 So again, I'd like to thank you all for coming. This is truly a labor of love for us we've been doing this for many many years and Have mixed the format of the conference up several times And so I'd urge you to provide feedback and let us know how we're doing. We initially had it was all straight lectures And then we moved to all straight cases and so this time we're trying to mix it up a bit I would really urge you to try and stay through lunch for the case presentations in the afternoon Where I put my colleague's feet to the fire and get them to really tell us what they're thinking how they're thinking and How they make decisions regarding patient care My topic is I've mixed it up just a little bit because I thought that management of locally Advanced kidney cancer is a little bit dry just talking about whether or not to do an lymph node dissection or Management IVC thrombus, and I think this topic is a bit more relevant to the people in the room And that is the role of adjuvant neo adjuvant therapy and the management of patients with locally advanced kidney cancer It's not an uncommon question. Actually, it's a very common question for patients to ask and their families to ask After surgery am I going to need chemotherapy? Am I going to need radiation? And it's also not uncommon to have patients when they recur as in the Jose's talk say well Why didn't you give me any chemotherapy? Why didn't you do radiation? So I thought I'd explain the rationale for that in this talk so The therapy for kidney cancer has changed dramatically over the last say 10 years and In fact, if we were having this conference back in 2006, we wouldn't have a whole lot to talk about Basically, I could show this slide and we could all go home Basically the management of stage 1 through 3 kidney cancer was treated with nephrectomy rarely partial nephrectomy And if you had stage 4 metastatic disease, it was nephrectomy followed by systemic therapy usually Immunotherapy which was largely ineffective and most patients died in a year But it's a new world in the treatment of kidney cancer now We have a whole host of different therapies to offer patients None of them are home runs But many of them are base hits and the question is do any of these therapies have a role in the treatment of patients with locally advanced disease Well, adjuvant therapy has been a passion of mine and a passion of many For the last decade or more so adjuvant therapy just to be clear means Do surgery and then give some kind of therapy to decrease the risk of recurrence as Opposed to neo adjuvant therapy, which means give some form of therapy then do surgery to decrease the risk of recurrence So a whole host of different agents have been used in the setting of adjuvant therapy for the treatment of patients with kidney cancer including radiation embolization of the tumor energy ablation a variety of different hormonal therapies Immunotherapy has been used including interferon as well as interleukin 2 a Whole host of different vaccine preparations as well as even the drug thalidomide and to date not one of those therapies Has been proven to be effective in the adjuvant setting to decrease the risk of recurrence and not only that in Many cases many of these trials the patients that receive the adjuvant therapy did worse than the patients who were just observed So what about targeted therapy? Is there a role for targeted therapy in the adjuvant setting? Well, there've been a host of different trials that are either been been been conducted or currently ongoing Looking at the role of a variety of different targeted agents in the adjuvant setting This is one such trial called the a riser trial We're a monoclonal antibody against a kidney cancer associated antigen called g250 or ca9 was used Patients were randomized to receive placebo versus this antibody Over a year's time and then looked for evidence of recurrence Just a side note this agent is also being explored as a kidney cancer specific PET scan where patients are given this antibody linked to a radioactive item molecule and Then undergo PET imaging to look at both the primary tumor as well as to look for a cult evidence of metastatic disease And if you want to know the honest truth, I think that is really where this agent holds the most promise But with regards to its use in the adjuvant setting as an adjuvant agent to decrease the risk of recurrence the trial Demonstrated no evidence of any benefit The assure trial is to date the largest trial done in the adjuvant setting where patients were randomized To receive one year of synitinib or suitent versus one year of seraphimib or nexivar versus one year placebo This trial recently was reported at G us go approximately a month ago One of the things that we've learned about giving drugs in the adjuvant setting is that toxicity really is key With regards to whether or not the agent is going to be accepted If I tell you that if you don't take this drug, you're gonna die You'll pretty much do whatever I tell you and tolerate the toxicity and everything else But if I tell you that your risk of recurrence is 20% and I wanted to give you this drug That's gonna make you feel miserable for a year and it may or may not work All of a sudden 20% doesn't sound so bad And that's the problem in the adjuvant setting what we learned from the assure trial is that Toxicity is not well tolerated in the adjuvant setting and in fact if you look at the statistics Almost half of the patients stopped drug early not because their cancer occurred But because of toxicity and in fact at MD Anderson 23% of the patients that we put on this trial and we were the major accruer to this trial Stop therapy early because of toxicity And this trial just read out as I said and it was reported at G you ask oh and unfortunately again There was no Demonstration of benefit for those patients who receive one year of synodinib or one year of seraphim versus those that receive placebo And in fact the patient patients that receive placebo Did better than the patients that got the adjuvant therapy. This is the s-track trial This is a trial that was sponsored by Pfizer It has accrued patients that were currently waiting to read out But again it demonstrates our randomization between synodinib versus placebo of all the different adjuvant trials that have been performed From my perspective, this is going to be the really true test of whether or not targeted therapy works in the adjuvant setting They had a very low dropout rate in this in this trial patients seem to tolerate the toxicity much better So we are anxiously awaiting the readout of this trial to see whether or not there is a role for targeted therapy in The adjuvant setting, but to date it doesn't seem that there is one This is the source trial that was largely done in the UK Where patients were randomized to three years of seraphim versus one year of seraphim versus placebo This trial was very difficult to accrue to it was very difficult to maintain patients on because even in the metastatic setting Trying to keep patients on seraphim for three years is virtually impossible because of toxicity they're currently awaiting the Evidence of recurrence in patients before reporting this out But all evidence would suggest that this too is also going to be a negative trial unfortunately We recently completed the Pesopinib new adjuvant trial this was Sponsored by GSK where patients were randomized to one year of Pesopinib versus one year of placebo They've accrued patients and currently are awaiting recurrences before reporting out This will probably report out in the next one to two years So what's ongoing will currently ongoing is the so-called everest trial this report this randomizes patients to one year placebo versus one year of everolimus This is currently accruing patients all histologies are included not just clear-cell But again, there's no reason to anticipate that this is going to be different from the other trials that have been reported out And then finally the atlas trial This is again ongoing where patients are randomized to three years of exsitinib Which is one of the newer targeted agents versus placebo Patients are treated for three years with follow-up. This is currently accruing patients and again We'll wait and see but I have no reason to hope that this is going to be any different than any of the other Targeted therapy trials in the adjuvant setting which were largely negative So when patients ask am I going to need chemotherapy am I going to need radiation therapy the standard of care in 2015 for patients with locally advanced or localized renal cell cancer is Observation we do not know of a single agent that decreases the risk of recurrence at the present time So here's a case. This is a 55 year old white male who presents with gross hematuria He has some hypertension some hyperlipidemia never had surgery. He had a bone scan, which is negative He had a CT scan, which is negative CT of the chest and you could see here. He's got a locally advanced tumor Involving his right kidney or sorry left kidney It's here locally advanced tumor involving his left kidney very large tumor And we know that stage really is probably the most important determinant of outcome in patients with kidney cancer And I can tell you going back That we would classify this clinically a stage 3 the tumors involving the renal sinus It clearly extends outside of the kidney. So that makes this a clinical stage 3 if not stage 4 So according to this this man's risk of recurrence is 40 percent So he has a 40 percent chance of having his cancer recur usually within two years of his surgery So what are his options? Well the standard of care I would argue is radical nephrectomy followed by risk-based surveillance It's the standard of care his risk of recurrence is going to be somewhere between 40 and 60 percent and If he does recur despite the data that dr. Quran presented, it's not likely that he'll be curable at time of recurrence Another option is radical nephrectomy followed by adjuvant therapy as I just got done saying the atlas in the Everest trial They're currently ongoing. He could go to some institution to get enrolled But he'd have a 50 percent chance of getting a sugar pill He'd have a greater than 50 percent chance of either reducing or stopping therapy early due to toxicity And quite honestly the real challenge in the adjuvant setting is how do we really assess efficacy? If I give you this pill for a year and it makes you feel like crap, but your cancer doesn't come back Is it because the pill worked or is it because you never had cancer in the first place? And didn't really need the pill. That's the challenge in the adjuvant setting of assessing efficacy Well, what about neo-adjuvant therapy? Why should we consider neo-adjuvant therapy as a treatment option? Well preoperative systemic therapy may eliminate micrometastatic disease and improve prognosis The therapy may downstage or downsize the tumor which may make surgery easier It may allow us to do nephron sparing saving kidneys is always a good thing And it may also allow us to use minimally invasive approaches as opposed to a large incision We can also use neo-adjuvant therapy to look at the evidence of response to therapy Which may allow us to better select therapy in the future if the patient recurs Why not use neo-adjuvant therapy? Well It's quite possible that your tumor may not respond to that therapy and it may progress locally or regionally Or even metastatically While on therapy and we may lose the opportunity for cure that window of opportunity But I would argue that if your tumor grows through the best therapy that we have Then you're probably not curable to begin with And it's also possible that the toxicity of therapy may increase the morbidity of the surgery Meaning it may make the surgery more difficult The patient may be deconditioned and not tolerate the surgery as well. Those are all concerns in the neo-adjuvant setting. I Remember and I'll show you data from one of our neo-adjuvant trials But I remember a patient who participated in one of our neo-adjuvant trials and I noted that the pre-operative visit He was just pacing around the room and I'm like sit down so you can sign the consent And he had such GI toxicity that he actually couldn't sit in the chair So how can we assess whether or not neo-adjuvant therapy is of benefit? Well, just to give you a little historical perspective Partial nephrectomy saving kidneys is really a very new concept in the treatment of kidney cancer and in fact in the old days Five ten years ago radical nephrectomy was the standard of care for virtually everyone that presented with a renal mess So for nephron sparing or partial nephrectomy to be accepted It had to show oncologic equipoise meaning it had to be equivalent with regards to cancer control to radical nephrectomy Obviously the benefit of nephron sparing speaks for itself And now we're even doing these cases minimally invasively and with a robot So I would argue that neo-adjuvant therapy has several hurdles to jump before it too can be accepted It has to be safe It has to show a lack of disease progression has to make sure that we don't increase surgical morbidity It has to improve patient outcomes with regards to disease-free survival and cancer-specific survival And you know if it results in primary tumor down staging or downsizing all the better Although I would argue this is probably the least important hurdle because it's the rare patient that presents with a tumor That's not surgically receptable So let's go through these and see where we stand. So is neo is neo-adjuvant therapy safe? So I show you this to remind myself of the potential problems associated with neo-adjuvant therapy So the way that targeted therapy works. It's called anti-angiogenic therapy And what that means is that it inhibits blood vessel formation. Hopefully specifically in tumors The problem is that every time a wound heals It has to have new blood vessel formation to deliver all the things that are necessary for the tissues to heal So this was a patient that took neo-adjuvant sunitinib and then was started on therapy about two weeks after surgery He was in a low-speed motor vehicle accident and he had complete dehiscence of his abdominal wound so this is his greater momentum sitting on his abdominal wall and This is another patient who took neo-adjuvant Bevacizumab which is an antibody against vegf and then postoperatively she was started back on it about eight weeks out Three months out. She coughed heard something rip and she had small bowel This is her small bowel peristalsin on her abdominal wall So there are real potential problems associated with the neo-adjuvant approach and therefore it needs to be studied very carefully Well, we did a retrospective review Looking at patients who had metastatic disease 70 of these patients received neo-adjuvant or pre-surgical therapy meaning they got the therapy before surgery and We compared them to 103 patients who had up-front cytoreductive nephrectomy, which will be the topic of my next talk And we looked at complications So what we found was that the patients who received pre-surgical therapy did not have an increased rate of Complications relative to those patients who were treated with up-front surgery However What we did note was that the group that received neo-adjuvant therapy were more likely to have delayed complications later than 90 days They were more likely to have more than one complication and Specifically, they were more likely to have wound complications relative to the group that received up-front cytoreductive nephrectomy and this included superficial wound complications as well as major wound complications such as fascial dehiscence and In fact, the only factor that predicted for patients to have wound complications were those patients who received pre-surgical targeted therapy But again to stress it The overall Complication rate between the group that received up-front surgery versus the group that had neo-adjuvant or pre-surgical therapy was no different So the patients who received pre-surgical therapy did not have more complications But they had different complications specifically wound complications relative to the group of patients who had up-front surgery So then we asked the question okay if patients who receive pre-surgical therapy are more likely to have wound complications Is there anything that we can look at that might predict those patients that are gonna have wound complications? Because we can do things at the time of surgery To reinforce the wound we can put in stronger stitches. We can put in wire We can leave the staples in longer all sorts of things we can do to help the wound heal What we found was that those patients who had a decline in their serum albumin, which is a protein that all of us have in our serum Those patients were more likely to have a wound complication relative to patients who did not have a decline in that serum albumin albumin So moving forward We can use this assay to better predict those patients who are more likely to have a wound complication and Do things at the time of surgery and after surgery to reinforce the wound and prevent that from happening With regards to overall survival what we noted was that those patients who received pre-surgical therapy Their survival was no different from the patients who had upfront surgery So what it tells us is that we may not be helping patients with this benefit with this approach But we're not hurting them with this approach either One of the real scary parts of neoadjuvant therapy is depicted in this study that was published in cancer cell So what these investigators did was they took mice and they gave them a short course of Therapy and in some of those mice they were bearing tumors others They did not have tumors, but then they injected tumor after they got that short course of therapy So that effectively they gave these mice neoadjuvant therapy and then they said what happens? And what they noted was that the mice that received the neoadjuvant therapy had a worse survival Their tumors were more aggressive and grew faster and they were more likely to be metastatic Now to be candid this was a very poorly done study. It's amazing that it actually got into cancer cell, which is a very good journal But it does give one pause with regards to you know, could this happen in the human experience So I want to show you a case This is a patient of mine Who presented with bilateral kidney tumors, so you can see he's got a large tumor Involving his left kidney this over here. This is just a cyst, but you can see again large tumor involving the left kidney and A very large tumor involving the right kidney Now these could be treated with partial nephrectomy, but they would be very difficult partial nephrectomy And there's a very high likelihood of losing both kidneys as a consequence of surgery So we enrolled him in our neoadjuvant ex-signal trial, which I'll report to you in just a few minutes So he took the therapy for 12 weeks and added he had a great response You can see that his left-sided tumor shrank significantly much easier partial nephrectomy And his right tumor shrank significantly You can see that you don't have to be a radiologist to say that this tumor is bigger than this tumor So he had a very dramatic response Now the problem is that we don't usually operate on both kidneys at the same time We typically will take the patient for staged partial nephrectomy. We'll do one side first Let them recover And do the other side the reason for that is that there's a higher incidence of renal shutdown and Dialysis if you operate on both kidneys at the same time So we took the patient for a left partial nephrectomy and let him recover brought him back six to eight weeks later And we said let's get a CAT scan just to be sure that there's nothing dramatically different And this was the CAT scan Not only did his right-sided tumor grow back It was actually bigger than it was when we started and the reason for that is so-called VEGF rebound When you use targeted agents they block receptors on the blood vessels to the tumor so you are effectively strangling the tumor So if I went out in the audience and started to strangle one of you guys, what would you do you'd fight back? So that's what the tumor does by increasing the amount of VEGF that it releases trying to attract new blood vessels So all of a sudden you have these elevated levels of VEGF in the system And you stop the drug therapy because the patient's having surgery and you need to let the wound heal That's called VEGF rebound and that's one of the one of the real concerns with regards to neo-adjuvant approaches So what about primary tumor downstaging or downsizing classically in the area of immunotherapy we're taught The patients who have their primary tumor in place that are given immunotherapy the tumor rarely if ever responds Which is one of the reasons that we do cite a reductive nephrectomy as I'll get to in my next talk Well The commission clinicians in the audience have all seen responses like this This is actually a patient of dr. Matines Who had a very large locally advanced tumor involving the left kidney as well as bulky lymph adenopathy? They went on to receive Sunitinib and you can see you don't have to be a radiologist to realize that this patient had a dramatic response So he went from having bulky disease that would have required a very difficult large surgery He was able to actually undergo a laparoscopic nephrectomy as a consequence of his response So the question is are these just anecdotes or can we rely on these agents to reliably downstage tumors? Because if we can I would argue we should do this for everybody my increase the incidence of nephron sparing and so forth What well, what's the data? This is one of the first studies that was published looking at 17 patients treated with Sunitinib with their primary tumor in place Overall response rate in the primary tumor was only 23 percent Although those patients that did respond had a very respectable response of about 31 percent These are data from Cleveland Clinic where patients were treated with their primary tumor in place with Sunitinib and You could see that the overwhelming majority of patients had little to no response in their primary tumor In fact half the patients their tumor actually grew while they were receiving the systemic therapy These are data from our bevacizumab trial that was conducted here at MD Anderson again a very similar story Virtually half the patients or more had little to no Evidence of response and in fact some patients progressed while on therapy These are these are data from the University of North Carolina where patients were treated with pre-surgical seraphim And although there were some major responses There were also evidence of patients who had progression on therapy and the vast majority have little to no response And just to give you an idea a 10% response here That's going from 10 centimeters to 9 centimeters Sounds impressive, but clinically really doesn't mean much of anything So we did a larger study. We looked at 168 patients who were treated with their primary tumor in place You can see there the statistics for the patients here And their reason for being treated with their primary tumor in place as opposed to undergoing nephrectomy Many of them had widespread metastatic disease and were not surgical candidates Some of them were enrolled in clinical trials and a variety of other different reasons are listed here And we asked the question does the primary tumor respond to systemic therapy? These are the systemic therapies that the patients received all of these are targeted agents the vast majority of them receive Sutent or synitin it and Unfortunately a very similar story There were some dramatic Evidence of progression there was some dramatic evidence of regression But the vast majority of patients had little to no response in their primary tumor despite receiving systemic neoadjuvant therapy One of the other scenarios that we frequently are confronted with is the patient who presents with an IVC thrombus And it's not uncommon even today in the community for the urologist that sees the patient to start them on targeted agents saying Here this will shrink your thrombus go to MD Anderson and wood will take it out So we looked at the patients that had an evidence of an IVC thrombus in our series and asked that very question Does targeted therapy shrink the thrombus and the answer unfortunately is no 75% of patients had no change in their thrombus 15% of patients actually had growth of their thrombus despite therapy and very few showed any evidence of thrombus regression So I would argue that the initial body of evidence would suggest That primary tumor down staging is not going to be realized with the current generation of targeted agents So here's the report card is it safe? Well despite the increased risk of wound complications, I would argue that neoadjuvant therapy is safe Does it reliably downsize or downstage tumors? I would argue no it does not there's no real evidence that it does So is this something that we should continue to pursue? Is this worthy of further study? I would argue yes it is for the following reasons In our Bevacizumab trial 50 patients were enrolled in the trial, but only 42 patients actually under one surgery and in fact six patients had disease progression and I would argue that using this as a litmus test to select patients allowed us to spare these six patients a Very morbid surgery that they clearly were not going to benefit from We then asked the question maybe we can use primary tumor response as a surrogate of outcome meaning Maybe it's the patients that are responding that are going to be more likely to do better to live longer and To tolerate the surgery better What we noted was that the vast majority of patients if they were going to have a response This is a spider diagram demonstrating the evidence of response over time If they were going to have a response, they were going to have it early It was going to happen in the first 60 days and if it didn't happen in the first 60 days Time to move on therapy is not going to work And what we also noted was that those patients who had a greater than 10% response in their primary tumor in the first 60 days were more likely to have a very dramatic response as opposed to those patients who did not have a 10% response in the first 60 days So then we asked the question can we use this response in the primary tumor as a predictor of outcome? So we looked at 75 patients who were treated with synitinib. They all had metastatic disease But were treated with their primary tumor in place and asked the question. Can we use response as a predictor of survival? And in our univariate analysis what we noted was that those patients who had a greater than 10% response in their primary tumor Particularly if it was within 60 days of starting therapy Those patients were much more likely to do better and survive longer than those patients that did not and in fact in the multivariate analysis Having a greater percent greater than 10% response in the primary tumor within 60 days Was an independent predictor of outcome So for the first time we can use response to systemic therapy and kidney cancer as a predictor of survival in patients with metastatic disease And in fact many of you are familiar with the so-called Sloan Kettering or memorial criteria that are used to segregate patients into good versus intermediate versus poor risk Response in the primary tumor does it better than the Sloan Kettering criteria with regards to predicting outcome And in fact our data were corroborated by a group from the Netherlands This is Axel Bex who also demonstrated that patients who had a greater than 10% response in their primary tumor Were much more likely to survive longer and do better than those patients who had less than 10% response I'm just glad that he found this out later than we did because we were able to publish our study in a much better journal than he did So I want to finish by talking about our recent recently published neo-adjuvant trial This was done by Jose Karaman myself Here at MD Anderson. It's one of the first of its kind first studies of its kind It was sponsored by Pfizer Where we took patients not with metastatic disease, but with locally advanced disease and Treated them with neo-adjuvant therapy prior to surgery now. I want to give you an idea of how this first Discussion went with the first patient Patient comes in has locally advanced disease and I have to convince him to be on this neo-adjuvant trial Patients sitting there and I say look we could take it a surgery tomorrow. We could cure you or I Could give you this therapy It's gonna make you feel like crap. I have no idea whether it works or not In fact, not only may it not work your tumor may progress while you're taking this therapy What do you say? You can imagine how those discussions went and I applaud the first patient that actually signed on for this therapy Once we were able to demonstrate that he showed evidence of response It was much easier to sign up other people subsequently and we had a total of 24 patients that were put in this trial They received neo-adjuvant exit and 5 milligrams The dose was titrated up to 10 milligrams and then after 12 weeks. They were taken for surgery We continued therapy up until 36 hours prior to surgery. We had an independent radiologist review all the scans So these are the criteria the patients the average age was 60 Most of the patients were male as is the case with patients with kidney cancer and all these patients had at least clinical stage 3 disease All of them underwent a biopsy to demonstrate. They had clear cell kidney cancer 22 patients were able to continue the therapy for the full 12 weeks one patient stopped therapy early because of toxicity All 23 patients underwent surgery is planned without delay One patient had to stop after seven weeks because of toxicity and he was counted as a failure because he was not able to take it the entire 12 weeks What we were able to demonstrate So there's something called resist criteria, which is what we use to monitor and measure response to systemic therapy in the metastatic setting and a partial response It means that the patient had at least a 30% reduction in the tumor that you're following as a consequence of therapy And in our study almost half of the patients had a greater than 30% reduction in their tumor volume as a consequence of systemic therapy And more importantly no one demonstrated evidence of disease progression while they were taking the neoadjuvant exit So here's again another spider diagram showing the response You can see again that the vast majority of patients had their primary response within the first seven weeks And if I had to do this trial over again, I would not make patients take therapy for 12 weeks I think it just increases the toxicity, but doesn't increase the benefit. I'd probably stop it like seven or eight weeks And again, you can see that response rates here the vast here Here are the patients who had at least a partial response greater than 30% reduction One patient had a very dramatic response almost a 50% reduction in tumor size so These are the surgical data 19 of the patients still underwent radical nephrectomy five patients were under able to undergo a partial 19 had open surgery five had loproscopic You can see that the operative time was relatively short The blood loss was relatively acceptable and these are the final stages pathologic stages that the patients demonstrated The therapy was fairly well tolerated although there were toxicity and I tell patients if you're not going to be tolerant of toxicity Then we shouldn't waste each other's time because you will have toxicity associated with this therapy The most common toxicities were hypertension for some reason patients develop torseness all of these were reversed after they stopped therapy and patients had fatigue as well So here's a The evidence of a response you can see this patient had a very large tumor involving their left kidney Actually, I think this was the first person that we'd treated with the therapy and you can see that they had a very dramatic response You don't have to be a radiologist to see that the tumor shrank significantly We offered the patient a partial but he wanted a radical instead you can see here's the response in the tumor this sort of encasement of This sort of fibrous tissue. There still was viable tumor, but a significant portion of the patient's tumor was dead Here's another patient who took the therapy and you can see very large tumor involving the right kidney Here's the evidence of response dramatic shrinkage You can also see this sort of central darkening which we call necrosis meaning that the tumor inside is dead and Here's the gross picture still some viable tumor on the outs on the periphery of the outskirts But the vast majority of the tumor was dead in necrotic So to conclude exidinib is well tolerating the neo-adjuvant setting in Patients with planned surgery for locally advanced non metastatic kidney cancer the drug showed tumor downsizing activity when given for 12 weeks Although as I said if I had to do it over again, I'd probably do it only seven or eight weeks Adverse events of any grade were common, but they were easily managed with routine care So to summarize this entire talk, I would argue that adjuvant and neo-adjuvant therapy is safe Although toxicity makes compliance a real issue To date there is no effective adjuvant agent for the treatment of patients with locally advanced kidney cancer and the standard of care Unfortunately remains observation Neo-adjuvant therapy is still investigational. You should not leave this room thinking that that's the standard of care Tumor down staging and downsizing is not a sure thing Response in the primary tumor may actually predict outcome And I would argue that the initial results that we've seen with neo-adjuvant approaches suggests that both of these approaches both Neo-adjuvant as well as adjuvant therapy are still worthy of further investigation Thank you very much for your attention. Have you happy to entertain any questions? Yes, ma'am So the vast majority of the new so the question was what type of agents are these targeted agents the vast majority of the New targeted agents are anti-angiogenic and they act on the BEGF receptor, which is a receptor on The blood vessels going to the tumor and the way that they work as they block that veg F receptor Which the tumor secretes veg F to attract blood vessels There are two agents Tempser Limus and ever Limus that are called mTOR inhibitors mTOR is just a different pathway It's not thought to be anti-angiogenic, but they act in a different pathway. That's important to tumor biology They act in a slightly different way, but the vast majority are yes anti-angiogenic Right so the question is are we looking at the tumors that had a dramatic response to targeted agents to see if there's something special about them That makes them different and perhaps might be able to be used to select patients in the future and the short answer is yes Here at MD Anderson we have you've probably saw the building across the street the Institute for personalized cancer therapy And they have a program called unusual responders and what they allow us to do is fund the testing that's required to assess those patients who've had an unusual response or Conversely had a dramatic progression despite therapy and those studies are currently ongoing what we do know is we've identified Some circulating micro RNAs in this in this in the circulation that are predictive of response Can't tell you what they are because we're still waiting to publish them and We currently have genomic and RNA analysis ongoing for the tumors that did demonstrate a response to see what gene factors Predict that response so we can use those to validate moving forward. Any other questions? So the question is can combination therapy be used can we combine maybe lower doses of the targeted agents or perhaps maybe use one of The anti-antigenic agents with one of the mTOR inhibitors to improve outcomes so what I can tell you is that Combinatorial therapy has been used in the metastatic setting the thought process is if one is good two must be better and three must be great and What we demonstrated in the metastatic setting is that combinatorial therapy is poorly tolerated even at reduced doses and Doesn't appear to be more effective So unfortunately, I think the answer is no and I think the toxicity even at lower doses is probably going to be going to significantly higher From my perspective adjuvant therapy, and we'll hear about this later on this morning Adjuvant therapy is going to go in the direction of immunotherapy We've gone there before in the past, but it was more non-specific immunotherapy kind of like trying to shoot a mosquito with a shotgun But now that we have more targeted immunotherapeutic approaches I think that's the direction that adjuvant therapy is going to be moving towards in the future And it may be combinatorial with like vaccines where you give a specific tumor vaccine And then rev up the immune system to target that vaccine. Yes, ma'am So they're doing the checkpoint inhibitors and we'll hear about that from dr. Gao later on this morning, but they are doing Studies in the metastatic setting and we are very interested in studying those in the adjuvant setting But those studies have not started yet. I think they're you know that the checkpoint inhibitors have been approved in melanoma I think that the companies are waiting for them to be approved for metastatic kidney cancer And then they'll start to think about the adjuvant setting the real problem is I mean these adjuvant trials I talk about them with one slide and on we go. You're talking about thousands of patients hundreds of millions of dollars invested in Potentially a negative trial. It's asking a lot of these companies to invest in that they will but it just takes time