 I was delighted to be asked, but imagined my horror when I found out it was a debate rather than a presentation. So I'm going to do my best. I've been asked to talk about targeted therapy prior to nephrectomy, which is obviously not an established approach, which I suspect gives me somewhat of a disadvantage in any debate. Nevertheless, I will do my best. A number of disclosures, equally imbalanced. We do nephrectomies in metastatic disease, and the reason we do it is a hangover from the pre-TKI era, where individuals who present with metastatic disease with very few effective treatment options were shown to have a significant survival advantage associated with nephrectomy. As we can see from this study here, and that a second study both published in the New England Journal of Medicine, so it's a well-established approach, but the challenge of course is if you look at the median survival of that group of patients, it's somewhere in the region of 12 months, so we're now talking about median survival of 30 months. So the question is whether or not this data is applicable for all patients in the VEGF-TKI era, and I'm going to put it to you that it may be applicable for some patients, but actually we shouldn't be pursuing a one-size-fits-all approach if we need to pursue an individualised approach. And that's what I'm going to try and convince you of today, successfully or not. And actually we know the answer to the question already, so the debate is effectively over. You can see from this slide here, and this is see as data is published or impressed in International Journal of Cancer, and you can see the incidence of nephrectomy increased with the publication of those two, and then VEGF-TKI therapy came along, and clinicians in the US are voting with their feet. They're having conversations with patients, they're saying we've got these new effective drugs, we're not going to do upfront nephrectomy, we're going to give you systemic therapy immediately and see what happens. So we know already what the doctors think, the question is what do the data show, and this is from the same publication which is also impressed, and this is a nephrectomy population, and this is a known nephrectomy population, and this is the era of targeted therapy, and there are many data like these, and when we look at retrospective analysis in the era of targeted therapy, it still seems that nephrectomy is important because these patients always do better. But I kind of put it to you that it's a bit more complicated than that, because what we're doing is we're selecting patients for nephrectomy very carefully. I sit in clinic with my surgeons, they see a patient and they say, Tom we're not going to do nephrectomy on this patient, and this is an example of that type of patient. This is a 67-year-old female, grade 3 clear cell cancer, clearly operable, so fulfills all the criteria, but MSKCC porous disease, raised LDH anemic, hypercalcemic bone and liver metastasis, and my surgeons are not operating on these patients. So when we go back into here, this comes into the known nephrectomy group, and so we are going through a process of careful patient selection with this data, and so therefore I don't believe this retrospective data actually is applicable for all patients. I'm going the wrong way, I'm sorry. So why not start VEGF targeted therapy in this individual, give it immediately, and then see what happens, and the approach to this is kind of, I can start VEGF targeted therapy within two or three days. I'm struggling with this relatively unwell lady, she's not going to have an effect in my institution for two or three weeks. She's going to have to go through a series of cardiac investigations, and other bits and pieces, and during this period of time, it's likely that these metastatic disease is going to be progressing, and it's going to be the metastatic disease that will kill her in the end. This is some work from Brian Renee's group, and I think it is important, and it emphasises the point a bit more clearly, in that it's not a one-size-fits-all approach, clearly if you have a massive primary tumour with one or two small lung metastasis and good-risk disease, everyone should have an up front nephrectomy in that population. But if you have a three or four centimetre tumour with porous disease and lung metastasis, clearly nephrectomy is not the immediate option of choice. This is an alternative approach that we've pursued, which is that we give VEGF targeted therapy immediately, and then after a period of time, an nephrectomy would occur in those patients who are developing clinical benefit. So, this is the established approach, and this is our one-size-fits-all approach, and this is more of a pragmatic approach, where we start therapy immediately and see how we get on. This was done within the context of a prospective trial, 110 patients using perzopinib metastatic disease, no previous therapy fit for nephrectomy and systemic therapy, so patients had to be fit for both treatments. We recruited 102 patients, and the key to this is the majority of all patients were intermediate or porous disease. These patients who are presenting with a primary tumour inside you are less well than those individuals who are presenting three or four years after nephrectomy with one or two lung metastasis. This is a challenging population, and this is why we need to be more pragmatic with this population. This approach is not about trying to get control of the primary disease, it's not about shrinking the tumour down, it's not about making the surgery easier. This approach does none of those, but it does gain clinical benefit in 83% of patients. What that effectively means is one in five patients are having primary progression of disease. That fits very much in line with what you would expect with intermediate and porous disease. The key to this is not all patients go on and get nephrectomy, as you would imagine. The second commonest reason, as I described before, is primary progression of disease. The issue, and I think this is an interesting debate, is whether or not we should be performing nephrectomies on people with inherently resistant disease. I'm going to show you a slide in the minute which suggests maybe we shouldn't. The other issue I think was interesting is the second commonest reason was patient choice. Individuals doing exceptionally well with targeted therapy, a small primary tumour, a big metastatic burden with a nice response, and they're saying, I don't want to stop this targeted therapy, I want to keep going. So that's somewhat pragmatic, and that's a higher percentage than I originally thought. We did it with presopinibic, clearly used with synitinib, and I'll show you some synitinib data in a minute. The question is, is this approach safe from a surgical perspective, and due to time I'm not going to go through spectacular detail, but what I can tell you is we've got a post-operative death rate of about 3%, which is actually relatively low compared to contemporary series in the metastatic setting, which can be as high as 15% in some published series. The other issue is you have to stop the targeted therapy 48 hours beforehand, and you probably shouldn't restart for at least three weeks, and there is this tumour rebound during that period of time in about 20% of patients, but effectively the surgery is safe. I'll keep going the wrong way. The progression for resurvival in this cohort was nine months, which as we know from COMPARS, which had good intermediate and porous patients, this has only had poor intermediate patients. A progression for resurvival of nine months in this cohort is a modest, a good result in our opinion. It certainly doesn't suggest that this is not effective. An immediate overall survival of 22 months. Again, for intermediate and porous population, relatively attractive. This is my first kind of slide which is going to say, should we be operating on all these patients? Let's look at that porous group, and you can see that all of these porous patients median survival about nine months, so you get a patient who presents with porous disease, a tumour incites you, that lady who I presented previously, and these patients, their median survival is only nine months. Should we be putting these patients through and nefract me under these circumstances? I'm not sure I know the answer to that question. There are randomized trials that are going to answer this very important question, but certainly at this time when we don't know the answer, surely a pragmatic approach would appear to be attractive. This is Sunitianib data, so everything I've talked about up to now is Pozopinib data in 102 patients. This is 66, two prospective studies, one of which is Axelbexes, and one of which is our own. What we were able to do is stratify patients into four groups, those using an identical approach, 18 weeks of therapy prior to surgery. In those individuals who had intermediate risk disease, who had obtained clinical benefit, you can see they're going on and doing very nicely here. But you can see, crucially, in those individuals who have primary progression of disease, particularly those with porous disease, go on and do very poorly indeed. Using this approach, we can select out patients who we know are going to do well, but we also, while there is uncertainty, are not putting patients through potentially a dangerous procedure. I mentioned there was a small progression during the treatment gap. If you restart the systemic therapy after this treatment gap, you can regain control of the disease. So the debate for me is not about this upfront approach being attractive, but in this time of uncertainty, whether we should be less black and white, not nephrect me, known nephrect me for all patients, not pragmatic for subgroups of patients, and say, in some patients, it would appear reasonable to start systemic therapy first and then wait and see, which is effectively what this slide is saying here. These are the two randomised trials that I mentioned. Axel Becks leads one, Bernard Esculier leads another, both answering different questions. This is nephrect me versus known nephrect me. Very important question. This is a second question saying, do you need it immediately or should it be delayed? These two studies together are going to answer the questions which I think need to be addressed as a matter of urgency in this field. So what can we say? We can say nephrect me currently has an undefined role in the era of targeted therapy. So immediate nephrect me in all patients seems somewhat counter-intuitive to me, which I think is the issue for the debate today. Some patients may not be benefiting from this nephrect me, and I feel strongly that that's the case, that some patients may not be benefiting. The attractive approach of giving targeted therapy is it can be started immediately and it can sift out patients who we know are going to do badly with vegef refractory disease, progression of disease in the bone in six weeks. Surely we shouldn't be performing nephrect me in those patients. And delayed nephrect me keeps options open for patients in the future and is therefore attractive. So this is not a reflection of my personal life. This is a reflection of this talk. A pragmatic approach with an individualised slant. While we don't have to, and while there's no evidence that we should, let's not commit early and never say never. I'm going to leave it there. Thank you very much indeed.