 I'd like to continue with the second speaker, Robert Hawkins, from the University of Manchester, to be discussing with us, who is your ideal Pozopinib patient? Robert. Okay, thank you for that introduction. So I'd say, I'm going to try and answer this by saying who is not an ideal candidate for Pozopinib after going through the data to show you that everybody should be considered for Pozopinib. So just some disclosures. So Pozopinib is licensed in the first line treatment and in prior cytokine treated patients, but there clearly are alternatives that are going to be discussed by other speakers. I suppose there are also post cytokine alternatives, synidinib and exidinib. I suppose the issue is how do you compare these? I suppose there are a number of issues with the treatment of renal cell carcinoma. It is a question of when do you start treatment? If you have a range of drugs in which you're going to choose, we've heard the case for synidinib, but I think there's a compelling case for Pozopinib in many cases and I'm going to discuss the evidence for that, but clearly there are patient-related decisions as well that may sway things since the evidence is far from perfect and far from complete. I suppose that the first issue in our philosophy is does the patient need immediate treatment? Is there a potentially curative treatment for that patient? Is there potentially a curative surgery for recurrent or metastatic disease? Can we use high dose interleukin too? If this is a palliative treatment, then what is the evidence of benefit? What are the overall effects on quality of life? And what are the choices between the different options? How do we choose between them? I suppose the data to suggest that you don't necessarily... You can watch and wait in patients with... in the tyrosine kinase era is shown here and this is the data from the first line study of Pozopinib where patients are randomized to receive either Pozopinib or placebo but were monitored very carefully on placebo and crossed over and although there was a progression-free survival difference, the overall survival was not statistically different and was very similar when you look at the curves there. I suppose the issue is, are there groups of patients who, within that, who cannot when you look back? There are some at the early stage where there appears to be a disadvantage. When you look in different subgroups, when you look in different subgroups at prognostic markers, this is a biomarker assessment described a couple of years ago, there are patients with poor prognostic markers such as high IL-6 who appear to do badly. These patients are randomized here between placebo and Pozopinib and this is a retrospective look in patients who had either high or low IL-6 at baseline and there's a clear apparent detriment to patients with who had high IL-6 at the start whereas there's no difference in the better prognostic groups who have low IL-6. So there may be a patient group, it may be difficult to define, who have rapidly progressive disease and I guess we make that choice regularly who clearly are not a candidate for watching and waiting. At the other end of the scale, there's patients with limited disease, those who are potentially curable by surgery or by other systemic therapies and we still select some group for high dose interleukin-2 partly based on their histology, partly based on their clinical criteria of fairly limited disease and what we would call favorable histology and the outcome in those patients is extremely good with around 40 odd percent of patients surviving long-term and free of disease. The key outcomes also are shown here in those patients who do achieve a complete remission, they have very prolonged survival and very rarely relapsed from treatment. So those are a group that we would try to exclude and give different treatment. When we come down to the first line treatment, although there are many options, there are no very few direct comparisons between relevant drugs in the first line treatment but the key comparators are the trials with Sunitinib between Pozopinib and Sunitinib, the Compile Study and the Pisces Study, both of which have been reported relatively recently. I suppose a key important criteria is that these have predominantly targeted patients with clear cell, renal cell carcinoma, they're predominantly targeted relatively good performance status patients and predominantly relatively good or intermediate prognosis. But when you look at the overall outcome in terms of PFS, there's very little difference. This is a so-called non-inferiority study but the hazard ratio is 1.047. When you look at response, there's a clear higher response, although again not very clinically different between the two with a 31% response rate to Pozopinib, 25% response rate to Sunitinib in the Compile Study. When you look at overall survival, obviously a key endpoint again, there's no overall statistical difference but the hazard ratio slightly favors Pozopinib. So there's clear benefits either way in terms of efficacy but really no major compelling reason. When you look at overall toxicity, this is shown in a scatterplot here, these toxicities favor Sunitinib and these favor Pozopinib. So there are clearly many that favor Pozopinib but some such as abnormal liver function tests which clearly favor Sunitinib. I suppose the other way of testing this is whether you can evaluate it in a patient preference study. So you expose patients to both drugs and then ask them the question, which one did you prefer and then do that in a blinded fashion and that's to enable patients to assess the overall effects of treatment in terms of toxicity over a period of time rather than a point measurement that you see when you measure toxicity on conventional scales. So this shows the overwhelming result of the Pisces study that patients prefer. Pozopinib in the case of 70% versus 22% with a few undecided patients. So clearly that's an important measure when we're talking about a palliative treatment, what we want is to know what patients think. So I suppose the question is how do you balance all these up? So there is a small non-statistically difference benefit for Pozopinib in terms of PFS. It's the reverse in terms of overall survival, but when you look at response rate, it is statistically significant in favor of Pozopinib. When you look at liver function toxicity, it favours Sunitinib. When you look at hematological toxicity, it favours Pozopinib. In terms of hand, foot and mouth effects, it favours Pozopinib. And in terms of quality of life and patient preference, favours Pozopinib. So overall, I would say, although there are pros and cons of both drugs and you need to make an individual choice, for most patients the balance favours Pozopinib. I suppose given that, how do we choose or should we just say Pozopinib should be the preferred treatment for most first line patients with metastatic clear cell renal cell carcinoma? All right, and how do we make those individual choices? I suppose that we originally thought maybe we should give it to a focus on less fit patients, patients who would not appreciate the side effects of Sunitinib, such as sore hands and sore feet. Those who use their hands and feet for work or pleasure. But I think as we, there are still patients who we would favor Sunitinib for, as we just heard, there's an extensive clinical experience with non-clear cell patients with Sunitinib, although there's some experience with Pozopinib, it's relatively limited. I suppose there's a lot of talk about patients who may prefer a treatment break and there are some patients whose lifestyle fits with that. But I think it's quite difficult until patients have been exposed to Sunitinib and they have experienced the toxicity, they realize they would like a break, but that's in retrospect. I think because of the liver toxicity, there is quite intensive monitoring and potentially treatment interruptions and some patients do find that difficult to cope with and so that may be a reason for choosing Sunitinib, although again it may be hard to identify upfront. I suppose we are wary of patients who have pre-existing liver disease, including those with extensive liver metastases with existing liver function abnormalities who liver toxicity may be difficult to interpret and adjust for. Those do we ever use interferon and benvisuzumab? I think we'll hear about that more in the future, but there may be some cases where patients may benefit from interferon or whether they're difficult in giving the drugs. I suppose one group where we've looked at, when we looked at our patients who we treated with Pesopinib, we treated some 130 patients now in a retrospective audit. We looked at all of the groups of patients and we did tend to select patients who had poor prognosis initially, reasoning that they were likely to tolerate Sunitinib poorly and maybe would benefit from a drug with less toxicity and better tolerated. I think in general we did find it was reasonably well tolerated, but when you look at, this is the outcome of our retrospective audit of patients by hang criteria, it's very similar, whether you look by MSKCC or by performance status that you see the good prognosis group. Overall survival is good and not really reached yet. In the intermediate survival, intermediate prognosis group it's around 20 months, but in the poor prognosis group it is very poor at around five, six months. Whether that would be better with any treatment, other treatment is open to question. They clearly are poor prognosis patients, but I think it has led us to question whether we should use more Tempserolimus in these patients than we have to date. So what do we actually do in practice when we consider our patients? If we have around 100 patients who start first line treatments, as I said, there is an issue, there's a fair number of patients who don't start treatment initially, they're monitored. I think we feel that they benefit from a potentially long period of time without any treatment at all. For those who do start treatment, we select a group of patients and of our patients around 7% get high-dose IL-2. A relatively low proportion get Tempserolimus, but that may increase as we've looked at the poor performance status patients in both posopenib and synidin-treated patients and we get very similar, but not encouraging outcomes. Most of our patients do get posopenib on the basis that it is a better tolerated treatment. Patients seem to prefer it and in terms of efficacy, it seems very similar to the alternatives. Obviously, the data is mostly in good intermediate prognosis patients almost entirely in clear cell patients and for reasons that I've outlined, we try to avoid patients with who may run into significant liver toxicity that's hard to interpret. Some patients will still get synidinib in spite of the evidence that it may be less favorable in terms of toxicity, particularly with the non-clear cell patients of whom there seems to be increasing numbers as pathologists look more closely at the pathology and a variety of other reasons, including patient preference and some of the issues that I talked about in terms of patients' lifestyle wanting breaks, not wanting to come for such frequent monitoring, et cetera. So thank you for that, but to summarize, the ideal patient would be a patient with clear cell carcinoma, good performance status, reasonable prognosis, those who are not suitable for potentially curable treatment and no contraindications willing to comply with liver function test monitoring, but that comprises the majority of patients. So thank you.