 Thank you very much, Emiliano, for this fantastic overview of new developments in the systemic treatment of RCC. So we have now a great panel here and we would like to start a discussion about using these drugs for our second line and I would like to ask you to participate in this in this discussion Because you know this is the chance to to ask all the questions So I would like to give you the first option to to to raise a question here. Who can I give the word? Okay, we started with the panel So my first question is for Camilo Camilo you showed us that we have actually Little but excellent data for so need to need to one schedule showing really decreased toxicity and and Possibly improved efficacy because people are able to maintain the dose of the treatment. So my question is Are you starting with the 2-1 schedule or are you waiting for? toxicities that would Kind of guide you to to modify the schedule Well, I think that the data presented by Sergio and also confirmed by the Canadian group Christian Kolmansberger Suggest that the 2-1 schedule of sneakening is definitely Mortality and this is a fact because at the end of the day we know from every day clinical practice that Toxicity tends to occur starting from week number three So it makes sense to to to give the patient a break then As far as the activity the data presented by Sergio are quite interesting of course They are retrospective so should be handled with care at the end of the day my attitude today is to Change the schedule as soon as relevant toxicity appears Not for the from the very beginning No questions. I would like to ask a question to Berna So you have shown that in fact for most patients The use of bevzuzumab in combination with interferon is a good treatment option If those patients fail, what would then be your second line treatment? Is there still room for a TKI or do you have to switch then to an M2 inhibitor? I think there is no doubt. I mean TKI after bevzuzumab should be given and I will not Discuss which one we should use in in second line if we use bevzumab But I would certainly use a TKI after bevzumab. It works. I mean it has been shown we've actually been shown we've sort of in It's probably also valid with a soon it even buzz open it So I do start with bevzumab and when I do that I will continue the TKI Probably now that we have accident but would probably switch to accident in second line Because that's probably the most important one I would use at that time. I don't have any data to present here Second thing we know is that when we use bevzumab as first line treatments The number of patients will go to second line is higher than when we use soon it even in first line That's what we reported in our experience. So I think it's another piece of information which could be Interesting. I mean because we are using selective inhibition and then we can use wider ones. So I think that's another agreement But are you starting with the low dose interferon or are you starting with nine million units? I think I'm very conservative So the same way I mean I'm starting with four week on two week off or soon it in a band switching As Camillo do when we have toxicity now I do start with nine million and I but I'm very happy to go down to Three million three million very rapidly if we have toxicity so I have no problem now We have the militia data to to go down to three millions Can use the microphone Bernard is always extremely good at defending bevzumab and interferon. I'm just wondering in your practice Is that what you really use as first line therapy? The the the unit answer is no Is no not really a lot and I think So that's a problem for me. I think we have been Pushed by by drug company and I think gsk and Pfizer is doing a great job and I think it's easier to give tki in practice and Patients like mostly to have oral drugs. I don't have to come back to to the hospital When I prepare this talk and when I look at the evidence we have honestly, I still think We are not doing the best job. We we should do in terms of clinical oncologist by not using this drug anymore And I think I think we are doing mistake. Honestly, that's what I think But I'm not using a lot of bevzumab So so just on Bernard can you just add on to that if it seems like with the other tki's There is at least a movement to use them later in the line of therapy despite lack of data But with bevzumab there's actually thoughts that it does not tend to work well in the post tki Setting so would you ever consider using bev into furan or single agent bev? In the second third fourth line setting after a frontline tki So so I would say I almost never do that Except I mean we have a program with targeted Targeted therapy where I do biopsy and if we have a vgf Passway activated we can use in a few patients bev a sumab alone in third or fourth line When you look back, I mean in 2006 and seven I mean we all have used bev a sumab in third and fourth line And we all have observed some activity So I'm sure that it has some activity when we discussed with rush and genetics some years ago to do a second line trial Or a third line trial. They said never we just want to be in first line. In fact, they are never they are nowhere So I think I think it's a pity for kidney cancer because that's a really active drugs that we don't use probably anymore Anywhere which is in my mind a mistake for the patients I have another question um, I'm working in Italy where we uh, have an agency ifa the Agency of pharmacology to tell us what we can and can't do And the way excitative has been approved has been approved based on the the pivotal study And we can only give excitative if the patients have had sunitinib So what about our patients with um, who have had putzopinib? Do you think this is correct that we shouldn't be able to give excitinib after putzopinib? Do you think we should write to the authorities? You think we need another study? Are you answering the question Robert? I'll try. I mean, I think that clearly is activity of excitinib after putzopinib. We've certainly used it quite extensively Um, but I would accept that there is no firm trial data and Ideally, there probably should be or at least an extensive retrospective analysis I would I would go to this question. I think uh, you Coral, Camellio, Sergio are good enough to go and see the Italian authority and say don't be stupid I mean these two drugs are really equivalent. So, uh Don't let I mean Go to the small guidelines go to NCCL guidelines. I mean excitinib is approved after TKI It's not because EME has given only putzopinib because The trial was done only after sunitinib that we should not use it after TKI in general So you have you have to do lobbying and go to the Italian authority Optimistic Emeyanov Yes, I have a question for dr. Hawkinson's school year Which is in the context of a patient that is receiving putzopinib for bebasisoma first line therapy without toxicity And with good efficacy How do you make a decision on when to stop treatment? I mean, I have cared for now for example saying that he stopped treatment with the patients on bebasisoma for example How do you decide when to stop for a patient that is getting anti tumor activity and perfect tolerance or almost perfect tolerance So I I don't know about about putzopinib and and bob is going to to answer this question about about bebasisoma When we use it a lot and we use it a lot for a certain period of time in viva and trial We used to stop at one year We used to stop interferon and because of the double-blind fashion. I mean many people Including myself stop at one year bebasisoma and we had very good results So I think it certainly makes sense at least after one year If you have a good stable disease or a partial response to stop and and we have the surprise I mean to have some patients with very long stable disease or partial response after stopping the drug We also have I mean some data with With tki about cessation and we have put with brian reny team. I mean our updated Study that will be presented at asco And I think some patients will also benefit from cessation. I would say somewhere around one year So so clearly the data would suggest benard that patient's the majority of patients are going to progress Six months to nine months after stopping therapy Whether you aren't tk or bev and so can you do you re-challenge them? Do you put them back on the bev interferon at that point or do you move on to another therapy? So I I I for for this patient I mean I did put them back to bebasisoma and interferon and it it worked in in many patients Of course, I have more experience with tk with this kind of interruption, but with bev it also works I suppose with with presopinib or with submitinib for that matter if the patient is is tolerating treatment well and continuing to respond We we would generally carry on if there is any suggestion of toxicity We'd have a low threshold for having a treatment break And going back on treatment and generally we've we've seen patients Respond again when they were responding after after stopping And I mean, I think there is there is a trial in the uk going on the the star study Which will formally answer whether that's a good strategy or or not, but It seems a reasonable one in the absence of data I would like to ask a question to Tom So, uh, I mean you presented very nice data, but I'm torinibiter. So in first line I I agree with you that term as the most evidence Face-free data, but in your own practice, how are you selecting those patients where you give them and those patients where you give Soonity but tki. What what do you do in your own practice? I use the ascudier patented eyeball test No, so so you know when the person walks in the door with porous disease without having to actually calculate factors So patients who are really potentially hospice candidates, but they're newly diagnosed Very, you know, they usually will have hypercalcemia malignancy and other of the porous features and and that patient My experience has been that that for some reason the torinhibition Doesn't necessarily cause a lot of tumor shrinkage. I've never been impressed with it being a drug that causes Response that way, but it seems to do something to the biology of the cancer It shuts off the biologic activity of the cancer to a point that the patients actually start feeling better for a period of time Before they ultimately succumb to the disease and and so in that unique patient population Which is a minority and i'm a tertiary quaternary referral center It's a minority of my practice. I will use it then now I'll consider the vegev inhibitors because there are some thoughts that maybe they have some activity in porous disease And maybe someone that isn't as poor risk By the eyeball test are more functional We think I think they can handle the toxicity concerns, but if it's a true porous person then I will use 10 Other questions from the audience No, I You better so I want to ask a question to Amelia. So you You raise the point about kabosantinib and the dose which is used in the In the phase three that it's it's certainly a good point We have the same question about time serolimus When we compare the dose we use in kidney cancer compared to what we use in mental cell cast for example So do you think uh with kabosantinib there is a real Plateau in activity would justify to go at 60 which is actually an accepted Those or do you think we are doing a very big mistake by using 60? I I appreciate the question because actually I am Atonist by the data that I mean by the design of the of the two randomized trials with kabosantinib. I mean it is like 40 percent of the recommended dose found in the phase one trials It is 40 percent of the dose that is recommended for Medi-Lari cancer of the theroid And we already know what can happen here We had experience with Jaffetinib in lung cancer Which is also given a 40 percent of the dose We have the experience with temserolimus temserolimus. It is given a 30 40 percent Of the recommended dose and as thomas was saying From a pharmacokinetically point of view and also from a pharmacodynamic point of view It is demonstrated that temserolimus is unable to inhibit the pathway as well as it is done with haberolimus because of the different dose So I am really concerned that if the meteor study Comes negative if it is a demonstration of luck of enough activity of the drug or because of just Not enough drug in the patient, you know So so let me just add to this because this is a very interesting point and many of you in the room May be a gu doctors who treat prostate cancer And so kabosantinib is being evaluated in prostate cancer and in other tumor types Every tumor type outside of thyroid cancer is at the 60 milligram dose So I've I've inquired about this too clearly We have seen the phenomenon that That some cancer types the patients with those cancers tolerate different levels of a drug And it's a phenomenon that I don't fully understand and if anyone in the room has an idea Why the thyroid patients seem to tolerate the higher dose Whenever I've used it off label because it is approved in the the us So I can give kometric, which is the brand name kabosantinib And I can prescribe it to them whenever people have started at the full dose with the thyroid They have kidney cancer. They have a lot of side effects And then we lower them down to 60 milligrams and then my anecdotal experience In prostate cancer and in kidney cancer is that we see profound levels of activity of the drug Now whether that's a bias because it's just my experience But the drug seems to have activity even at the 60 milligram dose and is certainly much more much more tolerated There's a question over here, please Actually, I don't have the answer to this question, but I have another question so Regarding the use of ever alimers first line in poor risk patients, so Besides the Registration and drives trials we have is there any strong argument against the use of ever alimers in first line in poor risk patients because These patients wouldn't have to come to the hospital once a week. They could stay at home with their families and Based on the data we saw in this morning at least The substance should be as active as tensor alimers I mean, that's what we would that we would think that I mean There's different people that have different opinions whether the drugs are exactly equivalent or as is Tensor alimers a weaker drug because of the bolus administration of it My experience has been that tensor alimers outside of the inconvenience of the patient coming in weekly seems to be more tolerated Then the ever alimers at home Certainly our breast cancer docs that use a finitor have issues, you know They've gone through this whole idea of of the side effects and management of them more so than than we have in kidney cancer Bernard was just mentioning to me that he has a trial looking at that Yeah, we have an ongoing trial in France with a finitor in first line in poor risk patients and The only thing I can tell you don't use it until we have the data from this trial I think that's important and we can't say that they're the same. We really need that data I I just wanted to go back to the cavozant and if I participated in the common prostate cancer trial Where the dose was 60 milligrams and I can tell you that in every one of my patients I had to lower the dose to 40 milligrams because perhaps the prostate cancer patients are sicker. They've been on adT They've had chemo. They've had adiparator on or anzolutamide and we thought that that was the problem and With the kidney cancer patients I would really be frightened to To start at any other dose after the experience in prostate cancer And I think that that it's it's probably enough to start in 60 It's really probably enough. Yeah, the thing is that prostate cancer patients are really much more fragile I mean, they don't tolerate soon eating in the same dose a taxa tear and also with cavozant in it But if you go to the recommended dose in the phase one trial by doctor chiuri It is for kidney cancer patients And the recommended dose is 140 so it is the same population I do not believe that our kidney cancer patients would tolerate that dose not from my experience anyway The data are there. I mean they have Not a high percentage of great C. Toxins. They were I mean at least in that phase one trial Okay, thank you very much. I think we should end here I would like to do to thank all the speakers for the excellent presentations I would like to thank you for being here and asking the questions And see you next time