 Okay, so we'll go ahead and get started with the second portion of our presentations. We'll focus on systemic therapy. We'll have our three medical oncologists focused on the treatment of kidney cancer speak. The first will be Dr. Nazar Taneer, who's going to talk about the role of targeted therapy in the treatment of patients with advanced kidney cancer. Nazar? Thank you, Chris. Good morning, everybody. It's a pleasure and a privilege to be here. This is my eleventh year, and it's great to see friends and survivors. This is why this is called Cancer Survivors Symposium. Over the last 11 years, we've seen dramatic improvements in therapies, and I am very excited about the future. We have hope, and this is why you are all here. We have more therapies now than we've had a decade ago. These are my disclosures. As you heard already from our colleagues, surgeons, Dr. Wood, Matin and Karam, there are many options for treating patients with metastatic kidney cancer. I'll focus my talk on systemic therapies, and the main two areas will be the VGF-directed therapies and the mTOR inhibitors. But radiation has a role for palliation of bone metastasis and brain metastasis. You heard from the surgeons about the role of cytoreductive nephrectomy in the management of metastatic disease, and there's still a role for metastasectomy in some patients where we resect the tumors in different organs, the pancreas, lungs, brain, and that is certainly plays a role in extending the life of some patients. When we are faced with a patient with a diagnosis of renal cell cancer, as you saw from the beautiful photos that Dr. Matin showed about the different tumors, we are struck with heterogeneity. The word that you hear about, it means that renal cell cancer, although it arises in the kidney, it's not one disease, it's one of many different subtypes. Histologically, the way they look under the microscope, but also molecularly. And also, we have for years recognized even the same tumor subtype, the most common, let's say, clear cell. You have patients who do very, very well and survive many years, even if they have metastatic disease. And you have, unfortunately, other patients who are not lucky and they do not survive one year. So there is that heterogeneity that we have recognized. And we have developed models, prognostic models, to try to understand who are the patients who survive longer than others and what are these clinical risk factors. So this is the model from the International Metastatic Renal Cell Casino Medata Consortium where they looked at performance status. You heard that word from Dr. Wood this morning, meaning how is the patient walking, asymptomatic, still working, driving, physically active, or does the patient have pain and has lost weight and has fatigue. So that's an important risk factor. So KPS is Karinowski performs code less than 80%. That's a risk factor. The patient who really needs some assistance, not able to do the things that they used to do. And if the diagnosis to initiation of therapy is under one year, that happens if a patient presents with advanced disease and they have the mass in their kidney. Or if they had surgery, as you saw from the slides of Dr. Wood, if they had surgery and the cancer recurred and metastasized shortly after surgery, within a year, that's not good news. That's a risk factor for prognosis. If they have low hemoglobin, anemia. If they have hypercalcemia, that's a high serum calcium in the blood. Or if they have elevated white blood cell count in the blood. Or if they have elevated platelet count. Each one of these six factors is a risk factor that influences survival adversely. And when you look at patients who have none of these, they're represented with the blue curve on top. Those patients survive an average of, you know, three and a half, four years. Those who have one or two of these risk factors that I showed you have an intermediate prognosis and they survive little less than two years when they have metastatic disease and are treated with the agents I'm going to be talking about, the target agents. And unfortunately, those who have three or more of these risk factors, even with the therapies that are available, that are FDA approved, unfortunately, their survival is not good with around eight to nine months. You've seen this slide from Dr. Wood's talk. Since 1992, when only high dose interleukin2 was FDA approved for the treatment of renal cell cancer. Since then, we have had seven agents come to the clinic. The first one was Saurafenib in December 2005. That came 13 years after the FDA approval of high dose IL-2. So it took 13 years before we really had anything effective. But since then, we're lucky that we had several agents, as you see here. A month after Saurafenib was FDA approved, Sunitinib came to the clinic. And then in 2007, Tamsirolums, the MTOR inhibitor, then in 2009, three therapies. And again, I'll go into the details with each one of these. And then about three years ago, Aksitinib was the last one. I anticipate there will be more therapies, more agents, more drugs added to this timeline in the next few years. This is a summary slide of the therapies that are licensed by the FDA for the treatment of metathetic renal cell cancer. So first, in the first column, you have the agent or the regimen, then the mode or the route of administration, IV intravenous or oral. The type of agent, what targets the agent or the therapy is after, and then the indication by the FDA. So Bivacizumab plus interferon alpha. Bivacizumab is IV, interferon alpha is given subcutaneously. It's an old cytokine. They target, Bivacizumab targets the VEGF or vascular endothelial growth factor, and it's indicated for the management of advanced renal cell carcinoma. Ivorulimus is an oral agent. It targets MTOR pathway, and it's indicated for the treatment of patients with metastatic clear cell renal cell carcinoma after they've had other therapies with tyrosine kinase inhibitors, specifically synitinib or soraphanib, but that can be extended to other tyrosine kinase inhibitors. Pazopanib is an oral agent, and again, it is like synitinib. Soraphanib we'll be discussing. It targets vascular endothelial growth factor receptors 1, 2, 3, but other kinases as well, and it's indicated again for the treatment of advanced renal cell carcinoma. Soraphanib targets, again, similar to the other, but it targets RAF, BRAF, that's a different pathway. Again, it's indicated for the treatment of advanced renal cell carcinoma, although the study that I will lead to it in the next few slides, the study that led to this drug being approved was conducted in the salvage setting, in the second line setting, but since it was the first agent that came to the clinic, it was given broad indication for approval. Synitinib, an oral agent, again, it's in the class of the TKIs, tyrosine kinase inhibitors, targets those pathways predominantly here that's relevant in renal cell carcinoma is the VEGF pathway, and it's indicated for the management of patients with advanced renal cell carcinoma. Tamseroloma is IV, mTOR inhibitors similar to everoloma, but this is IV, and it's indicated for patients with advanced renal cell carcinoma. Now, in Europe, the indications are a little different than in the U.S. In Europe, this drug is approved by the European agency only for patients who have poor risk disease as I defined it for you. Synitinib was the last one, and it's an oral agent, tyrosine kinase inhibitor, targets pretty much similar to the other agents, but it is more selective, more potent against the VEGF receptors, and it's indicated for the second line indication or use after failure of one prior therapy. So this is a summary of the first line Phase 3 trials. There were two trials using the Bivacizumab plus interferon, one conducted XUS, and that's called the Avorian trial. It was an industry-sponsored trial, and the control on for the Bivacizumab plus interferon was placebo for Bivacizumab, IV placebo, plus interferon alpha. You see the number of patients, several hundreds. You know, if you look at the summary here, the column to your right, the second one from your right, many hundreds of patients are needed when you do a Phase 3 trials. That's the issue, and this is what the cost as was alluded earlier this morning. And the primary endpoint is in the last column on your right. Then you go down the line, Bivacizumab plus interferon is a study done in the U.S. comparing Bivacizumab plus interferon with interferon alone. Again, several hundred patients, 732 patients to be exact. And the primary endpoint for these two trials was overall survival. Pazopanin was conducted in two cohorts of patients. Those who never had any prior therapy, we call that treatment naive, and those who were treated with a cytokine. What I'm showing you here within Asterix are those patients who are treatment naive, did not have any prior therapy. And that's why you see a smaller number of patients. The primary endpoint was progression-free survival. What does progression-free survival, for those of you who are asking, what does it mean? It means the time from initiate therapy until unfortunately death of the patient or progression of the disease, and you change therapy. So that time is called progression-free survival. And it's considered a surrogate for overall survival which would be a more robust or more relevant, stricter primary endpoint. But it's been FDA approved. The FDA does approve progression, has approved progression-free survival as primary endpoint for a lot of those studies. And then when you go down the list, Sunitinib was compared to interferon in 750 patients. And as you see, most of these trials were conducted one-to-one, meaning one patient randomized to one arm of the trial, one drug, the other patient is randomized to the other. But there were two trials here where the randomization was two-to-one. Pazopanib was the patients were randomized two-to-one, meaning two patients randomized to Pazopanib for one randomized to placebo. Tamsiralamus, this was a free-arm study. Tamsiralamus was compared to interferon as a combination of Tamsiralamus plus interferon. 626 patients it took to do the study. And the primary endpoint was overall survival. And that's the only study among all those trials where the primary endpoint was survival and it was met. And that's why the FDA approved it for advanced ryansoccasinoma. Nativozanib was a phase three trial with a drug that unfortunately didn't make it because of design issues. It did meet the primary endpoint of PFS, progression-free survival. When it was compared to soraphanib, it had a longer PFS than soraphanib. But the second line, survival was not, and there was inferior to soraphanib and therefore the FDA did not approve it and therefore this drug did not make it. Axitinib was compared to soraphanib in the first line, but although numerically the progression-free survival was longer with axitinib compared to soraphanib, it did not meet the pre-specified goal and therefore the FDA did not approve axitinib in the first line, but it approved it in the second line as we'll see here. So this is a summary now of phase three trials. Again, you see the numbers, hundreds of patients required for each one of these trials to complete and reach the endpoint. The first one that was conducted in the salvage setting was the targets trial, that's the acronym for soraphanib versus placebo after cyclokines. 903 patients were treated on that trial and the soraphanib results were better than with placebo in the second line setting with the progression-free survival, double almost with soraphanib and placebo that led to the approval of soraphanib. Every remiss was conducted versus placebo in the record one trial and again, more than 400 patients were treated and it did meet the primary endpoint of PFS versus placebo again, about double the duration, double the PFS time with every remiss compared placebo. Axitinib was compared to soraphanib in the access trial and this was a trial where patients who had either synitinib up front or interferon or high dose IL-2 or temserolomus or bivacizumab plus interferon were allowed to receive axitinib or soraphanib. Primary endpoint was PFS and for the whole group this was met and that led to the approval of axitinib in this setting. Temserolomus was compared as a representative of an mTOR inhibition strategy versus soraphanib after synitinib. So this was a second line study and the study was called intersec. The primary endpoint was PFS. Again, almost more than 500 patients enrolled while numerically the PFS was longer with temserolomus than with soraphanib. What was of concern is the secondary endpoint which was overall survival was inferior in patients who had were treated with temserolomus. 12 months was the median OS with temserolomus versus 16 with soraphanib. That put a cloud over the role of temserolomus as second line therapy after synitinib. Davitinib was recently conducted. This is a trial called the GOLD trial. This drug Davitinib targets BFGF and VEGF. It was felt that targeting a different pathway could circumvent the resistance that patients developed with treatment with VEGF inhibitors. Unfortunately, the trial was negative even though it was again more than 500 patients treated. The PFS was almost identical with Davitinib and its control arm, the soraphanib. The survival median average was 11 months as third line therapy. This was a trial that was conducted after patients had at least one tyrosine kinase inhibitor and one amtor inhibitor. So, what about combinations of these target agents? I heard the question asked this morning if one drug is good and another one is good. Can we combine and do better? And as Dr. Wood mentioned, unfortunately, these studies were done including one of our own we published last year combining synitinib plus TEMserolimus. We thought this agent targets the VEGF pathway, the angiogenesis, the other one, the amtor, why not combine these two and do better? Again, more toxicity, that's what we observed and unfortunately the results with the combinations were not better than single agents alone given sequentially. So, what about sequential therapies? There are several trials that have looked at and some are ongoing including our own. I'll discuss in a minute. This is a trial that was conducted in Germany called the switch trial looking at the sequence of synitinib followed by soraphinib, two TKIs versus soraphinib followed by synitinib. The results were better for synitinib in the first line compared to soraphinib in the first line but when you look at the overall picture there is not much difference. This is a trial that was run by Novartis looking at everolimus followed by synitinib versus the standard of care synitinib followed by everolimus and the results in almost 500 patients were in favor of synitinib as first line, had a longer PFS and the survival of the sequence of synitinib followed by everolimus was better than the survival of everolimus followed by synitinib. This is the start trial, a trial that we've been conducting here at MD Anderson looking at three different ages targeting three different pathways. Bivacizumab is an antibody against VGF A and pasaphinib is the tyrosine kinase inhibitor as we discussed targeting VGF receptors and everolimus deemptor inhibitor. So patients who have had their kidneys removed will enroll on this trial and they get one of those six sequences either bivacizumab followed by everolimus bivacizumab followed by pasaphinib pasaphinib followed by bivacizumab pasaphinib followed by everolimus everolimus followed by bivacizumab or everolimus followed by pasaphinib. So the goal here is not to just look at the first line which we will do and the second line but also the goal is to look at what happens from when they get enrolled on the trial and they receive two sequential therapies in the same trial. What happens? What's the long-term outcome? Can we predict who are the patients who respond to bivacizumab versus pasaphinib or everolimus? What kind of toxicities do we see when we sequence these drugs back to back in the same patient? We're learning a lot from this trial. We have tissue collected from the kidneys that the patients we removed in the patients and we have blood collected at different time points. So this is a trial that's rich with information and we hope to have the results soon. Another trial we're conducting in that poor risk category of the patients that I told you the survival is unfortunately even with therapy eight or nine months. We're looking at the drug that's now considered first line therapy for the space with poor risk disease, Tamserarmus, and we're looking at the tyrosine kinase inhibitor, pasaphinib, to see if there will be some patients who will respond to pasaphinib better than they will respond to Tamserarmus. So how do I treat my patients with metastatic renaissance calcinoma in 2015? What are the indications? What setting? What disease type? And here is a summary this is similar to the slide you saw with Dr. Wood. In the first line setting if a patient is previously untreated they come to us. As I said at the beginning you need to look at histology we need to discuss with the pathologist the type of tumor the patient has. Is it a clear cell? Is it some of these rare non-clear cells? That's important. And then you look also at the prognostic factors remember the things we talked about perform status, anemia, high calcium, etc. So if they have good or intermediate risk I think the data that I showed you those phase three trials that I summarized for you in the table synitinib or pasaphinib I consider are the two first line therapies that now are actually synitinib has been on the market a little over nine years pasaphinib five years but these are the two front runners that patients are being treated with in the community as well as academic centers. Now, bivacizumab plus interferon alpha from the two phase three trials that I showed you still has good data but in my opinion this combination is using an IV drug every two weeks plus an injection a parenteral and injectable drug interferon that has a lot of side effects even if it's given at low dose and it's given every other day so three times per week it's not practical it's cost is an issue and in my experience after three or four years if they respond to this a lot of those patients are dropping out from treatment because the bivacizumab after a few years patients develop nephrotic syndrome so in my opinion a tyrosine kinase inhibitor in the first line setting will be the front runner should be the off protocol if the patient is not being considered for a clinical trial should be treated with I put alternative high dose R2 this is a therapy that's been around for 30 years we are celebrating the 30th anniversary of high dose R2 since in 1985 it was first declared to be an effective therapy in melanoma and riansoccasinoma but it's really reserved for a select few patients who are really candidates for it not every hospital has that therapy or has the experience so it is reserved for a few patients poor risk we talked about Tamserolomus but I think you can also we can also from the phase three trial there were some patients treated with poor risk with synitinib so as an alternative it is an option for patients who had prior cytokines high dose R2 or interferon axitinib, soraphanib, or pazopanib have data from phase three but in my opinion it is axitinib or pazopanib but mostly axitinib why? because the data with soraphanib was inferior to the compared to axitinib in the access trial I showed you that axitinib was better than soraphanib in the access trial in the second line setting and it produced double the PFS compared to soraphanib so although there is phase three data the first trial that was conducted I think now soraphanib is basically rarely used in the clinic these days unless it's a clinical trial now if a patient had prior VGF like a synitinib or pazopanib what options do we have? I think the two trials everolimus from the record one and axitinib are there there is a debate that's ongoing and will probably continue for a while is it better to use axitinib or everolimus? I think there is emerging data to suggest that TKI followed by TKI probably is better than TKI followed by an mTOR inhibitor but I think this debate is going to be changing quickly as now we have emerging effective therapies with the immune checkpoints so I think this whole field here this is how we are talking about it today off protocol in the community what things we can do but really this is going to change tremendously as we have new drugs coming to the clinic as well as the exciting promising immune checkpoints but let me just say that in my opinion even with the immune checkpoint inhibitors coming and this will be the talk of Dr. Gao there will be a lot of patients who will not respond who do not respond to immune checkpoints but respond to target therapies and likewise there will be patients who do not respond to target therapies but will respond to the immune checkpoints so by no means I do not believe that these drugs are going to be put by the wayside or going to be footnote in the history at least not in the next few years so there will be a role for these agents still to be played in the treatment of our patients what about non-clear cell briefly non-clear cell is a rare a group of diverse entities but just in the interest of time to just let you know we did a the only trial that's presented that's randomized looking at an mTOR inhibitor and synitinib and this is the design we took patients with different histologies papillary, chromophobic unclassified or translocation we randomized them to an mTOR inhibitor evrolimus or synitinib and the results were disappointing in that the response rate with evrolimus in the first line was 2.8% and 6% with synitinib although numerically the results were better PFS and OS with synitinib the results were not statistically significant so what does that leave us I think in a non-clear cell the patients who have papillary, chromophobic et cetera these two drugs have very modest activity although there are trends with longer PFS if you give synitinib in the first line and longer OS those results did not reach significance there are higher grade of toxicities with synitinib chromophobic usually does better with these two agents our message is patients who have papillary, chromophobic et cetera should be enrolled on a clinical trial because there is no established effective therapy in our minds right now for this diverse group of rare tumors what about the new agents Dr. Yonash will discuss that but there is a trial that completed accrual 650 patients last November we awake the results this is a phase 3 trial looking at a met inhibitor which is also inhibitor of axel and VHF receptors versus a varolimus after patients had already progressed on tyrosine kinase inhibitor the primary endpoint as you saw with the majority of these trials is progression free survival so the results of this trial are awaited with earnest there is a theme that has emerged over the last 10 years treating patients with tyrosine kinase inhibitors targeting the VHF pathway can we predict which patients respond and this is a major focus of our research about predictive markers of response so there are some clinical criteria or clinical factors that help us predict which patients respond to these therapies for VHF receptor inhibitors hypertension, hypothyroidism hand foot skin reaction and fatigue have been found to be it's a double H sword patients develop these side effects but that's an indication that the drug is working or will work I want to finish the talk with two exceptional responses to just give you hope that there is a role for target therapy and I think that role will maintain, will remain this is a lady this is a gentleman who presented 9 years ago with a mass in his left kidney, he had anemia we were going to enroll him on one of the pre-surgical protocols we had with the biopsy of his left kidney mass, he had clear sarian sarcosinoma, he had anemia high LDH and he was treated initially with Surafin, that was remembered the first drug that was FDA approved, unfortunately he had rapidly progressive disease and developed bone metastasis and progression of his disease and liver and lungs and we changed the treatment and here are his scans after a few months of therapy we could see that without even treating his brain metastasis which were small but we did not give him any radiation or anything to the brain, the brain metastasis cleared up, the lung metastasis cleared up, the mass in the kidney shrank you could see it and then here are more of the pictures looking at the lungs, the chest the liver and the bone how it's healing the brain metastasis went away and after 5 and a half years of Sunitinib we decided he's in complete remission, why don't we take the kidney out, although it would have been people would have thought we're crazy if we did it up front rightly so, so we he developed also hypertension so we stopped the drug and after we controlled his blood pressure the patient had laparoscopic left reticine refractive but Hosecarum and long and behold there was no viable tumor in the kidney so this patient not only achieved a complete clinical response but achieved a pathological response we were so excited we published this paper just a few months ago he's off therapy now for more than 3 years, not receiving anything, so this is a patient who came with cancer in every organ, bone, lung liver, brain and he's alive without disease 9 years later more than 3 years without taking any systemic therapy this is the other patient I would like to mention who presented with abdominal pain and was found to have a big mass in her left kidney and work up showed a 15 centimeter, this is a huge mass in the left kidney that was touching a buttock the spleen and distal pancreas had enlarged lymph nodes but did not have metastasis to the lungs, bone, liver, like the other gentleman but she was anemic, she had high sodium LDH, so again these are criteria as Dr. Wood was mentioning you know, people are different this, the biopsy of this mass was chromophobic, this is one of those rare non-clear cells I talked about Dr. Wood operated on her she had a left reticin nephrectomy and splenectomy she had chromophobic RCC but worse than that she had 30 and 40 percent sarcomatoid de-differentiation, this is a very aggressive tumor and I tell the patients when they have, unfortunately, sarcoma under tumor, this is like turbo charge it's like fuel added to the fire, unfortunately a little over a year after she had her surgery she had disease in her lungs and she developed metastasis in the left supraclavicular area which was biopsid and confirmed the metastasis so she was enrolled on the ESPN trial that I showed you that I discussed with you she got first line therapy with synitinib she had a good response partial response for about several months but unfortunately had progressive disease with metastasis in a new area in the left external iliac lymph nodes which were biopsid and confirmed so she was crossed over that's after they received the first line we tried the second line in the same trial she was switched to the evoribus and she has achieved a good partial response now continues to respond for over two years close to three years without significant toxicity and you can see on the scans her lymph node now this is what we come to now this is where research is going why these two patients had such a dramatic response and others unfortunately didn't everybody wants if they're patients or they have loved ones or are patients want to have a scenario like these two patients so what's different about these patients so this is what I believe the next phase is the promise of genomic medicine for precision medicine or personalized care we harvest these tumors we take blood from them before treatment after treatment to try to understand why these two patients respond in others so that's the exceptional responders protocol we have in the trials as I said and we are doing this research to try to predict biomarkers of response we are analyzing tissue from these tumors as well as metastasis using next generation sequencing and SNP arrays on fresh frozen tissue from the operating room directly when we freeze it if we have available fresh frozen tissue or formally fixed paraffin embedded tissue at the extremes on the spectrum those are rapid progresses unfortunately don't respond to anything and unfortunately don't survive past one year and those are like these two patients surviving many years we also are checking blood as Dr. Wood mentioned to look at circulating biomarkers, micro RNA cell free tumor DNA and calf cytokines and genic factors to try to understand who are the patients who respond to this drug or the other in the start trial I discussed with you that's the venue where we think we can learn a lot from taken blood and testing for these biomarkers and response to this agent or the other or the other so in conclusions as of today we have seven target agents approved improvement in progression free survival has been shown with all agents but improvement in us with temporary elements complete response and durable CRS for five plus years are rare as I showed you I think it's imperative that early and active management of adverse events will minimize those delays those reductions and treatment discontinuations and may impact long term benefit adverse events may be predictive biomarkers of therapeutic benefit as I mentioned sequential monotherapy is the standard of care in 2015 but this field may be changing rapidly the optimal sequence is still yet to be determined and as I mentioned so far there is no established systemic therapy for advanced non-clear cell RCC and only through insights into the biology of RCC that we will be able to identify relevant targets and move the outcome I believe there is still a role for old immunotherapy Hadozal too but I see that role diminishing as we have the new kid on the block the immune checkpoint inhibitors coming and we are participating in these trials with immune checkpoints targeting PD1 and PDL1 and CTLF4 and I believe this is the next emerging strategy that will produce, that will break the cure barrier for many patients I would like to finish with my acknowledgments here okay so I would like to thank you sincerely for coming today I think thank you for trust, thank you for allowing us to enroll your loved ones and yourselves if your patients on our clinical trials you inspire us every day and remind us of the urgency of our research to make kidney cancer history thank you very much to do more sequencing repeat the question so the question is are patients with metastatic kidney cancer come to MD Anderson do they have blood drawn to test for the things I mentioned about and the answer is yes we do have a collaboration with Dr. Shefeng Wu and she is in the cancer prevention population science department where blood is collected on these patients in our department as well as in her departments to look at risk factors because I think that's what you're aiming with your question why do patients develop kidney cancer to begin with so I think this is the thrust of her research and we're collaborating with her but we also are collecting in clinical trials blood on these patients so we can study as I said the effect of therapies why some patients respond to this drug why others respond to a different drug so yes it is done in patients who are who agree to give blood not every single patient but I think the vast majority of the patients have given blood have consented to these front door protocols lab protocols some are within the context of clinical trials therapeutic trials but even others as I mentioned we've actually published many manuscripts on the risk factors from blood collected from patients yes ma'am right now what is more important and is used to determine which patient goes to trial is more biopsy the pathology it's not the blood but it's more the tissue obtained either from the nephrectomy at the time of surgery or a biopsy and I didn't have for the interest of time didn't speak about what we're doing so you have all these therapies that are patients receive them and they have progressive disease where do we go next instead of just taking a drug off the shelf and give it to the patient we're looking at their genomic profile the gene mutations and other things to determine if we find something in that tumor that's unique about that tumor then we can advise the patient to go on a trial that's biomarker based it's based on the genomic characterization or the gene mutation from that tumor so yes there is that's the effort now of phase 1 department at MD Anderson rather than just taking empirically a drug here and drug there and give them what is available at that time rather than that it's more precise more based on the biopsy result what mutations and what genes and do we have a drug for that so it's called actionable gene and target therapy towards that actionable gene now often we do a biopsy or the nephrectomy even and we don't have anything that we can target that we can go after with a specific treatment but I think this is better than the old ways how we used to do it in the days of old where just take a drug and give and we don't find any benefit yes of course yes it's no longer we're beyond just taking a biopsy to say okay you got kidney cancer and it's chromophobic or papillary or clearsaw we're now interested in the molecular you know diagnosis we're interested to know what genes are mutated what kind of particular tumor we can go after with one of these smart drugs any other questions happy to take questions later on if you want after the so to stay on time we can