 So continuing our conversation, so one of the questions that often comes up that we touched on a little bit this morning was, what do you do if you've had your kidney cancer diagnosed? Your surgeon says that all the tumor was removed, and your medical oncologist says there's no evidence of any disease anyplace else, but there might be a risk that you have for having the tumor come back. How do you approach that? So we're fortunate enough today to have David Quinn, who just flew in on the USC JET to come to visit us today to talk to us about adjuvant therapy for kidney cancer. Thanks for coming, David. Thank you very much. I'd like to apologize for wearing a tie. I am going to a wedding. And normally when Dr. Figlin runs these meetings, you get in trouble for wearing a tie. So I've been given the question. Should I receive adjuvant therapy after surgery, even if there's no evidence of the cancer? And the bottom line is no, you should not. So there's no current role in this disease for giving you therapy outside of a clinical trial. And I'll talk about some of those clinical trials. It is somewhat frustrating to us, those of us that work in renal cell cancer, that we don't have an adjuvant therapy that we can give you. And you'll see in a minute that it's not for want of trying. Just to make it clear that there's adjuvant therapy for all sorts of cancers, including most of the common ones, colorectal breast, prostate and lung, that reduces the chance of an individual relapsing by a factor of somewhere between 20% and 50%. We'd love to have that in renal cell cancer. Okay. So we're going back to when Bob Fieglund wore short pants when he was at UCLA. And he wore short pants, I think because he could walk to the campus or something. But this was work that he did as part of the UCLA renal cancer spore in what was a, in fact, a golden age of things that we learned about clinical kidney cancer. And what this shows is that if you follow a large number of patients with renal cell cancer, you can work out, after an ephrectomy, you can work out who's going to relapse now. And this is survival. So if you look here, you can see patients were stage four, and this is before any of the new drugs. All we had at this time was interferon and dilucan. So patients were stage four cancer did not do well, and a very vast majority of them by the time they got out to around six years, 72 months had passed away. Up here, these are patients that had surgery where there was likely not residual cancer left. And you can see the lower stage ones, one here, do pretty well. But once we get to stage two, which is a cancer that's bigger than seven centimeters or three something that's spread outside of the capsule, there is an increased risk of relapse. And over time, in that group of patients, it might be 50%. And then what the UCLA folks demonstrated, and it's been confirmed since, is that the grade of the tumor is important. Also necrosis within the cancer is important from the pathologist. And the performance status of the patient is also important. So patients with a performance status of zero have no symptoms after they recover from their surgery. The ones that actually have a greater than zero don't do quite as well. So it's all quite logical. And there have been a number of attempts to put this together to work out what the risk is of relapse after surgery. Now, the surgeons come out and they say to the family member, what? We got it all. OK? OK, we got it all. OK, very good. And they don't always say that, but actually most of the time. And the thing is, it's a time of great anxiety for family and patient. And we're not going to know for several days what the pathologist thinks. And so from that perspective, it's difficult to work out. And the surgeon is actually usually telling the truth. They're not actively lying. They did get it all out and they usually able to get the margins clear and all that sort of stuff. But when we look at trying to predict survival of patients, we'd like to work out who's got a high risk of relapse if we're going to give them adjuvant therapy. If your risk is zero of relapsing or less than 10%, which is pretty much the same, you're not likely to benefit from something that will reduce your risk by 20% to 50%. Whereas if your risk is 100%, then you may be willing to try anything. The truth is, some are in the middle. And that's what I tell most patients with whom we have this sort of discussion. And at the moment in the clinic, we don't tend to use this nomogram regularly, unless we're trying to enroll someone in a clinical trial. And we use it for balancing the arms. And I'll come to why we need arms in just a second. Why would anyone take a placebo? Anyone here? Would anyone like to take a placebo today? OK, so you had placebo turkey at lunch. OK, you didn't know it, but it was placebo turkey. I'm sure you felt much better. So we don't do many placebo trials anymore. It's because we have agents that make a difference. And we have been doing placebo trials up until, in fact, last year in prostate cancer, where I now have five or six new drugs to treat patients. I don't cure anyone with those drugs, but I can control their disease. And the issue was that we were comparing it to the standard of care, which was nothing. So in that setting, it's reasonable to have a placebo control trial and an actual fact to prove that the drug works. We need to do that. And so that's kind of where we are with our adjuvant studies. Now, the first large adjuvant study was this study run by ECOG, and it was called ASSURE. And that's an abbreviation for putting the two drugs that we had, which were the first ones that Dr. Fieglund helped develop in this disease, which are synetinib, also called sutent, seraphinib, called nexivar. And at the time this trial was designed, these agents had just shown promise in trials. And so we thought, well, why don't we give them to people after surgery? And there were some eligibility criteria, as for any trials. You can see we selected patients that were high risk. They had to have a PT2, which means the tumor larger than seven centimeters, or having spread outside the gland, and having had lymph nodes involved and resected at surgery. You could have either of those. And the patients had to be well and not have other major problems. We also picked clear cell, but also allowed other variants to go in. Now, in this study, the original design were three arms, synetinib, seraphinib, and placebo. So we had to blind everybody, which was complicated, and I won't get into it. But we started with this estimate of the number of patients, 1,332. And we ended up with 1,900. Now, we all like to do big trials to get power. But unfortunately, when you see this reassessment of statistics here with an increase in the number, it means we got it wrong. And the reason we got it wrong was that we knew that patients getting these drugs would have side effects. But the patients in the adjuvant setting, you'd had an ephrectomy, had their renal tumor removed with their kidney, actually got more side effects than we had anticipated. More than we saw with patients with metastatic disease. Now, we postulated this and I think we sat in meetings and said, do we think these people are just neurotic? Are they imagining their side effects? Now, I've got to reassure you that didn't last very long because we said, look, we know what the side effects are. And if someone's got a rash on their hands, they either have it or they don't. And we're actually pretty good at picking that up and they can't fake it. So patients in this setting did seem to have slightly more side effects, both objectively and also subjectively. And so the fatigue that we saw with the drugs in some patients was much worse and was a problem very early on. So we had a very high dropout rate. It was about 25, 30%, which is about double what we see in patients that are in metastatic trials treated over a similar period of time. So it was a problem. What was the endpoint that we're looking for? Well, these are abbreviations. Overall survival, time to progression. In other words, time to the cancer coming back. And we were looking at quality of life. Sometimes we call this patient reported outcomes, which is actually important because you want to balance the side effect or other toxicities with what could be a potential benefit from the therapy you're giving. Now, I put the source trial in because it's running in the United Kingdom and because it was designed with a slightly different aim. So source takes Nexavar or Seraphonib and gives it for either three years or one year. So three years here, placebo three years, one year of Seraphonib and then placebo to see whether there's a difference in the length of time in terms of outcome and that this trial is accrued and completed in the United Kingdom. We don't really have results from the primary outcomes that I can present you at this stage. I'll present to you a trial in a minute where there is an outcome, which I think is interesting, but unfortunately doesn't take us forward in terms of giving us a therapy. So this is an extended tabulated summary of the different trials that we've been doing and I'm not going to go through all of them, but to say that we've been trying to get this sorted out for more than 20 years. And so the trials at the top here are very old trials where we gave radiation therapy versus observation. A hormonal agent called Medoxypressurone acetate which is similar to megase that we give for appetite and stimulant, it's a progestin. These trials showed no difference. We tried giving a chairman with BCG no difference. We tried giving interferon and in a smaller trial, high dose interleukin2 and showed no difference. Whilst these were not statistically significantly different, this trial here with interferon led by Ed Messing who's now an upstate New York is important because you'll see here that the overall survival was 5.1 years versus 7.4 years. It's a couple of years, quite a lot. But the bad news was that the patients that got given interferon which was meant to be active versus those that were observed and got no treatment actually lived 5.1 years on average compared to 7.4 years. Now why is that important? Does it discourage you from going on trials? I hope not, but the issue is that we have placebo arms for this reason. We cannot necessarily conclude that because a drug works in the advanced setting for metastatic disease and extends survival, that there's actually gonna be the same thing seen in the adjuvant setting. And we have examples of this from other cancers. Now what I can say is that an old drug interferon which we use for years, the benefit to overall survival I think has since we actually stopped using it and some studies have come out that suggested that the benefit is kind of marginal. And we've had several other studies looking at immune-based therapies. One interesting one here which was the antigenic study which was an autologous tumor where we mashed it up and gave it back to patients. Well overall, to use as a vaccine. And overall there looked like there was a slight benefit to progression free survival in the patients given that vaccine, which was run by a company called Antigenics. And it happens that a large number of people accrued in St. Petersburg, that's St. Petersburg, Russia, not St. Petersburg, near Tampa and Florida. And in that subset of patients there was an overall survival advantage. So if you're Russian and in St. Petersburg it seemed to be very effective and that agent is approved in Russia for treatment. The government doesn't pay for it and they don't really have an insurance system but it's approved in that country. So there was a suggestion that this immune effect would potentially be useful in patients that had had an effrectomy for their cancer. And Dr. Figlun is actually leading a study where we're trying to do a similar thing in advanced disease in combination with SNETNib which I think is a very, very good concept. And then further we looked at other immune therapies down here. I'm gonna talk about this one in just a minute. It was presented by Dr. Bellagrant last year and I think it's interesting. So the other thing about adjuvant trials is we have to follow people for a long time and we end up doing CT scans on them. These are the CT scans per year. We usually start out with two or three and we reduce that over time so that after five years you're getting a scan once a year and from that perspective it's an undertaking to follow these patients. I'll just go through the different studies because you may see them reported. In assure we're starting to get toxicity data from the treatment of SNETNib or Serafnib for 52 weeks. Estrack was a French study that looked at SNETNib or Su-10 in a higher risk population and we hopefully will have results from that in the next year. The PROTEC study is just closed. This is with a drug called Pozopinib or Botrant. The Everest study is ongoing running through the Southwest Oncology Group with Everolimus, an M-Tor inhibitor and there may be some reasons why an M-Tor inhibitor might be better in the adjuvant setting to the other drugs that impact VEGF but I won't get into that unless people are interested. The SOAR study is closed, I mentioned that and then a study that has predominantly been conducted overseas but we'll open at a few centres here in the US called the ATLAS study with one of the newer VEGF drugs ExitNib given for three years. So we'd like a target apart from VEGF and this is a target that was originally worked on at UCLA but also by others, it's called carbonic anhydrase and we thought originally based on UCLA data that this would predict response to certain therapies, most particularly HIDO-symbolic 2. Be much better if we could select a patient and if you had a lot of carbonic anhydrase say you're a good candidate for this. The data was tested prospectively and we could not validate the UCLA findings and the reasons for that are not clear but this remains a target and is an antigen expressed in many renal cell cancers. And as part of the development targeting carbonic anhydrase R9, you can see it's sort of schematically illustrated. Here it sits on the outside of the cell, it's a transmembrane glycoprotein. So if we're trying to hit it with something like a monoclonal antibody, it's sitting there and should be accessible where if you're trying to hit something in the nucleus, it's much more difficult because your antibody's got to get through the outside membrane and the cytoplasm. And so this looked like a good target and this antibody here, Gerotuximab, which is unpronounceable, incidentally, they're designed that way, has a mode of action in that it induces antibody dependent cell killing or cytotoxicity. So this is what we'd like. We want it to go and find the cell, get the immune response to occur and then to kill those cells, especially if they're microscopically present. Well, Dr. Beldegren from UCLA led a study in which patients, almost 900 of them, were either given a vaccine in the form of them, sorry, given the monoclonal antibody in the adjuvant setting or a placebo. And you can see half of them got placebo and half of them got this targeted to a G250. And you can see here that there's not a great deal of difference between the two curves. They overlap and statistically they are not different. So it was a negative study and this was disease-free survival. So the time until the cancer came back and in this particular study, the median was not reached but almost 50% of patients had relapsed after they'd been followed for four or five years and they were selected to be more likely to relapse. It wasn't everybody. And then overall survival, you can see the curves higher, patients living longer, more than around 80% or so, but no difference between the two lines. So depressing reading for renal cell cancer patients and also for people that do renal cell trials. But if we look and select the population, we do this afterwards to find out where we went wrong and whether there's a signal. In this particular study, when the patients were not selected for this, if there was a lot of the carbonic anhydrase in their tumour and they were young, then there did appear to be a significant difference between the two lines. And you can see here that if there's a 15% difference between the two lines, somewhere between three and four years, that's probably something worth having. So I think that we may have needed to select patients in the study. This is something we're doing in other cancers, particularly lung cancer, we've been doing it in breast cancer for a long time to see whether in actual fact the target is there. And whether we'll revisit this with another study or not, I think is an interesting question that it may be worthwhile doing. Okay, just briefly, because I don't wanna go over time because that produces big trouble from Dr. Figlin. I wanna talk about neo-adjuvant. I know that there may have been a little bit of discussion, but this is a question I get a lot. Should I have some targeted therapy with senetinib or pysopinib or something similar before surgery to try and make the nephrectomy easier or to make me a candidate so I can have my kidney removed? And generally, we've done a number of these studies and this is not standard. And I'll show you a little summary of this. And what we're trying to do here is to downstage the tumor so that we can make it receptable. For a surgeon, receptability or operability is in the eye of the beholder, so it will depend on the ability of your particular surgeon. And before this is assessed, you need to be at a center that does a good volume of the surgeries because receptability at a small center is gonna be different and you're more likely to have a surgeon that says I can take that out when they're doing a lot of volume. There are some examples where we do do neo-adjuvant therapy and this is a patient who's lost their other kidney. In fact, it was to trauma and it was reported in a journal called Clinical GU Cancer and you can see here that the surgery would involve removing the whole kidney because we can't just take this little bit out. As it happens, they gave the patient some targeted therapy at shrank and they're able to do a partial nephrectomy. Why? Well, we don't want the patient to lose their other kidney and have to go into dialysis unless it's totally necessary and we know that in the absence of metastatic disease, the outcomes from partial nephrectomy are generally similar to a total one and this patient had had some follow-up. That's actually relatively unusual but it is an indication for potentially doing this and just quickly, the studies that we've done in this area have been led by Cleveland Clinic and MD Anderson predominantly, also one study done in London led by Barts and the issue with giving these drugs before surgery, the thing we worry about and you can see here there was a 17% wound healing, bleeding and renal failure complication rate and also some issues in the MD Anderson study with or without a pill called a lotneb where they had problems. So this is not a standard and at this point in time, we do not have phase three studies going forward. Generally, if you're gonna benefit from the operation, it should be proceeded with before you start therapy and it can be revisited in selected instances. So just to summarize on perioperative therapy, therapy before or after nephrectomy is not a standard of care at this time and we have some phase three studies. If you want to look at this therapy, especially after surgery, if you're higher risk, you should actually try and get onto a phase three study which will entail some sort of placebo or observation arm. And then in the neoadjuvant area, I think it needs to be done selectively in specialized centers that have surgical and also oncological expertise. And that's it from me and I'll take questions if Dr. Fiegelman will allow. Thank you. Any questions for David? Use the microphone please. According to the chart you shown us, looks like the night ears is the cut of the ear for no relapse. That's my question. Okay, so if you get to nine years, are you safe? The odds are very much in your favor but I think Dr. Fiegelman and I have seen the 25 year patient who's had a relapse. It often occurs in funny places. So a few years ago I presented a patient who had a relapse in a nasal pop which was removed and that was, I think six or seven years ago, that was removed, the patient's not had further disease. So the odds go down the further you go out but it never gets to zero. Should you have a CT scan every year? Well, generally after 10 years I discourage people from doing CT scans and ideally after five years I try and switch to chest x-ray. And there are no specific guidelines for following people after they've had an ephrectomy but we tend to temper it by risk. So look, if you're at nine years you're probably beyond the disease but no one can give you a total assurance. So if you get a nasal polyp or something fun, some lump in the skin, you need to tell the doc who's looking at it, look I had renal cell cancer back in 1990 and patients that get late relapse often actually respond quite well to therapy if they need it. So I just try and reassure people. Thank you. Thank you David.