 If you want to see more of Matt, he'll be on the Phil show one Monday. Thank you, Matt. So you can obviously see why Matt's a very special person and looks at disease and cancer patients and survivors and health in a very different way. And it's just wonderful to hear him speak. So now we're going to turn to some of the more practical aspects of kidney cancer care. And our first speaker is going to be David Hoffman who's going to talk about the standard care treatment for kidney cancer that's spread. So David and I met when he was a fellow at UCLA. I convinced him that kidney cancer was something he wanted to spend some time studying. And he's now a partner at Tower Hematology Oncology in a very experienced and skilled clinician. And David, thank you for coming. Thanks for having me. Thank you. I'm grateful to be here. And it's funny whenever I'm asked to talk, I'm a little surprised because I feel like these are like Thanksgiving dinners and I should be sitting at the kids table. But as Bob said, I was at UCLA as a fellow and it surprises even me to say it was 17 years ago that I started over at UCLA. And when you start there, the chief asks you to identify a research mentor and I asked Bob if he would be mine. And the chief was really surprised and taken aback a little bit because at that time you could count the number of FDA approved therapies for kidney cancer on one finger. And thanks to people like Bob and Tenancy and actually to patients who participate in clinical trials, there's really been a revolution in this disease over the last 10 years. I don't think there's been a solid tumor that's had as much progress as in kidney cancer. So it's been very gratifying. So we're going to talk about where we are today. And then later on you'll hear some other speakers talk about where things are going in the future. Kidney cancer is one of those strange diseases that because it's so different than many other solid tumors, it really makes you think outside the rules. It forced people to think in a way that just didn't listen to the rules and pay attention to the convention. So it really was an important model for expanding treatment among all different solid tumors. It turns out unlike many other solid tumor cancers, there are a lot of limitations to treating kidney cancer. And we heard a great talk about the surgery of early stage kidney cancer from Dr. Kim. But oftentimes when kidney cancer has spread, surgery is not the answer. Nor so is ionizing radiation because kidney cancer compared to other tumors tends to be resistant to radiation. What about chemotherapy? That's often the last thing we think about in advanced kidney cancer. And immune therapy can help people but just not enough of them. We know from what Dr. Lutheringer said that kidney cancer comes from a particular part of the kidney, the cortex, and that disease kidneys have a very different appearance. But thinking about cytotoxic chemotherapy, you know what is chemotherapy? It's really just a poison to dividing cells. Kidney cancer doesn't really seem to be amenable to the use of poisons. So unlike chemotherapy, which we consider kind of a blunt instrument, the treatment of kidney cancer has started to use much more precise precision type of weapons. And thanks to people like Dr. Folkman, Judah Folkman who published a paper in 1971 that talked about trying to starve cancers of their blood supply that took 35 years to make a medicine that did that, there have been advances. And of course everybody in this field is moving away from the one size fits all mentality. We heard a little bit about trying to individualize or personalize the treatment. And that clearly one of the ways of the future, to find a treatment that really fits the individual. Now when I started at UCLA, using the immune system to fight cancer was kind of a not very well accepted technique for anti-cancer treatment. But now we know that using the immune system can work in this disease and in others. And it's been through the work of clinician scientists and laboratory scientists they're finally starting to unravel the molecular features of this disease. So here's an example. And we heard Dr. Lutheringer talk about von Hippel Lindau. And instead of just calling a cancer a cancer, it's probably best to understand the way it works, the abnormalities in the cells and attack it in a much more scientific way. So this is one example that talks about mutations that happen in clear cell kidney cancers and the downstream effects of that and then where the potential is for treatment and intervention. Here's some more. So we know that once we can identify certain potential weaknesses on the cell, on the surface of the cell either of the tumor or in this case on the surface of blood vessel cells we could maybe intervene at these places, right? And instead of just poisoning away with blood instruments, targeted therapies that can attack strengths or weaknesses of the cell can make big differences in the way that we treat these diseases. Kidney cancer turned out to be the leading model for this kind of intervention. So are we making progress? We are. It's not easy progress. It's an uphill battle, but we're clearly walking up this mountain together. Since the, since, let me go back just a sec. Hydrocyl-2 was approved in 1992 by the FDA and was the only FDA-approved treatment in this disease until the mid-2000s when the VEGFR, TKIs, seraphimib and sunitinib were approved. And since then, as I said, there's been a significant improvement in terms of the number of treatment options that we can give people with advanced disease. This is the incidence of kidney cancer and we can see that it tends to be a disease of people in their middle ages. So in the year 2013, about 60,000 new cases were diagnosed and there is a rising incidence of this. We know that the number of patients who died in the year 2013 was about 13,000 and that with advanced disease, metastatic disease, the five-year survival is still less than 10%. At initial diagnosis, about 20 to 25% of patients have metastatic disease. Others develop metastatic disease during the course of their illness. There are some hereditary risk factors and there are some risk factors that are considered to be sporadic or acquired, but as Dr. Lutheringer said, kidney cancer is not one disease. There is a variety of different diseases. We know that clear cell kidney cancer is the one that's most typical or considered kind of the garden variety, but there are many others and the word kidney cancer just does not really give justice to the diversity of this disease. How does it present? What kind of things can happen from kidney cancer? A lot of different things, of course, right? So we know there's a classic triad of hematuria that's blood in the urine, pain on the side and an abdominal mass, but that classic triad is seen in only the minority of patients. Many other symptoms or signs can arise. And there are a bunch of clinical syndromes or other findings, both laboratory findings and clinical findings, that makes this disease such a diverse presentation. Where does kidney cancer like to go? Anywhere it wants basically, right? It can go to many different places. The pattern of spread is also protein. So frequently the disease can spread to lung, to bone, to regional lymph nodes and on and on, including to the brain and almost every part of the body we've seen disease spread. How do you predict the prognosis? Well, we know we talked about the staging and the grade, both Dr. Kim and Dr. Lutheringer talked about that. There's also something called the performance status. You know, when we see patients, we kind of gauge how are they doing? What's their performance status? How are they handling the disease? Do they have a lot of symptoms? Are they in bed? Are they up and around? This helps predict prognosis. I'm not going to reiterate what Dr. Lutheringer said about the Furman grade. And we know that there's a reason that people are given a stage when their disease is diagnosed. It's to help predict prognosis. But even among those with metastatic disease, there's still a range both in terms of how people do based upon risk factors that we can identify. So how do you pick a treatment for somebody who has untreated, advanced metastatic kidney cancer that's already spread? Well, here was a trial that was interesting that looked at taking a medication called suenitinib, which we all know in this room, and compared it to an older immune therapy, interferon. And interferon was one of those immune therapies that worked in a kind of a non-specific way to boost the immune system. You know, many of us believe that one of the reasons cancers spread is that the immune system has failed to do its job to protect the body from cancer and somehow strengthening the immune system might be a way of fighting the cancer, that the immune system could be somehow empowered to fight the cancer rather than using a medication to kill the cancer itself. So interferon was one of those older immune therapies and was compared to this newer medicine suenitinib, which was an offshoot really of that work from Dr. Folkman, which said that one of the ways that cancers grow and spread is by nourishing themselves with a blood supply. And maybe you could, instead of just poisoning cancers, starve them to death by choking off their blood supply. Suenitinib is an oral medicine that tried to do that and tries to do that. And you can see compared in this study, suenitinib outperformed interferon in terms of the rate of response, the time to progression, and it was a trend towards an improvement in overall survival. Another medication similar to suenitinib, even before it was approved was seraphonib, and it was also tested against interferon and showed similar kinds of improvements in terms of tumor shrinkage, but not as great an overall response rate. Bevacizumab, Dr. Kim mentioned this medication. This is another one of those angiogenesis inhibitors, one of the medicines trying to starve the tumor of its blood supply. Again, with an immune therapy interferon versus interferon alone. And as Dr. Kim mentioned earlier, this led to the approval of Bevacizumab in this disease. What about the so-called poor prognosis patients? There are some people who have some adverse risk features at their initial presentation that make them higher risk or poor prognosis compared to others. And in those patients using a different class of medicines, inhibitors of an enzyme called mTOR, in this case the medication is called temsirilimus, poor prognosis patients appear to have a significant benefit. So we try to identify these features in patients. These are the so-called poor risk features. In the temsirilimus trial, three of the six features mentioned here needed to be met in order to call one a poor prognosis. That was an elevation of an enzyme lactose dehydrogenase. Hemoglobin that was low, so-called anemia. An elevated serum calcium level. A rapid presentation after nephrectomy. A rapid relapse there, I'm sorry, a poor performance status in multiple sites of metastases. Those are so-called poor risk features. And in that trial compared to interferon, temsirilimus outperformed. Are these medications safe? When we treat people with advanced diseases, we try to adhere to a principle which is, let's not give a treatment that's worse than the disease. That doesn't seem to make any sense. So it's important not only that the medications are effective, but they need to be safe as well. And it turns out that these are, and when matched up against things like chemotherapy, really look much, much more favorable. So there are side effects with these agents that can't be glossed over, but they're not the kind of side effects we worry about with chemotherapy typically. So there are some laboratory changes we see, and we track them. There are some clinical changes that we look for, but for the most part they're very tolerable. What about the home run? Is there a chance that we can still hit the home run in this disease? That's syndrome 2. So Hido Center looking to, I briefly mentioned it was approved by the FDA in the early 90s. It's a very interesting medication. It has no specific anti-cancer properties. It is purely an immune stimulator. It, in a non-specific way, increases the immune system with the hope that some of the cells that are generated by this medicine can identify a cancer and eradicate it. And work that was done by Dr. Ficklen and his colleagues showed that though there was a small response rate, the majority of people do not respond to Hido Center leucan. A significant number of them who do respond can have a durable, long-lasting response that may even be a cure. Who benefits from interleukin? Who do we offer this medicine to? Well, typically it's people with clear cell cancers, rather than non-clear cell. And those who can withstand some of the toxicities, there are some pathologic correlates potentially that might also predict for response, although that's still a work in progress. And again, this talks a little bit about the molecular biology of those who might be better candidates for Hido Center leucan versus molecular targeted therapy. Once people have been treated with initial therapy, most of the time the disease will change. It evolves, and there will be a need for second-line treatment. So targeted therapies, the ones that were developed in the late 2000s do prolong survival, but they don't often cause a complete remission. And most patients, as we say, will eventually require second-line therapy. If someone's treated with cytokines, when I say cytokines, I really mean interleukin or sometimes interferon. And there is a need for second-line treatment, treatment after failure or disease progression. We've used seraphanib or our medication called axitinib or sunitinib or Bethesizumab. What if you started treatment instead of with a cytokine, but with a targeted agent like sunitinib or another VEGFR tyrosine kinase inhibitor? Everlimus, which is an oral M-tor inhibitor, has been used and has shown success. There seems to be an importance of the sequence of treatment. And there have been a variety of trials that have looked at trying to figure out what is the right sequence? Is it angiogenesis inhibitors first, followed by VEGFR TKIs? Is it a sequence of the VEGFR TKIs? Is it M-tor inhibitors before or after? And are these safe in these sort of second-line? Can you offer these kind of agents to patients who've already been through therapy? And the answer is yes. What about giving interleukin to after someone's progressed? That one doesn't look to be as effective. There isn't any really good data that says that people who've already progressed after receiving angiogenesis inhibitors would benefit from high-dose interleukin-2. Which really means that if someone's a candidate for high-dose interleukin-2, we try to offer that as the first treatment. So how can we do better? What are we doing now? How can we optimize our treatments for people who have advanced disease with the current treatments that we have? We know that there's a bunch of new or available targeted agents that are approved by the FDA. We need to figure out how to optimize the dose, how long we treat patients, and how to manage the side effects. And that, we hope, leads to improvement in outcome. And the truth is there's really an overlap of those kinds of goals, right? And there seems to be some sweet spot that shows where there's optimal efficacy. Well, for long-term survival, we have to overcome what appears to be the emergence of resistance to current agents. When agents work, over time, disease becomes resistant. Maybe there's a sequence or a combination of agents that we can use that can overcome that resistance. Maybe we need to make novel agents and you'll hear about that later today. Maybe we need to individualize the treatment instead of being that one-size-fits-all mentality. Try to treat the individual based upon his or her molecular features. That helps to appropriately select the agents and maybe there are some biomarkers that we can use. Again, getting back to the diversity of the disease, different parts of the kidney make different types of cancers and it's important for us to recognize that. And with the scientific tools that are now available, that is becoming a reality. Understanding and exploiting the pathways, both at the blood vessel over here and at the tumor cell over here. And you can see that just as an example, at the blood vessel, there are a variety of agents that will inhibit downstream signaling to eventually prevent the proliferation of blood vessels. In the tumor, there are agents that are here to block signals that are sent through the cell, that tells the cell to grow. Not only is the disease a diverse disease, the patients who have this disease are a diverse group of patients. It's a heterogeneous group. There are some long-term responders. There are those who don't even need therapy. There are those who have primarily refractory disease and there are those who are kind of in between. And it's important for us to learn how to select and identify these different patients. So the current state, there's been truly an explosion in the choices over the last less than 10 years. Now there are eight FDA approved drugs where only a few years ago there was but one. Three different classes of agents. They've proven to slow down the progression of this disease. They prolong patients' lives. Immune therapy is still available to us and can still be the home run. Inhibitors of the vascular endothelial growth factor, right? This is blocking angiogenesis. A variety of these agents, including agents that are not yet approved like the one at the bottom of the screen there. And inhibitors of the enzyme mTOR. In the immune therapy era, the previous era, there were a variety of different ways to predict the prognosis. Those appear to be changing or maybe evolving in the targeted therapy area. We now look at some blood tests that help us again. Who is more likely to respond to make those kinds of predictions? NCCN is a collection of academic cancer centers that publishes guidelines of treatment based upon the available level of evidence. And if one looks at the guidelines for the first-line therapy for clear-cell kidney cancer in unresectable disease with stage 4 advanced disease and clear-cell histology, there are a variety of options, including the drugs we've talked about and also maybe critically clinical trials. And remember, every medicine that we have now came through the pathway of clinical trials, through the participation of patients and through the work of clinician scientists. And it's always the first thing we ask when a patient needs treatment is, is there a study for them that might be potentially better than the standard of care? What about for non-clear-cell kidney cancers? They're the minority of cases, and they have a different biology, but there are still options in non-clear-cell cancers. Of course, the immune system. The disease remains a potentially immunotherapy-sensitive disease both with interferon and hydrocentricin. And the important point, of course, with hydrocentricin is that there is no targeted therapy. It's the bottom line of the slide. There is no targeted therapy that has been able to produce durable responses like hydrocentricin, too. So a bunch of trials. I don't need to belabor the data, but there is, here's a summary slide for patients with poor-risk disease, first-line therapy, temsirulimus is a standard option. For those who are treatment-naive, who have a better risk profile, there's a variety of different agents that are mainly VEGFR TKIs or Bevacizumab with interferon-alpha. And we know that as time has gone by, there's been a lot of real-world experience with more than 4,500 patients with Sunitinib that proves long-term benefit and tolerability. We know we're going to try to find this sweet spot for effective therapy management. We're going to figure out how much daily exposure to some agents like Sunitinib is meaningful and whether longer exposure might be better than shorter exposure. It turns out that maybe longer exposure is better. That the longer you're on these agents, the better they work, as long as there's not an important reason to change. There was an interest in trying to figure out the sequencing of Sunitinib, whether it should be an everyday treatment or some time on, some time off. It turned out that the intermittent therapy was superior. There was a trial that was comparing Pizopinib versus Sunitinib in a trial called Compares. These are similar agents, and it looked like they were quite similar in terms of efficacy, but maybe there was a favorite side-effect profile with Pizopinib versus Sunitinib. It's certainly non-inferior and may have a better side-effect profile. This constellation is Pisces. This was the trial called Pisces that asked which patients like better, a medicine like Pizopinib or an agent like Sunitinib at standard dose and schedule. These are blinded studies. People didn't know which one they were taking, but there was a patient preference towards Pizopinib in the Pisces trial. And then a trial comparing Everlima and Sunitinib and crossing over, trying to again get the sequence. What's better first, a VEGFR TKI or an MTOR inhibitor? That using the... These slides I don't need to go through, but to let you know that it looked like giving Everlima's followed by Sunitinib was not as good as giving it the other way around. That sequence of first-line Sunitinib followed by Everlima's was a superior event, a superior strategy. Just to wrap up, NCCN guidelines again, subsequent therapy. Second line for clear-cell kidney cancer. Clinical trials always first and foremost on our mind, but a variety of these agents that are both MTOR inhibitors like Everlima's or VEGFR TKI's that are developed for second-line therapy like Exitinib have a proven role. And that's summarizing the same thing. Is there any way to predict the future? Well, there are some prognostic and predictive markers, including those who get hypertension, expression of certain chemicals in either the tumor or in the blood that might predict, including hypertension. So if patients become hypertensive on these medicines, they may be the ones who respond best. It's important again that we manage the adverse effects. And one of the reasons that medical oncologists like myself exist is to manage the side effects of the treatments of the drugs that we give. It's important that patients are educated about these things and that they are monitored closely and they're in close communication we know that there are some common adverse effects among all of these agents, some more so than others and that there are class effects associated with VEGFR TKI's as well as with immune therapies and MTOR inhibitors. We're going to keep on working to find better treatments and better agents, more potent agents, more novel using different targets and different strategies and that despite the advances we've made and they've been real, this sequential therapy appears to be the preferred strategy these days rather than combinations of targeted agents, but novel agents may change that. I'm going to stop there and take any questions. Thank you very much. We have time for a few questions. Step up to the microphone. You just have to talk into it. Concerning the blood pressure, you were talking about by raising it to make the one of the other drugs work better. Is that done by the doctor just by changing your medication if you're already on hypertension drugs? Or is that how you basically manage that? Well, in terms of managing, so there's two points. One is some patients develop hypertension from these drugs. The drugs cause hypertension in a certain number of patients. It turns out that the patients who become hypertensive are the ones who seem to benefit the most. So it's kind of a marker for us. We kind of hope to see a rise in the blood pressure when these agents are given. The hypertension needs to be treated and managed medically. So we do treat patients for hypertension that is a secondary side effect of the drug. But we don't induce hypertension. We don't try to make people hypertensive with medicines. We want to see if they become hypertensive. Okay, thank you. Thank you.