findings into context and explains what they mean for patients. ASCO would like to thank Dr. Rini for summarizing this research.
Dr. Rini: This is Brian Rini from the Cleveland Clinic Taussig Cancer Center, providing an update on the kidney cancer abstracts that were discussed at ASCO 2015, and I think probably there's three broad categories of abstracts. The first would be an update on what are called checkpoint inhibitors, a newer form of immune-boosting therapy. The second was a trial that was conducted in patients with non-clear cell kidney cancer, which is a more rare subtype of kidney cancer. And third is some combination data of inhibition of angiogenesis and inhibition of what's called M-T-O-R or mTOR that has been around for a while, but with some new combination data. And we'll go over each of those in turn.
The first is checkpoint inhibiting therapy. Checkpoint inhibitors refer to a newly-developed class of molecules that remove the breaks on the immune system. So all of our bodies naturally have an immune response against foreign proteins, be they viruses or bacteria or cancer cells. Part of the theory of immune-based therapy in cancer is that our bodies are trying to fight the cancer with an immune response, but the power of that immune response is limited by various factors. These factors are called checkpoint molecules. Again they're the natural breaks in our immune system, and now there are a series of drugs which can remove those breaks and enhance a patient's anti-tumor immunity as we would call it. These have been developed in a wide variety of cancers and are currently being developed very rapidly in kidney cancer. There was an update of some data presented at ASCO 2014. One was of a trial that randomized patients with previously treated kidney cancer to one of three doses of a drug called nivolumab, which is one of these checkpoint inhibitors. And what this trial showed was that many patients had tumors get smaller. The response rate, which means tumors shrinking by 30% or more, was 20% in this study. And although the average duration of disease control was only about 4 months, the survival in this study was over 2 years, which is very good for a trial in the refractory setting, remembering that's an average.
One of the important things about immune therapy is that not only can a fraction of patients benefit, but some will do so quite dramatically for the long-term. So unlike some of our other therapies, which probably have a more broad effect on patients, immune therapy generally is characterized by a more dramatic effect in the patients who have a benefit. And I think we're starting to see that with some of these results in kidney cancer. The data presented at ASCO regarding nivolumab from this particular study, which was presented by Dr. Betsy Plimack from Fox Chase, showed this. So again, we would call it a tail of the curve, when you're looking at a patient's survival over time, of course we want that tail as big as possible. We want as many patients as possible surviving long-term, the goal of everything we do, especially this kind of therapy. So this was an update of that particular trial, and I think continued to show benefit, and also importantly showed tolerability. So this drug given by itself is really very well-tolerated. There can be some immune-related side effects, but in general the drug is very well-tolerated.
There was another abstract presented involving this nivolumab drug. This was presented by Dr. Hans Hammers from Johns Hopkins, and this was an interesting study, again first presented last year, which combined the nivolumab drug I just talked about with another immune checkpoint drug called ipilimumab. Ipilimumab is a drug that's approved in metastatic melanoma. It inhibits a different checkpoint molecule than nivolumab, and based on some very exciting data in melanoma of the combination, this combination has been tested in kidney cancer. So it's basically double immune therapy as a treatment approach. And this combination in various doses was given to a large cohort of kidney cancer patients, most of whom had received prior treatment. What was seen was response rates in the 40-50% range, so these are response rates that are equal to or perhaps greater than our current targeted therapy. Also that tail of the curve phenomenon where we see some patients do well for a while.
I think what was interesting about these data also is that unlike the nivolumab drug when it's given by itself, when you start giving drugs in combinations, you will always get more side effects. I tell patients two drugs are always more toxic than one. And so this trial showed the same thing, that unlike nivolumab by itself, which was very well tolerated, there were a number of toxicities with this approach. The drugs are trying to stimulate an immune response, an inflammatory response against the tumor, but they can also do so against normal cells. So the drugs can create inflammation against normal organs such as skin, bowel, causing diarrhea, or the liver, causing liver function abnormalities, et cetera. And that was seen in part in this study.
And I think what it tells us is sort of that there's a balance between risk and benefit, and of course we know this as physicians and as patients. We want to strike that right balance where we're trying to be aggressive and treat the cancer aggressively, but not over-treat the cancer to the point of causing the patient too many side effects. And I think one of the things that will play out over the next couple years is this balance of which patients need 1 drug, which patients need 2, and how do we balance that risk and benefit in an individual patient. This was an update on some very exciting data, and clearly this combination is going forward. There is a large phase III trial for previously untreated kidney cancer that has launched on the basis of the trial that I just spoke about, and we will see whether that combination can produce benefit.
There was another abstract presented by Dr. Choueiri regarding Nivolumab. This one was a biomarker study basically that took blood and tissue from patients both before treatment and on treatment to look at what predicted response. When we develop cancer drugs, we're always trying to figure out who's going to respond to our drugs and who isn't. Can we spare the people that won't respond the therapy that's not going to be effective, and can we identify patients for whom it may be effective? And the results of this particular study aren't terribly important for this audience. They didn't show a definitive way to recognize patients who will benefit, but I think they mostly speak to the kind of trial that's being done in cancer now where we're really making an effort to get more biopsies from patients to try and understand our drugs better. I think gone are the days of just giving drugs to patients and hoping for the best. And this is really to be encouraged, this kind of trial, although more labor intense and risky on the part of the patient, will pay dividends in terms of how to select patients best. So checkpoint inhibitors are clearly being developed in kidney cancer. This year we just saw an update of previous year's data, but in the next 2 to 3 years we're going to see an explosion of clinical data in kidney cancer, hopefully leading to FDA approval of one or more of the drugs.
The next major topic at this year's ASCO was non-clear cell kidney cancer. So the vast majority of kidney cancer is what's called clear cell, because the cells look clear under a microscope and it constitutes probably 80% to even 90% of patients with advanced disease. Everything else is termed non-clear cell, although that bucket of non-clear cell includes many other diseases such as papillary kidney cancer, chromophobe kidney cancer, et cetera. Treatment options for those patients are very unsatisfactory. We don't understand the biology of their disease as well. We treat them as we treat clear cell, although we recognize that our drugs aren't that effective, and so clinical trials are to be encouraged in that patient population.
The data presented at ASCO, by Dr. Andy Armstrong from Duke, was the results of what was called the Aspen Trial. This was a trial of over 100 patients who were randomized to either receive sunitinib or everolimus. Sunitinib is a VEGF receptor inhibitor and anti-blood vessel drug, and everolimus is an mTOR inhibitor. Both are approved for kidney cancer, although have not really been adequately studied in non-clear cell kidney cancer. So this was an attempt to say which of these 2 drug categories works best for this more rare patient subtype. A very ambitious trial, because again, with the rarity of these patients, it's very difficult to do clinical trials. So the investigators are to be congratulated.
This trial showed that for most patients the choice of sunitinib was a better drug, whether in terms of response rate or what we call progression-free survival, that I usually explain to patients as duration of disease control. How long can we keep disease stable? What we saw is that duration of stability was over eight months for sunitinib and was about five and a half months for everolimus. So again unfortunately, what we see here is that our current drugs are less effective in the non-clear cell population and still frankly quite unsatisfactory. But at least these data give us some direction as to how we should treat patients outside of a clinical trial, which is still highly encouraged for these patients. How do we treat patients with this more rare subtype of kidney cancer? And these data provide really the—among the first prospective evidence of which drug may be more beneficial. Certainly, more work needs to be done in terms of finding better treatments for patients with non-clear cell kidney cancer.
The last abstract that I want to discuss by Dr. Motzer was a randomized trial of three different arms. So patients with previously treated kidney cancer were randomized, either to the everolimus drug, which we've talked about, which is a standard of care mTOR inhibitor in refractory kidney cancer, to a drug called lenvatinib, which is similar to the sunitinibs and pazopanibs of the world in that it's a VEGF receptor inhibitor, or patients were randomized to the combination of both those drugs. This was a relatively small study considering its randomized design but had some interesting results. I'll remind you that mTOR inhibitors and VEGF receptor inhibitors were developed in kidney cancer over 10 years ago, and as oncologists we like to combine drugs to improve outcomes, so the combination of these drugs has been tested, not with these specific drugs, but with other similar drugs over the last many years.
To summarize many trials, what was found is that very often the combination of these drugs was not tolerated, and when it was tolerated, it didn't appear to be any more effective than giving one of the drugs by itself. So it was very disappointing and frustrating to us as drug developers that we couldn't take two effective drugs and put them together for benefit. Then these data came along. So again, 3 arms—one drug, the other drug, or the combination. What was seen, quite surprisingly, is that if you look at that metric of progression-free survival, average duration of disease control, for the everolimus it was 5.5 months, which is exactly what you'd expect. For the lenvatinib it was 7.4 months, which is also what you'd expect. But for the combination, it was 14.6 months, which is more than the sum of the two arms. So this I think caught people by surprise in light of all the other data that I alluded to. One thing that's not clear is that the average duration of treatment wasn't that different among the arms, so it's not quite clear why the progression-free survival was so long. But the company has announced that they plan to do a large randomized phase III with this combination to see if indeed there is benefit, so there may still be hope for combination therapy of these drugs. Of course, this is happening in the setting of the checkpoint inhibitors, which I mentioned initially being developed. So again, how these are all going to play with each other, meaning which therapies are going to be the most useful for specific patients, how will we sequence these therapies, how will we balance the risk and benefit of specific therapies for specific patients, really still remains to be seen. But some interesting new data nonetheless in the arena of kidney cancer.
I would summarize by saying what we saw in renal cell carcinoma at this year's ASCO was an update on the checkpoint inhibitors, but I think we're waiting for future years when some more robust data comes out. There's some large randomized trials that are ongoing now, both in a refractory and untreated setting, which will define the role of these agents. But we have some reassurance that they're clearly active and also some clues as to in whom they might be active in. We saw some data in non-clear cell cancer, about what I would call modest benefit of sunitinib over everolimus. But again, overall still pretty disappointing, and we need to do a better job of understanding the non-clear cell cancer in patients who have it and trying to encourage those patients to get on clinical trials to find new and better treatment. And then lastly, the data on the combination therapy of existing modalities of drugs was some exciting data, although I think more work needs to be done because again, we want to balance the risks of giving two drugs and enhanced side effect with benefit, so it remains to be seen whether that particular combination will move forward. Thank you your attention.
ASCO: Thank you Dr. Rini. If you have questions about whether new research may affect your care, be sure to talk with your doctor.
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