 Yn y gallu, dyma'n ymlaen, roedd ychydig i mi i ddim i'n gweithio. Rwy'n meddwl oncologist ac rwy'n meddwl i Cambridge, gyda'n y profiad mewn meddwl oncologi, ac rydyn ni'n cydnig i'r cantor ni ac rydyn ni'n cyntaf arill. Rydyn ni'n helpu i'r rhaid i'r gweithio clinical ar y cantor ni'n cydnig i Cambridge. Rydyn ni'n cydnig i'r cantor ni arall, o'r wneud o'r dechydau iawn. I was involved with the initial development, particularly of seraphonib and then some of the other drugs involved. Yes, I'm presenting a summary, if you like, and my view of the data that will affect the choice of first-line treatment recommendations for patients. So, I think there are a number of things that I'd like to cover in this. The first is that we've had a generation of agents—synitonib, seraphonib, pazoponib—which are very similar to each other, they're what we call multi-targeted tyrosine kinase inhibitors. They target angiogenesis, new blood vessel formation, which is very important in kidney cancer, and they do it by hitting a receptor called VEGFR2 and another number of other receptors. So, I think they're more similar than initially we first thought. So, we have very effective ways of controlling the kidney cancer with these agents for between 9 and 12 months nowadays with the existing first-line agents. The data that I'm reviewing at this conference is comparing two of those agents—synitonib and pazoponib. The bottom line is that in effectiveness terms, they are pretty similar. We couldn't see any statistically significant difference between them in a large study. Those data are presented by Bob Mox's data originally, presented by Camilo Porter at this conference. The other data I'm thinking about are what I would call the second generation agents. These are agents which are also similar to synitonib, seraphonib, but they are more potent at hitting the key target, and they are much less potent at hitting the targets we don't want to hit. So, this is trying to give the idea that we have on-target things that we do want to do and off-target things that we don't want to do, because they cause side effects without benefit. So, the second generation of agents like tyvosynib and axitonib do cause side effects, but they cause on-target side effects—things like high blood pressure, things like dysfonia, so you can get a hoarseness of the voice. Why that's on-target? We're not sure, actually, but we do recognise it with all these agents, and it correlates with how potent the agent is. Another thing sticking with the neck is that it can tone down the thyroid glands and hypothyroidism. We would consider all of those to be on-target effects. Examples of off-target effects are things like the skin rash, the hand-foot syndrome that one gets, the diarrhea. We think those are off-target effects, and another one, which is important, our liver function test abnormality. So, it's a question of balance between the side effects on the one hand and the effects on the other hand. Now, when we're comparing data from the COMPAR study, which compares sunatonib, which is our existing standard of care with posoponib, which is a very similar drug, but used in a slightly different way, we find that in effectiveness terms, there's really nothing between them. There's no statistical difference between them, but what there is is that patients seem to prefer the posoponib. So, these are from a separate study called the Pisci study, where patients were given first one drug, then the other, and asked, which did you prefer? And neither the patient nor the doctor or the nurse knew what treatment the patient was getting. And 70% of the patients actually said they preferred posoponib compared to 20% saying they preferred sunatonib. So, it's not 100-0. Not everyone could choose between them, most people could, but most people who could choose chose posoponib. We didn't see such a clear distinction in this COMPAR study. The purpose of the COMPAR study really was to check that you weren't swapping slightly more convenience and slightly fewer side effects for much less effectiveness, because I think that's a very difficult thing to square then. So, I would say that the bottom line of those data of importance today is that for most patients who have no liver problems, most patients would probably tolerate posoponib a bit better, it would be a bit more convenient, it would be a bit easier just to include it in your normal day. But I think that sunatonib is still a good drug and will still be better for several patients. Now, in certain parts of the world, you'll be able to get both drugs. In the part of the world I come from, you'll probably have to choose one or the other. So, it may be more important data in one respect for me in that it helps me if I've got one shot, which shot do I offer the patient. So, those are the data for today. There are also data for tomorrow, if you like, which I don't think are quite ready for prime time yet. The most advanced data are with a drug called tyvosanib. That's one of these second generation drugs, highly potent, highly specific. And that was compared with seraphonib, which was, I suppose, meant to be a drug which is easy to beat. Interestingly, we are much better at using seraphonib now. We recognise how to use it better. And so, the results we're getting with seraphonib are really in exactly the same ballpark as the ones we're getting with sunatonib and posoponib. Interesting. I wouldn't say that's really established it as a first line of care at all. But in this study, tyvosanib was found to have a longer period of controlling the disease just over a year. It's the first time we've gone over the year mark for patients who've not had treatment before. And apart from these on target effects, tyvosanib was otherwise pretty well tolerated. So, we are getting hypertension. We are getting dysfonia, the changing of the voice, and we are getting toning down of the thyroid gland, all of which can be coped with, particularly the blood pressure, hypertension and the thyroid gland. The dysfonia is trickier, actually. Although it sounds least serious, you can do less about it. And so, for some patients, this is irritating. From my experience, it's not terribly irritating, because it does happen with the other drugs as well. It tends to happen a bit more with these highly potent agents. So, I think tyvosanib, you could say, well, it's a good drug, it should be available immediately. And in fact, the company has applied in the US to use it. And I think that would be a reasonable thing to do. So, for somebody where quality of life is the number one consideration, and that's certainly in my practice in the United Kingdom quite a lot of patients, I would say tyvosanib is quite an attractive option. Other patients would feel efficacy and long-term survival at best, and we don't have those data reliably. In fact, interestingly, this study was mainly done in Eastern Europe. About 80% of patients came from Eastern European countries, where the situation is very different from the US. Often no effective treatment is available outside a clinical trial. So, in this trial, patients who got tyvosanib were able to go on to tyvosanib after that drug failed, after tyvosanib failed. But the same was not true, or the opposite was not true of patients who were allocated to tyvosanib. So, after tyvosanib, most patients didn't get any other treatment. And that is one plausible explanation for why patients in the tyvosanib arm going on to tyvosanib survived longer. So, there is a significant difference there, but the data are early. And I think although the explanation I've given is plausible, just because it's plausible doesn't mean it's the right one. And I think we have to say that that is a caveat. My own feeling is that we can get a little bit bound up in detail in oncology, but I think this is quite an important distinction. I don't think we need another phase 3 trial to show that tyvosanib causes the same, or helps the patient to live for as long as, shall we say, pysopanib or sunitanib, because I think that's going to take another three or four years. So, I don't think we need another phase 3 study to compare survival, but I do think we need some data to show that the results we're getting for patients with tyvosanib are very, very similar to those we're getting with sunitanib. So, I think those are data for tomorrow. And the other data for tomorrow will, I think, be available sometime at GUASCO next year, are with acsitanib. So, there is a first line study comparing acsitanib and other second generation with syrhaffanib, the drug that everyone wants to beat, because it's meant to be the weakest of the available options. So, I am expecting that we will have data for that drug as well. And I think those could be very persuasive data, and the importance of those would be that acsitanib could then be brought forward as a first line option. And I think that depending on how good those data are, that may well establish acsitanib as the agent of choice in the US, where it will be available first. In Western Europe, that would be much slower. So, if you like, in my view, pyzopanib has a period of time in the sun, but then there are new agents coming down the line. And the very last comment I want to make is that this is not the end of the story. I think we're very close to achieving all we're going to do with single agent tyrosine kinase inhibitors. But at this conference and other conferences, about new immunotherapies, new targets for drugs, we're going to get adjuvant therapy data, all of which may cause major benefits for patients in the years to come. And I think this is a really exciting prospect where hopefully we will be controlling disease for much longer. And of course, the golden chalice, if you like, is to get rid of it all together. I think there are two questions that everybody should ask their doctor when they get this sort of news. And the first is, can you tell me exactly what's wrong with me in my kidney and elsewhere in my body? Because that's going to determine what some of the treatment choices are. And I think that you do need to know these things if... And I say if, not because I'm a particularly patronising person, but because not everybody wants to make their own decisions. Other people want to listen to what the doctor, the nurse, their primary care physician suggests and do that. Other people want to be very involved in the decision. If you want to be very involved in the decision, then there are some basic things you need to know. The first one is, where is my disease? What is my disease? And what other problems do I have? Those are all important because they will tell you, or they will tell your advisers, if you like, what treatment options you theoretically have. So, for example, if the disease is limited to the kidney, surgery is going to be your best option. What kind of surgery? If you have disease in different parts of your body, is surgery really an option? No, probably not. It might be in a few cases, but usually not. So what treatments are available? Am I fit enough for them? What are the pros and cons of each of those options? So, I think the second thing to ask is, what are my treatment options, given what you just told me about what's wrong with me, and tell me the pros and cons of each of them, please? And the last thing I would say is, there are very few decisions in kidney cancer which need to be made on the spur of the moment. Much, much better to take your time to reach a decision not necessarily that you're happy with, it may not be a happy situation, but the important thing is to make the best decision for you. You must be satisfied with the decision and the reasons you've reached that decision. And if you're in two minds and you want to be guided, then ask for that guidance. And there are people who can guide you. The nurse specialists who are helping you are often extremely helpful at putting it in the right language rather than the medical jargon that I and others often use. You need to understand the issues if you want to make the decisions. And most doctors and I think most nurses would like most patients to have a part in the decision even if it's not the whole part but a significant part. It just makes life much easier. You will do better in my view if you feel that the decision is something you can live with. Yes, the importance of asking questions is it's important at the time that you understand what you're told. If you don't understand what you're told, that doesn't mean you're thick. It means that you just don't understand what's been told. So we all break into jargon at times. Do please clarify things which are not clear. You are not wasting our time. It's one of the most important parts of medicine to make sure that you are communicating properly with the patient. And actually for me it's much easier for somebody to say, hang on a second, I didn't understand that. Then for me to whitter on at length and then ten minutes later work out that actually stage A wasn't understood so everything else that I've been going on about hasn't been understood either. So please, please, don't feel embarrassed. We are there for you. You're not wasting our time. Much better to interrupt us.