 Thank you John. Thank you to KCA for the invitation and the question here is Which is the ideals in the patient? and I think that the Key word here is patient Because we have to realize that this one is an advanced the kidney cancer patient as It is the other case, but of course these two clinical scenarios as completely different one from the other and we have also to realize that taking into account the patient characteristics We speak about the disease related characteristics such as the number and sites or metastatic Sites the presence of asymptomatic or asymptomatic disease based on of course and the Risk group classification either with VMS KCC or a hands criteria But we have also patient related characteristics that are definitely quite important for example age of of course performance status the presence of comorbidities But we have also treatment related characteristics for example previous treatments if any But also the realistic treatment treatment Hain because sometimes we have to Go for a huge tumor shrinkage other times. We just want to preserve quality of life with all the other options in between So several years ago with a few friends we designed this kind of patient-focused approach to treatment Identifying several features several characteristics Related to disease to the patient and to the treatment and then we try to find the evidence supporting the use of any given drugs in the field of kidney cancer to Find the ideal treatment for each different clinical scenario And I try to do the same today with Sunitinib and Indeed going through the literature and using Sunitinib and kidney cancer I was able to retrieve more than 1,000 papers Just reflecting the fact that the Sunitinib is out on the market since 2006 2007 dependent countries and so we gather a huge experience with this drug and Trying to look for the evidence in favor or against Sunitinib in the different scenarios. I Tried to code color The different options with green I indicated a strong evidence in favor of Sunitinib use With yellow no data in favor against Was gray areas of treatment choices and you read the strong evidence against But considering the life is not black or white. I consider also moderate evidence in favor and also moderate evidence against And trying to do this exercise. This is exactly what went out Of course, I'm not going to go deeply through each of the different characteristics and Through the different evidence supporting or not the use of Sunitinib in each of these subgroups But nevertheless, I'm going to present you data relative to some of these features That are in my opinion particularly relevant And let's start to the indication of Sunitinib according to disease related characteristics These are the results of the exercise I made but I want to go a little bit Into details talking about the indication of Sunitinib using poor risk patients In patients with bone and brometastasis and in patients with non-clear cell histologies Let's start with poor risk These are the this is the subgroup analysis of the registry trial Sunitinib versus interferon clearly showing that even though the overall amount of benefit in poor risk patients is lower as compared to patients with more favorable features Nevertheless the advantage of Sunitinib over interferon is maintained also in poor risk patients Meaning that that we can use Sunitinib in poor risk patients taking especially into account that the poor risk Doesn't mean necessarily poor performance status Let's move to Bormatastasis we see a paper published by Cesaris Cilic and his group clearly showing for example that if you take into account the activity of the two Oldest Tarzan can ease inhibitors Sunitinib and Seraphinib then there is a clear cut evidence of a superior activity of Sunitinib as compared to Seraphinib for the treatment of Bormatastasis in terms of time to progression of pre-existing bone lesions and time to progression as The occurrence of novel bone lesions What about brain math again? We have the subgroup analysis of the global expanded access program Clearly showing that we can achieve benefit also in these difficult to treat patients This is a case from Stefano Dard a patient who did receive just Sunitinib for the treatment of his disease And who responded quite well as shown in this slide also on the brain Non-clear cell histologies are very complicated and variegated Clinical situation, but we have at least four face-to-studies We are talking indeed about a relatively rare patient population Showing that Sunitinib may be active almost in every histotype Non-clear cell histotype of course again the results achieved are Inferiors in absolute values as compared to the results achievable in clear cell histologies But nevertheless a clear cut evidence that Sunitinib is active also in these specific humanist types Let's move to the Indication of Sunitinib according to patient related characteristics I'm going to briefly touch the issue of kidney impairment and the issue of control hypertension Of course a patient with uncontrolled hypertension of severe cardiac disease are not Candidates for a Sunitinib treatment might maybe not candidate at all for an active treatment Let's start from the patient undergoing dialysis This is a rare patient group subgroup or nevertheless a quite important one because we know that for example The allies is increases the risk of kidney cancer then we have this retrospective analysis From the Italian group showing that at the end of the day in these patients The results achievable with Sunitinib and to be honest also seraphim in this case in terms of progression free survival As well as over survival are absolutely in line From with the results we can achieve in real world in a patient population not undergoing dialytical replacement treatment Ipertention Ipertention is a very complicated issue because we know from several papers that Ipertention is a biomarker of efficacy of Tarazan kinase inhibitors activity, especially of those Tarazan kinase Drugs targeting the VGA VGA receptor spot way and we have a clear cut evidence that Sunitinib induced hypertension is Something that correlates with a better Pognosis for patients with advanced kidney cancer and Then moved to Sunitinib indications according to disease related characteristics and I want to briefly touch the role of Sunitinib when a prior Targeted therapy is given The role of Sunitinib when the realistic treatment name is to prolong survival and when the realistic treatment name is to maintain quality of life Well, of course Sunitinib is the most commonly used drug in first line But nevertheless we have Some retrospective data and few prospective studies ongoing That suggests that Sunitinib use as a re-challenge treatment may be quite effective for advanced kidney cancer patients That clearly shown by this paper by Brian Rins group Again, the results achievable are in absolute values inferior to the results we can achieve As a first-line treatment but again clear cut evidence that re-challenge with Sunitinib may give patients More progression for survival advantage and benefit What about the overall survival we perfectly know that the Registrative trial of Sunitinib didn't show a statistically significant overall survival benefit But please take in mind that the trial Was not power enough to answer another survival question because the primary endpoint of the study was progression for survival Nevertheless when in unexploratory analysis the patients who caused over from Interferon to Sunitinib was censored then Novara survival benefit was observed and it was statistically significant showing that At one of the day we can also improve Over a survival with this drug that is at the end of the day the ultimate goal of every cancer treatment What about quality of life? this analysis shows that Sunitinib is able to significantly increase quality of life as compared to Interferon meaning that Its impact on patients quality of life could be also positive of course we know that Sunitinib lose to pasopony in terms of quality of life from the compass and past study, but nevertheless don't be too worried about your safety profile and Not being too worried about your safety profile It's also worthwhile after that the Sergio Bacardi asked could you presented these retrospect Italian data suggesting That the more defined Sunitinib schedule could lead not only to a Definitely better safety profile, but also potentially with all the biases coming from a retrospective analysis To a longer progression for survival at least using the 2-1 schedule Instead of the classical for to schedule so to conclude Sunitinib is out of the market since a long time and we have gathered a huge amount of experience with these drugs Really nothing to compare with any other drug registered to date for the treatment of advanced kidney cancer Evidence to support Sunitinib efficacy and safety in a number of clinical situation does exist Clearly suggesting its use in situation where no evidence of activity at all exists for other right drugs Even though we are talking about active drugs furthermore We should also realize that the use of alternative schedules may contribute to you Ameliorate the safety profile of Sunitinib making this treatment feasible even when toxicity Represents a prior artery issue And at this point and this is the main conclusion of my talk today We can now say that almost every advanced kidney cancer patient is Potentially an ideal candidate for Sunitinib treatment If not probably we have to consider the idea of giving this patient just by supportive care Even though of course This doesn't this does not mean that other drugs could not be regarded as reasonable Alternatives for many but on but not on not only but on not all The patient characteristics that I considered in my presentation. Thank you very much for your attention