 Felly ydych chi'n rhoi ychydig yn ffaith i'r Caeneryswyriau Maennyllewyr, Pamela Porter, a Jan scrape Patard, fel i'n gwieithio ym mwy angen â'r ystod yn bwysig y knead a'r mystaeth ymarfer o'r tynni Gawr mynd i'r ysgolais llawer a'r bobl yn cyflu peisiwn defnyddol. Ond fyddwn i'n gwiswch yn ei maen nhw'n gwybod, oherwydd hefyd yw'n gwybod i'w oeddech chi'n Ono, mae'n rhaid i'r wrthig fydd ar ddweud hynny mae'n mynd i ddweud yma yw Martin cyflawnr y ddweud yn ddweud wedi'u bwysig yna yn 2004. Mae'r dweud wedi'u dros y bydd yr dysgu ddweud, a'r ddweud os ymddir o gael yma, a'r ddweud yn ddweud yn ddweud yn ddweud o'r ddweud. Martin's efforts in kidney cancer research have been tireless over the last 20 years and his efforts along with those of friends and colleagues, many of those in the room, have brought about many of the advances that we've been lucky enough to discuss during the course of this meeting and have improved the treatment of this disease and indeed our understanding of the disease. You can see on the slide now, there's a few other things that I'd like to tell you about Martin Gore that perhaps his friends in the kidney cancer world don't all know. Where are you, Martin? You don't need to worry. Oh, there you are. Good. I'm glad he's here. So, the first thing to say, actually Martin isn't just an internationally recognised figure in kidney cancer. He's actually an internationally recognised figure in ovarian cancer and melanoma and that's actually not very common I think these days in 2014 to be widely recognised in three different tumour types. Another thing is that, as Martin likes to say, he has a management job and typically modestly when he says that what he's actually concealing is the fact that he's the medical director of the Royal Marsden Hospital, so not just the department, the entire hospital. He's done that for most of the last decade so that is not by any means a small job and actually in the last decade we probably had the most difficult period in the long history of the institution with the fire in 2008 which I suspect many of you know about which actually damaged a large part of the hospital in Chelsea without Martin's guidance and leadership but that stage I think we could have seen a very different outcome. I'd also like to point out and it tells you on this slide that Martin I think over the years has meant dozens of doctors in training, some of whom are in the room. You heard from Tim Eisen already this morning and you heard from Charlie Swanson yesterday. I certainly wouldn't be a medical oncologist if it wasn't for Martin. I turned up at the Marsden about 15 years ago as an undifferentiated junior doctor not sure what career to pursue and it's absolutely as a consequence of Martin that I'm a medical oncologist and I think that should be recognised and I think mentoring is one of those things we perhaps don't talk about enough or take seriously enough. Martin has dedicated his career actually to public service to the Marsden and actually also to the national health service and again I think that's something we perhaps don't talk about enough but I think most importantly I'd like to finish by saying that Martin is a staunch advocate for patients with cancer and despite all of his commitments at the Marsden nationally and internationally not a week has gone by in which Martin hasn't been in the clinic looking after patients and their families and fighting to improve the treatment of this disease. So with that Martin I'd like to invite you up on stage to give the Eugene P Schoenfeld lecture and kidney cancer gazing into a crystal ball. What will the treatment be like in 2024? Martin. Thank you very much. Dear friends and colleagues this lecture is dedicated to two surgeons who are sadly no longer with us Bill Henry who when I arrived on faculty in 1988 and started treating patients with interleukin II with kidney cancer and melanoma he pulled me aside because the other urologists would not perform nefrectomy. And they made that very clear the second day I was there and Bill pulled me aside he said I will do whatever you want me to do you want me to take the kidneys out I'll take them out. I don't know if you're right or wrong with what you're doing but at least you're trying to do something you tell me what you want done and I'll do it. And for a young person arriving on faculty that is really something to hear from a hugely senior and respected surgeon. And then poor Tim Christmas who was his student who was probably the most talented surgeon in the UK of his generation died tragically young. He was on staff with us took over from Bill in 2000 and was an enormous supporter of myself and a great help a wonderful person to work with terrible terrible sense of humor very irreverent certainly kept me in my place but he sadly missed as well. I want to thank the KCA on behalf of really Bernard and myself because without their support this meeting would never have happened. We wouldn't have dreamed of having it and you know the fact that it initially at the time was an American patient advocacy advocacy group meant so much to Bernard and myself because they were reaching out to us in Europe. Bill Brod likes to stay in the background but I want to pay tribute to him because his personal drive and support for us has been immense and I think he's the main reason why we're all here 10 years later. And of course, dear Ron Bacovsky as well who with Bill kind of kept kicking Bernard and I to get on with it. So thank you very very much Bill and the KCA I really appreciate it. So this audience probably doesn't know about Eugene Schoenfeldt who was a co-founder of KCA. He was an academic as Carrie said yesterday in journalism mainly. He founded his own company having completed a PhD at Northwestern and tragically he was diagnosed with kidney cancer at a young age and in 1989 became the founding president and chief executive officer of KCA. And not many people know that in fact KCA grew out of a patient group that Nick Vogelsang who many of you know who's been a great friend and inspiration to so many of us had a patient group which with great foresight and Gene went along to the third meeting. And KCA was born and he drove it and he drove IL-2 the licensing of IL-2 at the FDA. He traveled up and down the country and he was a great advocate and he tragically died from metastatic kidney cancer at the age of 54 only. And this was the FDA's eulogy to him that appeared in his obituary and I think it's very interesting that it comments on patient activism something that's very much and quite rightly with us now. And this is a man himself. I guess we have two things in common one he got kidney cancer and I started treating kidney cancer at about the same time. And also we we both seem to like rubberware quite a lot. So we're both scuba fans. So this is a look at what's happened and what's going to happen in 10 years time. But you know you don't know where you're going to go to if you don't know where you've come from. And I'm a great believer in learning from the past. So what was it like in 2004? We're now 2014 and the lecture will be about 2024. Well these were the oral presentations at ASCO in 2004. And you can see from from the titles and I put in red the salient points. We were starting in the targeted era. The education session had education sessions on SNP. We were attempting. This is Nick Macy's work who worked with us on infliximab anti TNF. Phyllidomide was around and we were starting off in the targeted era 10 years ago and look where we are today. 10 years later with a lot of information and twice the overall survival for our patients which is important. This is taken from the education book in 2004. And these are the investigational strategies that are described. And I draw your eye to the immunotherapy section because I think it's relevant and it's interesting that the list is a bit like David McDermott's list yesterday relating to combinatorial therapy. And I'm going to cover that. And then here are the other investigational strategies that you can see listed here. And really some of the lessons that we learned we made so many mistakes. If you look at the date of this this is Sylvie Negrion and Ben Ars group looked at poor prognosis patients to prove what we kind of already knew or thought we knew from retrospective series that if you had a poor or moderate prognosis you did not benefit from interferon or interferon IL2. But look at the date it took a long time for that to get to print. And the whole issue about complete remission rates on interferon or did you need interleukin 2 and what were the real rates of durable CR really were only known 10 years ago. And it took a long time when you think that we were using interferon in the 80s to get to some of these quite simple answers took a long time. And it took a long time because we did not do the right randomized trials. We were over optimistic and you cannot beat randomization particularly when you're manipulating the immune system when there are so many biases about which we do not know. And remember that is the reason for randomizing patients is to get rid of unknown biases. Could we move the slide forward please. Thank you. So treatment in 2024. So as far as the targeted agents are concerned we will not be using the TKI's or at least we will not be using them as we use them now. They are too toxic for chronic treatment in my view to have great even grade one diarrhea for two or three years is pretty miserable to have hand foot syndrome grade two for six months is pretty miserable. This has got to stop. I do however believe that the target will remain a target because it's such a powerful biological factor in this disease. But we will develop new molecules and whether they'll be on chromosome three as Charlie was talking about yesterday or whether they will be different targets. I don't know but always remember that however well we do systemically and however much people write about I saw a patient with a cerebral metastasis who responded in their CNS. Remember CNS disease will always be with us as a sanctuary site and none of these treatments are that good for CNS disease. So however well we do systemically always look always look to the brain. Remember childhood leukemia was not cured until CNS prophylaxis was successful. So can we move the slide forward please. I believe the next 10 years will be dominated by immunotherapy. We spent the 90s completely dominated by immunotherapy and we're going to spend the next 10 years dominated by immunotherapy in this condition and probably in melanoma as well. Next slide please. And immunotherapy is wonderful. Immunotherapy is the world's greatest pharmaceutical company. It is an automated continuous personalized molecular identification patient selection. GMP synthesizing GMP compliant manufacturing treatment delivery system and it's all in vivo. And it's continuous and it works 24.7. And the data from melanoma is extremely exciting because we are waiting for some very important results and the results in melanoma are going to guide other tumor types I believe. This is data which demonstrates that if you wait long enough and you follow patients up for minimum of five years as in this randomized trial with epilimumab in one arm. You are able to answer the plateau question and that you cannot answer the plateau question if you do not wait five years. Because what you see is that plateau occurs after three years but not before. And if you look at some of the data that people are excited about with anti PD one plateau has not been reached and cannot be defined because as you can see from the sensor points it is too early. And what worries me about anti PD one as a single agent is when I look at this curve and just to be fair to all companies involved with anti PD one. I got a horrible feeling these curves will not platter with PD one by itself. We will know that very soon I think very soon meaning in the next year or two. But do not always look at the sensor points and always look at the x axis because plateau we know from epilimumab can only be defined provided you really really follow everybody up for five years. These however are the data on which I make the statement that the next ten years will be about immunotherapy. The combination of in this case nevolumab and epilimumab has been quite striking. I have been involved in more false dawns in my career than I care to tell you about. I'm the man who's never performed a successful randomized trial in terms of finding anything useful. But nevertheless I believe in this and I think this is extremely important. And what we are learning is that some of the old rules of immunotherapy still apply and please don't forget that. For instance LDH and this has just been published with our colleagues at the NKI is a prognostic factor in the same way as it was way back in the past when we were doing bio chemotherapy with chemotherapy in aisle two and interferon. So some of these truisms stay true and immunotherapy is immunotherapy even though the tools may be different. There are two pivotal trials that we will know the answer to. The first is this trial that we're waiting the answer for which is a dose question. This will influence our thinking. We think 10 milligrams per kilogram is better but we don't know. This will tell us and it will fundamentally change the way we think about this because there is a there is some evidence with interferon and look into that things are. Could be as far as doses concerned that there may be a bell shaped curve is more better in immunotherapy. Well not always and checkmate 067 is extremely important because it will tell us whether the combination makes a difference. And it will also give us randomized data on anti PD 1 and epilimumab by itself to look at the plateau with combinatorial therapy. Our experience is that there's quite a lot of toxicity. It's unexpected it's quite difficult and everyone is simply throwing corticosteroids at these patients. And I believe we need to go to our hematol oncology colleagues in transplantation and get some advice about how we manage these patients. And combinatorial immunotherapy will be the way that we will go and we're going there already but it frightens me to death because that's where we were in the 90s. There's a series of terrible uncontrolled phase two and phase one B studies and we called them all sorts of things and we learned nothing. I did a small randomized phase two trial in Melanoma which we included GMCSF and I ought to interfere on it. It was totally underpowered hugely toxic. Yes the old immunotherapies are back such as adoptive immunotherapy because immune checkpoint inhibition is so important. I'm not saying we should not do this but if we do not do the trials properly we will run into all sorts of problems. And you know meet the new boss same as the old boss Pete Townsend wrote and recorded in 1971 on the Who's Next album and you need to really reflect on this big time. Because if you look into the face of Ronbukowski and myself and Bob Figglin and Mike Hakins you see battle scarred veterans of people who did not learn the lessons quickly enough of immunotherapy and trialling it. Immune monitoring will re-emerge patient selection I hope will become routine. I think pet technology or at least diffusion weighted imaging will help us define who's got an inflammatory response and what that means and remember CNS disease. We saw increasing numbers of CNS potassium disease with bio chemotherapy in Melanoma in the 90s because we had a high response rate for about 40 percent and we were clearing the disease systemically or be it temporarily and patients were relaxing in their brain. So the clinical trials must be either biologically based with a biological rationale or and you don't hear this very often. Some sort of systematic rationale for instance you might not have the biological basis for knowing when and how to do maintenance. So think of it in a rational practical way of how you might deliver it in the clinic. For instance you might want to randomize patients between elective continual maintenance elective intermittent maintenance and relapse directed quote maintenance unquote in other words allowing the patient to have an early relapse and jumping on that immediately. That's the sort of pragmatic approach and we need to do those sorts of trials even though they're not biologically based. We must examine dose and schedule early. I mean look at the conversation today about the one to the two one synitimid regimen for instance with 10 years down the line and we've missed a trick with a treatment schedule that I believe would be is when I've used extremely patient friendly always always randomized in immunotherapy trials. I did a randomized phase one trial level of Amosol believe it or not and interleukin two in the early 90s and it is doable. I mean it was completely hopeless but it is doable these sorts of designs to look for the dose. We have got to stop doing medians and talking about medians. It's completely useless and it's incomprehensible to the patients besides anything else. We must do time point comparisons and raising the plateau I believe in 2024 will be what we are looking for. If the baseline plateau is 20% at five years i a time point analysis but it's a plateau analysis as well what is the effect of treatment X. Does it go up 10% 30% 40% very very important data that the patients want to know about and I suspect the funders of health care would as well. I would like to see by 2024 regulators demanding that post trial treatments and outcomes are collected. The amount of data we have lost by not simply asking investigators tell us what you gave at second line and what happened. I mean it's not rocket science it's dead easy it's in the patients chart anyway and I believe that should be mandated by 2012. Immunotherapy versus targeted agents is not a competition what the immune checkpoint inhibitors have taught us is that it's all about signaling. It just happens to be about signaling and immunocytes but the two fields are coming together in terms of translational research. I don't believe that combinatorial therapy is going to be successful. I think we will end up sequencing or alternating targeted agents and immunotherapy in 2024. Regotherapy is going to arrive big time in the management of patients with cancer. Watch in 2024 you will be going to an education session on carbon ion radiotherapy as sure as eggs is eggs. The abscupal effect of radiotherapy is going to be very important to us involved in immunotherapy. First described by somebody who worked at the Howell Atomic Energy Research Institute in the UK in 1953. It's interesting the word comes from abs away from and which is Latin and then Greek Scopus which means a target and away from the target and it was described all those time all those years ago by R.H. Moll. Stereotactic radiotherapy and maybe carbon ion therapy is going to make the management of relatively slow growing disease that is oligometastatic a complete subject. You will go to an education session on the management of oligometastatic disease the non-systemic treatment of it in 2024 ASCO G.U. I think RFA and maybe even partial nefrectomy will be ablated by stereotactic radiotherapy and carbon ions. You will go and you will listen to the results of a randomized trial between partial nefrectomy and carbon ion therapy perhaps and you will need to give some money to the poor starving surgeons outside the session whose children are starving and they can't afford. We won't be able to afford to go to the meeting poor loves. It's going to make two comments about translational research just to say that I think that pharmacogenomics has been greatly ignored too much. It is in some ways the zenith of personalized medicine and I don't think we pay enough attention to it and the different ethnicities and the different pharmacogenomics in those ethnicities. I think it does have an importance particularly in this globalized world that we now live in. I just really want to make a comment about phishing for biomarkers. The therapeutic target is not a biomarker so could we stop calling Eastern receptor HER2 and BRAF mutations a biomarker. They are a self fulfilling prophecy that a treatment is going to work. Biomarker is when you go fishing for a molecule to try and guide you what to do because you can't work it out for yourself or you're too lazy to do the clinical trial. Terrible history of biomarkers. I mean there almost has never been one that has been discovered through a phishing expedition. Someone could tell me at lunchtime I'd be very grateful so I can change the slide. And anyway with biomarkers even 80% is not good enough because a patient who is in the 20% will say well I want to give me the treatment anyway. I think what's more important is diagnosing response early and methods to do that. I want to just finish off by talking about the patients. Quality of life has become a tick box exercise and this is the quality of life forms for a study that James and I have just completed. It is a farce what is going on with quality of life and in 10 years time it will change. I think we will learn from the qualitative world of research nursing how to handle things because when you look at the data on what doctors think patients want. It is a terrible indictment of all of us in this room who look after patients. It's an example from breast cancer. The red of what the doctors think the patient wants in terms of keeping the breast as a top priority and considering prostheses or why you have chemotherapy and it's completely askew and out of kilter with what the patients actually want. Knowing what the patients want and having people really properly informed and sometimes using video assistance and different types of learning material actually saves money. It's been calculated that when patients really direct their treatment about 20% of patients opt for less treatment about 40% opt for less surgery. Actually just by giving patients what they want could save huge amounts of money. Money is what I want to finish on because the relationship between the economy and money for research and service and drugs and whether healthcare dollars are moving towards the east away from the EU and maybe the US as well. Is very important for all of us academics in the room and we cannot bury our heads in the sand about this. We do need to confront it and we do need to work out what we are going to do about it and I suspect in 2024 we will have had 10 years of reducing resource and we need to have a strategy now for that. So I was wondering when I was talking about this you know the Marsden will carry on brilliantly I'm sure under the leadership of my young colleagues. The question is whether our sister institution the Gustaf Rusi in Paris what that will look like in 2024. Well I believe it will thrive and obviously the question on everybody's lips is what will Dr Escudier be doing at the Gustaf Rusi in 2024. Well he will still be interviewing fellows to work with him so little will change there I'm so pleased to say. So thank you to my team the residents in training our fellows our data managers and of course our research nurses. Four people particularly six people particularly I want to thank 1988 Jackie Moore was the sister of our intensive care unit and she left her job to join me and open together the biological therapies unit which we called grandly. We actually didn't have any patients for a bit but she really drove the whole thing and Linda who I had known as the most junior houseman at the Marsden she was staffness on the ward in 1978 came to join Jackie and I a few years later and has been the complete driving force for our research nurses and it is a great it is an enormous support. To myself and has been for many many years. Tin worked with me for a long time and he helped with the he actually was the first author on the very first paper to describe the actually the activity of the lidomide in cancer. He helped us with the inflix madd program and he drove the targeted therapy program in reedle he closed down the therapy program and then left for Cambridge and left me with no therapy program which is why we are now several years behind and I just want to thank him for ruining my career. But but you know yeah thanks. We are we have repaired it to relatively new faces for us Lisa Pickering another medical oncologist and David Nicole who we appointed a little while ago as our chief of surgery user urologist who you heard from yesterday who's been a fantastic support and I thought we would never replace Tim but we have in spades. David is wonderful and of course my dear colleague and friend James who now runs the show and who I work for although as medical director I am still in control of his salary. Finally of course the patients and their families thank you very much.