 So, I'd like to thank the organizers of this conference for allowing me the opportunity to talk to you guys about kind of novel combination therapies for the management of kidney cancer. Here are my disclosures. So, you've kind of seen this list multiple times now. Ever since about 2005, we really have had 11 FDA-approved drugs for the treatment of metasatric kidney cancer, and this is really phenomenal growth and advancement within the field. You know, up until about 2005, or 2015, most of which have has really been single-Asian therapy. So, back before 2015, this was kind of the treatment paradigm, and if you had asked me like, do we do combination therapy, the answer would have been no. What we really did was we took treatments and we used them kind of one after another in a very sequential sort of fashion. So, you, you know, progressed on one, and then you moved to the next, and then if you progressed on that, you would move to the next. So, this is kind of looking at the different categories of medications in which the 11 can be classified into. The first of which, you know, this has always been the largest group, and this has really been based off of the mechanism by which the kidney cancer derives its growth, and it's really targeting the blood vessels that feed the kidney cancer. The second category is, or the Amtour targeted agents, and they are medications that work by changing the metabolism of the kidney cancer that regulates growth and proliferation. And more than new kids on the block now are the development of the immunotherapies, which you've heard multiple times, work by boosting your own immune system to have your immune system better fight and recognize the kidney cancer. Now, back before 2015, there have been multiple attempts to try to combine these medications with multiple clinical trials looking at that as a possibility. But up until that point, we really, this story was very simple. Like, you combine the medications and we never really saw any increased benefit by using this combination. I mean, it seems like a very straightforward question. Like, you know, you take one from one category, and you combine with one from another category, you're attacking the cancer from two different directions, and you would think that this is something that would work better. But what we actually saw was, when we combined some of these medications, the amount of toxicity that we ended up seeing was significantly higher, high enough that we actually weren't able to get to kind of high enough doses of the medications, such that we could try to harness this sort of efficacy information. So that's one of the greatest pitfalls of using combination therapy, is whether or not we actually can get the both of the drugs, which were initially designed to be used individually, to high enough doses that we can actually use them in combination. Other times, we've tried to combine two drugs that target the blood vessels, and we've also seen by, we saw great responses, but unfortunately, we saw a lot of toxicity that came along with it, in which they weren't able to move forward, just because of the amount of people that develop toxicity from it. So the first medication, or first combination, I mean, a combination that was FDA approved, was the combination of lumbatin and plus feralimus. And this is a combination that takes one drug that targets the blood vessels that feed the kidney cancer, and one drug that targets the metabolism. So this was done in a randomized phase two clinical trial. So at the time, it wasn't designed as a registration trial, the company wasn't thinking about using this to get FDA approval. So it was a relatively small trial that took in about 150 patients. Patients were randomized to either the combination of lumbatinib at 18, feralimus at 5, or lumbatinib at a higher dose at 24, and feralimus at 10, which is the FDA approved dose. And they wanted to see whether or not the patients were able to be treated, how long the disease-free survival was, and also to see whether or not they were stopped at unacceptable toxicity. The trial was designed to kind of look to see whether or not the length of response for each drug was better than feralimus. That's kind of the comparison arm. So this is what they ended up seeing. So they ended up having about 50 patients in each group, and then the patients who got combination lumbatinib feralimus had 43% of them had shrinkage of their tumor, compared to 27% with lumbatinib alone, and 6% with feralimus by itself. And this was thought to be statistically significant. Now, most of these are what we call partial responses. And what a partial response really means is that, you know, you have greater than 30% shrinkage, but you also have not, it doesn't completely go away. The other number to look at is how long was the duration of response. So as you can see, the duration of response for the people who responded, they had a median duration of response of 13 months. And, you know, for the single-agent arms, lumbatinib was, you know, 7.5 months, and then feralimus by itself was 8.5 months. So even though there was a small percentage of people who had shrinkage of their disease, if you did have shrinkage of their disease, it did, you know, convey some good clinical benefit. Here, another Kaplan-Meier plot that you've probably seen multiple times. And what you do see is clear separation. So the cyan-colored is the combination of lumbatinib plus feralimus. And, you know, on a whole, the median progression-free survival is 14.6 months. And then, you know, feralimus doing the worst with 5.5 months. And lumbatinib by itself kind of in the middle. But this in and of itself doesn't really answer the question. And we may not necessarily get the true answer to the question of, what if we just use them one after another? Like, you know, that's, that type of trial often is, we aren't capable of doing. And so as a result, you know, we use these as kind of proxies. Like, you go ahead and you get the drug with kind of the highest possible response. And, you know, you kind of, you know, assume that doing it this way is a little better. This is looking at the overall survival numbers. And, you know, because this trial wasn't powered to look at overall survival. And overall survival gives us a better metric of what would happen if we use them sequentially. But if you just don't have the numbers, you may not necessarily see that. You know, from a numerical standpoint, the combination of lumbatinib plus feralimus is improved in comparison to people who got, you know, either feralimus by itself or lumbatinib by itself. So moving forward, the new interest right now has really been looking at how can we combine the immunotherapies with other drugs. Because with the immunotherapy drugs, a lot of excitement has been centered around this. And it does seem like using the immunotherapies are a little bit easier to combine. Whereas the drugs that we've used for kidney cancer in the past, we've run into a lot of toxicity issues with that. So as you all have known on Checkmate 205, this is a randomized clinical trial looking at nivolumab or uptivo randomized against feralimus with a primary endpoint looking at overall survival with a key secondary endpoint of looking at the objective response rate. So if you look from a progression free survival standpoint by itself with single agent immunotherapy, you know, progression free survival may not necessarily give you the entire answer because from this you can see that progression free survival on nivo was, you know, 4.6 months, feralimus was 4.4. What really does interest us about the immunotherapies is the duration of the response. For those that respond, they tend to do much better. And the idea behind combination therapy for this population is really to see whether or not we can either improve upon, you know, the response rates or kind of see whether or not that long tail can be maintained. And this is what we can see with the swimmer's plot. So a swimmer's plot is basically every patient, they get started on treatment and you kind of, you know, see how long it lasts for. And you can see that quite a few people who were treated with nivolumab, you know, were still on ongoing treatment and kind of maintaining those results. And this kind of bears out in the overall survival data, which was the end point in which if you got single agent immunotherapy, you definitely did better than not having gotten single agent immunotherapy. So checkmate 214 was the first, was one of the combination immunotherapies studies looking at nivolumab and nivolumab, which you've heard about. This was done in the first-line setting. But at the same time, so this was a one-to-one randomization of getting combination immunotherapy versus the standard of care at the time, which was sootent. Patients were stratified based off of their risk stratification, whether or not they had favorable risk, intermediate risk or poor risk. You know, they were kind of put into separate buckets, making sure that, you know, kind of the arms are balanced. And patients who were again treated until either progression were developed kind of unacceptable toxicity related to the medications. And this is where we see something very interesting. So in people who had intermediate or poor risk disease, and this is a very clinical sort of measurement of how patients are stratified. You know, this has, you know, we're taking numbers that just come from us strong in the blood that don't directly relate to, you know, the biology of the cancer and taking metrics as also in terms of how you feel as a patient. And again, like that gives us some clue about, you know, the cancer and being able to, you know, see differences in the treatment approaches. And what we ended up seeing is for people with intermediate and poor risk disease, they did better on the combination of two immunotherapy drugs than they did on the standard vegetative therapy at the time, you know, with a 42% objective response rate versus 27, which was statistically significant. However, for people with favorable risk disease, we actually saw a reverse trend. So for people with favorable risk disease, you actually did better just going with run-of-the-mill synitinib. This is the drug that would just approve, like at this point, you know, about 10 years ago. And giving you more drug doesn't necessarily mean that we're getting better affects. And in terms of, you know, the percentage of people that are responding. So this is one of the things that we always have to look at before we start, you know, jumping into just like, you know, combining things at random and implementing them is really to be able to make that comparison and looking at, you know, what are the groups that are going to benefit from kind of getting additional treatment and, you know, because additional treatment always comes with a little bit of additional risk. So within the intermediate and poor risk group, this is the overall survival data. And then you can see that the curve separate pretty nicely in which, you know, people who had intermediate and poor risk disease, you know, at the time in which they evaluated, you know, the median overall survival hadn't yet been reached while as the people who were treated with synitinib in the first line setting had a median overall survival of 26 months. So then the question becomes another possible combination. So what if we take one of the drugs that, you know, targets the blood vessels? Because we know the response rates in the people who clinically benefit from that medication seems to be rather high and we paired it with one of the immunotherapy drugs and see whether or not what the response rates and clinical outcomes would end up being. And then there is some rationale for making this combination. So one immunotherapy drug is the drug of Tessilismab and one drug is Bevacismab. And the rationale for combining this really is the drugs that target the blood vessels probably have some effects on the immune system also. You know, it's very tough for us to know in advance what the exact mechanism by which we see this cooperation. But, you know, whether or not it's, you know, increasing the immune cells ability to present the cells or opening up the tumor so that more immune cells can come in or just decreasing the number of immune cells that inactivate the immune system, that really still remains kind of an open-ended question. I don't think we necessarily have the definitive answer. But without having that definitive answer, it doesn't really change the fact that we do have clinical studies that can give us some insights about information about efficacy. So in the phase three clinical trial comparing this combination to Synitinib and people who expressed PDL1. So this was looking as a primary endpoint, you know, expression of the marker that the immunotherapy targets. You know, we saw, you know, good separation of the curves and, you know, an improvement in progression-free survival in comparison to Synitinib of the 11.2 months versus 7.7. And from a toxicity standpoint, because immunotherapies in general haven't had that many side effects, and Bevacizumab, you know, for a medication that targets the blood vessel and, you know, makes it relatively easy to tolerate and, you know, has been, you know, combined with multiple agents including different chemotherapies, you know, and has also been combined, you know, successfully with the M4 targeted agents. Overall showed less side effects that people find to be bothersome in comparison to Synitinib. Granted, you know, there are some other targeted agents that, you know, may be a little bit easier to tolerate than Synitinib, but, you know, the comparison wasn't done against that group. And in this, you know, we do see, you know, some evidence that, you know, doing this type of combination from a patient standpoint in terms of, you know, tolerability, we see benefit. However, there is certainly the inconvenience standpoint of when we were talking about doing IV infusions on an every two-week basis. So right now there are multiple Phase III clinical trials that are really looking at the use of immunotherapy plus a checkpoint inhibitor, you know, with, you know, pretty much almost all of the different tyrosine kinase inhibitors or anti-angiogenesis drugs that, you know, are available. So there's the clinical trial with Linbatinib, which is a large Phase III. It's looking at Linbatinib plus Pembrolizumab, Pembrolizumab being the immunotherapy, against Linbatinib plus Everlimus, being the FDA-approved combination in the second-line setting, random guys against Sinitinib. For Exitinib, there have been two clinical trials that are completed accrual. So, and we're kind of still waiting for the release of those results. One is with Exitinib plus Pembrol. The other one is Avalubimab. Avalubimab is just a different immunotherapy that can be combined with the Exitinib. And then the Bevisizumab plus Atezo, as I had mentioned before. And then also up and running right now is the combination of Cabazantinib plus Nevolumab randomized against Sinitinib. So right now, we don't have Phase III data for this sort of TKI-IO sort of combination, but we can gather some quick glimpses at what we may expect. Or, you know, a lot of caution has to go into looking at, you know, data from Phase I and Phase II trials because historically speaking, you know, our results have sometimes been a little bit better. Perhaps it's patient selection. Perhaps it's just the small numbers of patients so we don't get as clean of a look. So this is a 52-patient study in which about 56% had an objective response. So this is a very high, like, you know, as you can see from the waterfall pot, like almost all the patients did end up getting shrinkage to their tumor, even beyond, you know, the 58% because the 58% looks at that dotted line and that cutoff right there. And what we still don't yet know is whether or not this objective response truly predicts for how long the progression for your survival is. And from your standpoint as a patient, like, and I've told all my patients this when they've gotten TKI's, is, you know, it's always, you know, shrinkage is always better than growth. But what you are interested in is not necessarily shrinkage, but how long the drug is effective for. Like, you know, what you, the last, like just because you get shrinkage and then the next scan afterwards, the disease grows right back, like, you know, you didn't care you got shrinkage. Like, you know, I think that what you want is the medication to work on a kind of a more ongoing sort of basis. So this is another one of these clinical trials looking at this type of combination and this is with an abandoned plus pembrolizumab and this is a trial that looked at patients that were both treatment naive. So having not gotten any previous treatment and patients who got previous therapy. So they got a TKI beforehand. What they end up showing was, you know, it's a small trial of, you know, 30 patients. If they looked across the entire 30 patients, 63% had an objective response. If you looked only at the treatment naive patients, so the patients who hadn't got any previous therapy, 83% of them had shrinkage of their tumor. And then if you looked at the patients who got previous treatment, then about 50% of them had shrinkage of their tumor. And as you can see from the waterfall plot, you know, there's not good prediction on whether or not you got previous treatment, whether or not, you know, you had more shrinkage or less shrinkage. And then the other thing that we, again, often look at is PDL1 status. And then, you know, as you can see from the random smattering of colors, like, you know, PDL1 status didn't actually well predict whether or not you were going to get shrinkage of your tumor. You know, with this sort of combination, the question is, you know, what is the toxicity like? You know, so when we look at toxicity and when we look at combinations, you know, it's probably to be expected that you're going to get the toxicity of the two treatments. What the issue really becomes is also, like, do you get additional toxicities? When you have combinations, the two drugs interact in some sort of way that, you know, in the same way that we would like them to enhance their efficacy, there's also the possibility that the drugs may end up enhancing their toxicity related to each other. And at least on early follow-up, they didn't see any safety signals to suggest that there were unexpected toxicities related to the medications. And this is their update in which they looked at progression-free survival, especially when we look at small trials like this. The median progression-free survival on here was 18 months. However, the actual, you know, that's a very wide curve. It only takes a couple of people to change how long that number is measured. So we really do have to wait for the phase three clinical trial to make, you know, firm assessments on what the true progression-free survival end up being for this combination. Another one, the combinations with CABO plus Nivolumab, and this was done either without or in combination with Ipollumumab. So this was only 13 patients. Again, you see kind of within the same ballpark, you know, around 50-some percent of people have shrinkage of their tumor, most of which being partial responses. And the question really becomes, you know, how long is this and the duration of response going to be looking at. So this is really going to be a really important look that we're going to get in October of this year for one of the first trial, first phase three clinical trials with the TKIs and immunotherapies with Avolumab plus Exitinib. You know, we know from the press release that this is a positive trial, but what a positive trial means, we don't yet know. So we're kind of anxiously awaiting to see what those results wound up being and like, you know, whether or not, you know, this type of combination will end up being better than and you know, kind of supplant, you know, the current clinical approach. So in summary, you know, I think that combination therapy in RCC is really a promising future approach. You know, we don't yet know whether or not the using these in combination is going to be better than using them sequentially, but we do have some hints to suggest that that might be the case. And then right now, kind of, the big question in the room is for the multiple TKI immunotherapy combinations, you know, we've seen these impressive, you know, response rates, like, and whether or not those response rates are going to translate into either cures, which would be great, but you know, whether or not they would translate just to, you know, longer responses. You know, anyways, that's, thank you so much for your attention and I open to questions.