 So we're going to turn our attention to targeted therapies. Ed Pisatus is the director of our general urinary oncology program at Cedars, an expert in prostate testicular bladder and kidney cancer, and he'll talk to us about what's been accomplished. OK. Sorry about the last minute panic, but we're going to do a little experiment, because I actually believe that this group is more savvy than some people think. So I had to make a last minute change with the slides. I'm going to plug this. I'm going to ask you all a favor. For those of you that are social media savvy, we've created a hashtag, OK, the KCPLA15, all right? So if you're taking photos, making notes, tweeting, Instagramming, or Facebooking, do me a favor and cite the hashtag, and we'll try to create kind of a social media awareness to see if we can make this an even bigger thing, because these kind of patient conferences are pretty useful on the whole. And this is a nice, quick, easy way to get the word out there. And as the day progresses, Amy and Nancy will be kind of posting things along on the KCP15LA, all right? So small adjustment, but that's an aside. So I get the pleasure of following Bob. This is a little bit of a challenge, but Nancy and Bob asked me to address the issue about targeted therapy in renal cell carcinoma and kidney cancer, and to ask the question, or try to answer the question, is it working? So first, let's talk about what is meant by targeted therapy. Doctors like to use this term a lot, and patients hear it a lot, but what does it actually mean? So I thought I'd go to the National Cancer Institute website to see if I could glean what at least the US government tells us what targeted cancer therapies are. And they actually have some very specific ideas, which are kind of highlighted here. So targeted therapies differ from standard chemotherapies, kind of bread and butter tool of medical oncologists in the way that they work on specific molecular targets associated with cancer. They're deliberately chosen to kill, to interact and kill those particular targets. And their effect is, and the term that you're going to see is cytostatic, rather than cytotoxic, meaning they kind of hold things at bay, but they actually sometimes just don't do that. They actually go further, and they do kill the cells at times. But this was kind of a very cool concept, right? So everyone's afraid of the medical oncologists, because we have these horrible drugs that make your hair fall out, that make you nauseous, that make you feel terrible. But in 2015, our momentarium has changed a lot. We still use a lot of the very standard therapies, and even a question about chemotherapy in kidney cancer has come up during the course of our conversation today. The honest truth is there actually are some cytotoxics that are used. They're not used anymore very commonly. But we have so many better drugs that are out there that kind of target the cancer cell, or at least target things relative important to the cancer cells. I wanted to tease that out also. So the cancer cell, and these are the kind of pathways we like to draw in the laboratory, the different molecular pathways that are involved in making a cancer cell grow, making it move about. And not just the cancer cell, but these cells don't just live in kind of their own isolated space. They have an environment they live in. And Bob touched on a lot of that in his discussion about the immune microenvironment. But in addition to the immune microenvironment, there are blood vessels, there are supportive cells, all of which are subject to different biological alterations. And so the idea is that you can take out these blue, nasty cancer cells and leave the normal cells alone at the end of the day. And this to me was kind of exciting. So part of my job here at Cedars when I'm not in the clinic is actually to go up to the laboratory and work with my team to do research on molecular targets. As we sit in the laboratory, we try to tease apart those molecular networks to look for different ways to treat cancers. And we try to bring those from the laboratory over to the patient. And I want to give you a little bit of a success story because this was a real paradigm shift in kidney cancer and in many cancers that we take care of. So there were these very bright guys out and out across the ocean who developed this compound that they called BAE439006 that evolved into a compound that many of you may have heard about called seraphonib or nexivar. So the idea was that they had developed initially this kinase inhibitor that actually was a RAF inhibitor. A molecular target we don't talk much about in kidney cancer, but it actually hit a whole bunch of different things. And in the early studies, and Dr. Mehta, who's a director, one of the co-directors of our phase one program, will talk to you more about phase one trials. But in the midst of the phase one studies that were done, it turned out that there was a nice signal developing in the kidney cancer patients that were being seen. So in early, we call it phase two trial, was put forward looking at the activity of this drug in kidney cancer. And with a positive signal from a phase two study, this went into a big phase three study which I published in the Wingham Journal of Medicine showing these kind of survival curves. Now these again are the kind of things that doctors like to look at, but they're a little confusing. So let me kind of summarize it a little bit. In the study that was done with seraphonib, there was an improvement for patients who were treated with this drug. And these are typically patients who had previous immune treatment. Their survival shifted on kind of for the middle guy, the median survival from 19 to 15, from 16 to 19 months. I'm gonna put this thing, and I'll show it to you a few times, called the hazard ratio. So for those of you that are gambling folk, the hazard ratio is a change in the odds of something happening. So a hazard ratio of 0.77 means that there was a 23% reduction in death associated with treatment, this drug. Progression-free survival, which means that on a CT scan or on some kind of imaging, something was getting worse. Typically that happened at about 2.8 for patients that got blanks and 5.5 months for those patients that got the drug was a hazard ratio of 0.44, a 56% improvement in time to progression. So these were kind of very astounding facts because this was not an immune therapy, it was not a cytotoxic therapy, and it made a dent in the armor of one of the most fierce solid tumors that we deal with in the medical oncology clinics, and that's kidney cancer. So this was a real kind of triumph, and this went over to the Food and Drug Administration and got approved. Well this kind of was the tip of the iceberg because what's happened since then is that armamentarium has gotten much, much better. And so for those of you in the audience that have had to deal with these kinds of drugs that we have now, these are a few of our very common weapons that we use now in the first line. Kind of the, when someone has metastatic kidney cancer, the first drugs that we think of. And I'm gonna admit to you this talk and myself we're a bit biased. So we're gonna talk solely about targeted therapies and not the immune treatments at this point. But there were several, I kind of put it in very academic detail, the comparators, what the survival benefit was, the progression rate, response rates the number of times the tumor shrunk and the date of approval. And you can see that we've had these drugs now around for a while and what their molecular targets are. These are probably more familiar things for those of you that have been on them, what the pills actually look like at the end of the day. And the point of this is to say that look, we've gone from having nothing than having one drug to actually having a bunch of different choices now even at the first line space. And this is only the first series of treatments. If you look, we've actually even developed a next layer of treatments. Different drugs like Nlaida and Affinitor which have been shown to work even when the first treatment that you get if it's Su-10 or Prasap and it fails. So our ability to treat kidney cancer patients is no longer purely experimental because of the successes that we've had with previous clinical trials and those brave patients that stepped forward to help define that activity in these spaces. I mean, we really owe them a deep gratitude of a deep sentiment of gratitude for what they've done for us and these are the drugs again that we've used. But I wanted to make another point, through different clinical trials, we figured out that, well, you can't just randomly throw things at these particular tumors. So another drug that's been around for a while called Torosel, which we actually will use more commonly in the first line setting for more porous cancers. It actually was tried as a second line agent compared to Seraphonib in a formal clinical trial and it actually didn't show that level of benefit. So these trials really help us not only to know what we should do, but what we shouldn't do. And again, as a clinical researcher, I really kind of, I wanna make that appeal to you that these clinical trials that come forward are really, really important. So while we've answered some questions, a lot still kind of exist out there. For example, now that we have several patients, several different drugs in the first line setting, like I just showed you, well, which one should you be on? Which one should come first? Can you take something that works and can you pair it up with something else that works? This has been kind of an old tried and true thought in medical oncology and not just in oncology, but in a whole bunch of different disease spaces. I mean, for example, a lot of folks are on combinatorial blood pressure medications. You take one, you take the other, we'll put them together. Sometimes they're even better. Sometimes they're not. Are there better ways to use the drugs that we have? Dr. Sher touched on some of that. I wanna show you, kinda remind you about his sentiments again. And then what new agents do we have for the drugs? What new agents do we have for the targets that we already have? And I wanna touch on this a little bit because I don't think we know everything that we need to know quite yet. And finally, as a scientist, questions are particularly appealing, but are there new targets? Are there new types of ideas that we can bring from the laboratory into the clinic? And I think these are all very important trials. I'm gonna try not to offend Dr. Figlin by showing you this in a very crass way, but for that question about which drug do you go for first, who, Tent, or do you go for Votrient? This has been kind of a burning question. I feel patients ask us this all the time. And actually, there have been a series of trials done. And for those of you that are aficionados, Dr. Figlin and several colleagues, of his colleagues in the kidney cancer field are online and they go through a very lengthy discussion about the Kompars trial and the Pisces trial. But this is one trial, one of those trials that actually looked at the difference in progression-free survival and overall survival between the two different drugs. And lo and behold, this is actually an interesting conclusion that actually they look pretty similar. Do we have mathematicians or statisticians in the audience? Okay, this is a finicky point because when we do trials, we have to design them in a way that answer a very specific question. This is what we call a non-inferiority trial. So the purpose of the trial is to show that one was not worse than the other. Okay, and that's a different trial than saying that one is better than the other. And mathematicians will tell you it's a very clear question in their minds. To us, to other folks, it's a little bit harder. But the bottom line of this trial was that the one drug, Pazopinib, was not inferior to Snitinib. And so other questions came up. Well, which ones are easier to use? Which is less toxic? Which ones do people like more? And this came out as part of another clinical trial. And you can see that at least in this trial sponsored by a Galaxosophanic client that makes Pazopinib, the results were that patients pervert Pazopinib and doctors pervert Pazopinib. I mean, how do you kind of weigh that at the end of the day? It's difficult to know. But it's also important to know where these trials come from and to figure out how to put them together. So the bottom line, if you ask me, what do I think about these? We have two good first line drugs. If you have kidney cancer, especially a clear cell carcinoma, we have two really good drugs that you could be on. As far as we can tell, one is not inferior to the other. And the toxicity is maybe different. There may be some preference choices, but every patient is different. And sometimes you and your doctor gotta sit down and kind of talk about it. It's a very individualized decision. It's hard to make it seem like one size fits all. Another interesting study that came forward was something called the Interact Study. Now there's a drug called Temsarolimus, which works. And many of you know a drug called Avastin or Bevacizumab that's been studied in kidney cancer. What's pretty nice is that both drugs are fairly well tolerated. And so there became this belief that maybe you can take these two pretty well tolerated drugs and put them together and get even more out of them. And a lot of folks, honestly, when this concept kind of started circulating, some doctors in the community were going ahead and just doing this combination, AdLib, without any kind of investigational protocol over seeing this. And this became a bit of a concern to those of us in the field, understanding that these pathways do interact and cause more harm than good sometimes. So this was a study looking at that particular question about using Temsarolimus versus Bevacizumab versus interferon alpha and Bevacizumab. There wasn't any significant difference in the infirgation free survival. In fact, it was a little bit worse for median overall survival. Response rates were similar, but the kind of big problem was this. The side effect profile went up. So basically, you didn't get any gain and you incurred more harm by this combination. And so making willy-nilly combinations of these active agents can be dangerous. And one should not just jump ahead and say, well, I'm gonna take drug A and drug B and hope to get the best out of it. This is a discussion that should be had with a doctor that knows about these drugs and how to handle toxicities. Dr. Scherer gave a very nice talk this morning. My slide is nowhere nearly as pretty as his, but the point of this study, but the point of this slide is to summarize the fact that we've been looking at new ways of applying these effective drugs to cancers that we have. The setting that Dr. Scherer focused a lot on was this after surgery setting when you take the kidney out to try to beat up any leftover disease that might be within the body still. There's actually an additional study that the NCI has sponsored looking at, even for those patients with metastatic lesions, taking out the metastatic lesion, giving pazopinib afterwards, to try to, again, perform an adjuvant approach or a mop-up approach for this type of treatment. And while those are great concepts and important, oh, and by the way, just so everyone can see this, the drugs that are in bold, they're here at Cedars, they're open now. So if you know someone that might be appropriate for this or thinking about something like this, please make sure you reach out to us because while many have been done, completed, as you can see in the columns, many are still active. And these are important clinical questions that we have to address to move forward in the future. There are new drugs that are being developed in kidney cancer. They range everywhere from vaccine-type approaches, another trial that we have here at Cedars. Dr. Scher talked a little bit about that and Dr. Figlund talked a whole bunch about that. Nevolumab, the bulimumab, to immune, there would be kind of checkpoint inhibitors and then a very interesting series of new biologically active agents that we have on trial here at Cedars that I'll tell you about in a bit. So let's talk about this term angiogenesis. So doctors Kim and Shao and Dr. Huo Hoffman had touched base on this earlier. Angiogenesis is the process of blood vessel formation. It's actually a part of normal wound healing. So if you go out and you're working in the yard or working in the kitchen, you cut yourself with a sharp object, your body's gonna heal, okay? That's because the body knows that something's broken down, blood vessels kind of go in, blood, while you're bleeding out a little bit, not hopefully not seriously, but while that bleeding's occurring, different cells are making their way into that injured area to initiate repair, okay? And this is, again, part of the normal biologic process. Cancer cells have this kind of funny behavior. What they do is when they sense that there are low levels of oxygen that are affecting them because these things are kind of growing out of control. They're not really paying attention to their neighbors like good cells do. Good cells always kind of look to their left and their right and say, well, this is my share of the pie so I'm gonna take this and my neighbors are gonna take theirs. Cancer cells just say gimme, gimme, gimme. And when they'd start to demand oxygen, they actually begin to send out a series of biochemical signals that promote the formation of blood vessels to make up, to compensate for that low oxygen condition. And as the previous speakers mentioned, this is something that we can target for therapy because we know some of the biological components. I know it's in a really small print, but I figured you didn't want a long list of pro-angiogenic growth factors on a Saturday, even early in the afternoon. But we've begun to understand these different molecular pathways and we know that, again, hypoxia induces expression of these particular growth factors and that results in the angiogenesis blood vessel formation that allows tumors to grow. So a lot of the agents that we already have, like pseutent, like zopinid and LIDA, these all target that particular VEGF-directed behavior that seems to choke out the tumors. But that is one, or even if we include PDGFR, those are several important aspects of this blood vessel formation process. There are others that are out there. Some very smart scientists discovered another important molecular signal known as CD105, and this is a protein called endaglin, that actually works as a complement to those VEGF signals. And so this became one of those situations where maybe the combination might look interesting. So actually there was a phase one trial. We were one of the sites of the phase one study, looking to see if you combine a VEGF inhibitor, like exitinib or in LIDA, along with this endaglin blocking agent called TRC105. And actually we and others had reported out to the community that this particular combination seemed to actually lower toxicity in certain ways, which was pretty impressive. And so as a result of our findings here and in concert with our collaborating sites, we've actually moved this ahead into a phase two test that we have here for patients that had previous therapy with a drug like Suthentropazopinem. So this is a very exciting study, and Dr. Figlin has treated several patients with this particular combination. And while blood vessels are great, there are actually other things that we can kind of think about other ways of being kind of sneaky with the cancers. So one of them is actually to put drugs into little particles called nanoparticles. So just to give you kind of an idea, because sometimes these things don't make a lot of sense, at least to me, because I'm a very visual kind of person. If you think about a baseball, giving you kind of a hallmark for size, baseball is about 100 million nanometers. And these particles are all on the micron, or even on the nanometer, even subnanometer size. But that puts you all the way down here. So you can get an idea going from a baseball to a period to a cancer cell, how these things kind of scale down. So these are very, very, very small particles that in which medicines can be trapped. And in this particular compound called CRLX101, this polymer nanoparticle has this very nasty kind of drug. It's called the campethesin. It's a double poison. It blocks, well, it's a direct cellular poison blocking topolyte inhibiting, or excuse me, the topolyte summaries in one inhibitor. That means that it actually enters DNA repair. It also blocks HIF1-alpha. And I'm gonna come back to what these different HIF signals are, because they're important. These hypoxia-inducable factors are part of what drives this whole blood vessel formation. But if I kind of take all the fancy stuff out and put it in simpler terms, basically these nanoparticles let the drug stay in the body longer, and it hides the chemotherapy from normal cells. And that's because this kind of shell, this kind of coating exists that targets the tumor cell. It gets into the tumor cell where it's broken down in a certain kind of unfavorable environment. So then it releases its payload where it's supposed to go rather than where it's not supposed to go. This was actually the kind of research that I did all the way back in college. And it's nice to see that it's still very much alive and well, because it's a pretty clever idea. It's a bit of a Trojan horse idea at the end of the day. And so this new compound is now entering early clinical trials. We're a center for that here at Cedar Sinai. So this is a kind of trial that would be available for someone that's been through one or two previous treatments, looking for kind of a new direction. In fact, along that same line, one could turn the right to another concept I wanna share with you, but let's take a step back for a second because I kind of dropped this HIF-1-Alpha thing on you and I apologize. So these hypoxia-inducible factors, all right? So hypoxia means low oxygen, and low oxygen makes these different factors come up. The one that we typically think about is what we call a HIF-1-Alpha, which generates all these different molecular events that leads to production of vascular endothelial growth factor. It has a brother called HIF-2-Alpha that sometimes we think about when we discuss. It's been a little less beat up on at this particular point. But there's a new drug that's just been brought up in the clinics. Some very, very smart scientists have been able to design a drug that blocks the HIF-2-Alpha component of these clear cell renal cell carcinoma cells. And basically what this thing does is it comes in and it hits the HIF-2-Alpha, which prevents it from binding to the normal signals that it wants to go to, so it can't make all the different growth factors that needs to produce blood vessel development. So this is taking yet another different route on this blood vessel blocking formation that's very different than what you get with sutent, pazopin, or exitinib. So for those folks that have been down that particular road, maybe going in a new direction is a better idea. So this is a first in human study. It's an oral agent. It's not one you have to come in and get an IV infusion for, but it's something that's very, very exciting. It looks fantastic from the early preclinical models. So I'll bring this to a close by addressing the question. If you said, our target therapy is working, I think the answer is yes. I think it's a resounding yes. We've already, we've been able to take kidney cancer patients from a place where we were putting them through severe immunotherapies now to a place where oral agents are able to maintain good quality of life. My patients are working, my patients are productive, their fathers, their mothers, and they're working, their brothers and sisters, they're productive members of society. But as good as we're doing, clinical trials are still very, very important for us to keep moving the mark forward. We've come a long way, but we still have a ways to go. I don't want anyone to leave here thinking that clinical trials are only for patients who have run out of options. That's a very, very bad perception that exists in the community. These questions that we're asking happen at very different points all along the spectrum of kidney cancer because sometimes an earlier intervention can make the difference between being on therapy later or not being on therapy at all. So again, it's always appropriate to speak to your doctor about whether a trial is appropriate for you. And finally, the bottom line is kidney cancer patients are now living longer and better today than any time in prior history. So thank you for your attention. And I think we have a little bit of a question and answer at the end of the session. So on behalf of myself and the army of folks that we have here at Cedars, you're seeing a bunch of us today, but this is our big urologic oncology program thinking about kidney cancer, prostate cancer and others. I wanna say thank you and thank you for helping us out with our mission.