 I ask Tom to come to the podium and to make his talk about optimal systemic therapy in setting of hepatic and renal dysfunctio. Thank you very much for advising me. The optimal systemic therapy in hepatic renal dysfunction, which is an appropriation view of what I was doing last night. I've pressed the wrong slide already. I'm going to start with renal dysfunction if I may and then move across to hepatic dysfunction. I think the hepatic issue is more complicated. I don't think we know enough about either to be honest. I think the reason we don't know so much about renal dysfunction is actually the problem isn't as big a problem as perhaps we make it out to be. The issue with hepatic dysfunction is I think actually we lack a little bit of an understanding about exactly what we're dealing with. I think as a group including myself we're just a little bit confused about what a transaminitis is and what hepatic failure is. This is the, obviously, compars and this is looking at increased creatinine associated with pisoponib and snisnib and as you can say it's vanishingly rare. These drugs are not associated with dramatic problems in terms of renal function. This is a patient. I've got a couple of patients which I'm going to talk about who we saw just recently. 67-year-old female nephrectomy in 2010, non-insubprenent diabetes, grade 3 clear cell renal cancer in the remaining kidney. Relaxed, contralaterally, creatinine 240, creatinine clearance less than 20, as you can see a big mass. We have a long debate I'm sure you all do in the room about whether you remove this mass. The problem with this individual was actually that they had widespread metastatic disease with liver and lung disease. The issue is what we do here, do we give them systemic therapy and I can see from the graphs of the questions that we've answered already that people are keen to treat these patients. Certainly the options go along nephrectomy and systemic therapy. We wouldn't do that because obviously you would render them dialysis dependent by doing that nephrectomy. The second option is systemic therapy which is attractive, observation alone and Brian talks a bit about observation. This individual had immediate risk disease and we tend to start targeted therapy in these individuals and then nephrectomy alone which I don't think is a particularly attractive option. We went for option 2, systemic therapy. Which therapy do we give and at which dose? I think the second question probably is more important than the first question because there is a little bit of data out there suggesting to us that actually we may be playing around a little bit with these drugs. The data that is available, this is a creatinine clearance of less than 60. Actually this is relatively common, lots of patients have a creatinine clearance less than 60. This is not an uncommon situation and in fact I, looking at a creatinine clearance of less than 60, I am actually not too concerned about this sort of level and I wouldn't bat an eye about giving full dose and going straight in and I probably wouldn't get over excited about it either. You can see from here and I accept the numbers are very small and this is about the best data we've got. But you can see from here that there's nothing standing out on this page to suggest that synitinib is not safe in this population. I guess the same applies for mTOR inhibitors. Again very small numbers but effectively in this population with moderately impaired renal function both drugs look very safe. The key question I guess is in this population with moderate renal impairment, do the drugs actually work? Very few of these patients require a dose reduction and you can see with a progression free survival of 10 months with response rates in the 20%. There's no suggestion in this moderately impaired population that number one we should be playing around with the dose. Number two is we can give any of the drugs and we should be comfortable with all of them, pysothinib, synitinib and mTOR inhibitors. And number three is we shouldn't expect necessarily patients to do badly although I accept completely the numbers are small. And you can see here from the tolerability slide that actually the drugs are relatively well tolerated. Again nothing stands out from the page suggesting that we should be doing anything different in this population. This is a slightly more complicated issue and Simon Chowdery led this study from another retrospective analysis looking at more severe renal dysfunction. So these people have a crack in the influence of less than 25 or they're on hemodialysis. And two things for me. Number one is I expected a lot more toxicity. I expected a lot less, this is supposed to be an F not a D, I apologize. I didn't expect a progression free of 10.5 months. I was expecting a mismatch of patients. The one thing that did stand out though is over 50% of patients started at less than suboptual doses. So that's most patients starting synitinib 37.5 or pysothinib 400, lots of people those escalating without problems. I think that to me demonstrates a nervousness and that nervousness is being generated by a lack of data. So I think what we have is in moderate renal impairment we have no concerns in more severe renal impairment. We have a nervous community but actually when you give the drugs the toxicity profile and the outcome actually looks pretty good. So perhaps we should be confident or slightly more confident in this population. Remember the drugs aren't metabolized by the kidney. So we shouldn't get too focused on that. There are some PK results and I'm just now on the final part of the renal. I'm going to talk about hemodialysis patients. I'm nervous about hemodialysis patients and I've created half a dozen perhaps. There has been some quite nice PK work done both here and in a couple of slides I'm going to show in a minute. The key to this PK data is twofold. Number one is when you give synitinib both that decreased dose and at higher doses. You can see from this curve here, it's this bar, it's the bar here, the solid buff is the dose that one would like. You can see from here that we can achieve doses that are equivalent to those done in the phase one PK studies on hemodialysis. So give the drugs seems to be the message from these results. Number two is the synitinib concentration seems to be independent of the timing of the dialysis. So we shouldn't get too fixated on giving the drug two hours before or two hours after dialysis. So remember the half-life of these drugs are relatively long. So that's a question which I'm often asked is if you're on hemodialysis when should we be giving the drugs? It doesn't seem to matter that much. Should we be giving 37.5 or 50, 400 of pysopinib or 800? Again, I don't think we know the answer to that question. I would suggest close monitoring of these individuals because of the lack of data that we have. But I think caution is wise but I don't think that this is a hopeless situation and we should treat these patients where we can appropriately. This is more pharmacokinetic data supporting the previous slide but not actually adding very much to it. Beyond the PK suggests that the dosing on hemodialysis falls with the PK data falls within what we would acknowledge as standard type PK results. So just to summarize the first part of this and I think it's the easier part. I think the data is not great and I just think maybe why is the data not great and I don't think it's because we don't have the opportunity to publish because I'm sure that any of us in the room could gather a group of friends together and get two or three hundred patients within a year. I think it's actually because we're not as excited about this area as we could be because the preliminary data that's come out suggests that there isn't a problem and it's very rare for me to speak to people about patients with problems in this area. So I don't think we should get too focused on this issue. I think we should work towards standard dosing and I think this applies for particularly those individuals with moderate and more severe renal impairment because it doesn't appear that these patients are compromised and it does appear that we can get good efficacy results. And I wouldn't get too fixated on the hemodialysis issue either. It doesn't necessarily make things more complicated. I would encourage close monitoring but I don't think again it's a hopeless situation. I'm now going to move across if I made the second part of the talk which is totally unrelated to the first part of the talk but follows a similar line and that is actually hepatic impairment. And liver toxicity is graded by a child-pew score. These are the parameters. It's like the Heng criteria. You get points and then you go from A to C and with this you can predict treatment algorithms and outcome. And this is what the liver doctors do at all of our institutions day in, day out. What they don't do is they don't focus on CTC criteria of a transaminitis. They don't actually look at the transaminitis as I'm sure we all know when an individual goes in with liver failure after a paracetamol overdose they're not talking about grade 3 or grade 4. They're interested in albumin, they're interested in INRs, they're interested in encephalopathy. But what we're doing with all of the VGFTKIs is we're giving drugs and we're identifying transient transaminitis. And I think at times we're calling this liver toxicity and I'm not sure those two fit particularly well with one another. And again, CTC criteria and I've banged on about this many times and I will again today, they weren't designed for VGFTKI therapy. They were designed to assess chemotherapy toxicity. And it's very important that we remember that these figures here of grade 1, grade 2, grade 3 and grade 4 are very much plucked from the air. And don't really mean if you have grade 3 toxicity, there's been work to suggest that's worse than having grade 2 toxicity. And that's a really important message that I'm going to try and get out today if I can because it's again a question that I'm asked a lot. So actually there is a real dearth of data in this area about what it actually means if you get a transaminitis, whether or not you need to stop the drugs and whether or not you can reach out and I'm going to try and address some of those issues today if I can. So I'll do this with a patient, so this individual, a transaminitis, 62-year-old male, starts with an ALT at baseline, perzopinib 800mg, standard doses. On cocodamol, there's this paracetamol issue which people sometimes talk to me about. And after five weeks we've got a grade 3 transaminitis. I'm not going to ask the room what they would do but we kept going and we actually kept going. So a week 7, they'll move from a grade 3 transaminitis, sorry, it'll move from a grade 1 to a grade 2 transaminitis. ALT, the upper limit of normal and continuing on perzopinib. I hope by the end of the talk on the next five minutes I'm going to have given you some clarity about what we should be doing on this individual. So what's the data that we know? So this is synisotib, again, this is the COMPARS trial. So as you can see, it's raised ALT, both drugs causing 60%. Grade 3 or 4 toxicity, that's a transaminitis, so remember that's going to be the raised level. And you can see perzopinib higher than synisotib here. So a transient transaminitis being caused by both drugs but perzopinib more of the grade 3 toxicity and the same applies for raised ALT. So the question that I'm often asked is when does this occur? And this is some work, some retrospective work that we did in a series of 125 patients, a number of people in the room involved both from London and the United States. And the issue here is you can see that actually the occurrence is occurring particularly in the first 12 weeks of therapy. So 90% of these events on perzopinib occurring in the first 12 weeks. And in fact the more severe the grade 3 and 4 transaminitis, all of it occurring within the first 10 weeks of therapy. The current guidelines for LFT monitoring are this 3-weekly process. So you can see from this, looking at these blood test measurements, you can see that we're measuring them regularly and we are going to identify most of the transaminitis during this period of time here. As time goes by when you look at these patients here, some of these patients of course they've developed transaminitis, some of those are associated with things like progression of disease. So after this period it appears to be very rare. And the second important question is okay so we've developed the transaminitis, how long does it take for the LFTs to normalise and when can we expect to restart the patient back on therapy? And you can see from here the median time is approximately 4 weeks to get back to a grade 1, a less than grade 1 transaminitis. The issue about grade 1, as I said before, is that's never been validated at the time to restart. And many people in this room and many people I'm speaking to are restarting drugs with patients who still have a raised ALT or AST. And so therefore most people are starting, are restarting between 3 and 5 weeks in this series in which we looked at. So the next question which is can we give the same drugs safely for a second time? Can you re-challenge with Pozopnib or if it occurred with Stunisnib or Seraphnib, can you re-challenge with those drugs too? So 32 of our patients were re-challenged and many of them were re-challenged back at the original dose. And actually the recurrence of the toxicity only occurred in 7 of these 32 patients. And so one of two things is happening, either there's a tolerance is occurring, this is a transient period which is self-resolving or the dose reduction is effective. I'm just going to point out this one patient, so one patient for whatever reason actually didn't stop. He developed a grade 2 toxicity and didn't stop Pozopnib, just kept going straight through. And actually it was a self-resolving problem. So this may actually be a self-resolving issue. Yes, I do think we need to address it and particularly for those patients who develop an extreme transaminitis, but I don't think it's again a hopeless situation. I think we need to be very prudent, we need to wait for normalisation, but I think we can re-challenge. Whether or not you re-challenge with the same drug or switch to a different drug is very much up to you as I see it. Just the last couple of slides and the numbers are very small and I don't want to be too provocative. But for those patients who developed a grade 0 or a grade 2 to 4 toxicity, you can see there may be a small difference between those and the individuals who developed this grade 1 toxicity. So the issue out there is like the hyper tension. Is there a correlation between development of toxicity and outcome? This data does not suggest that. More data is required, but I think it's an interesting area. And I just thought I would just give this slide and this is the recommendations on posopenly related liver toxicity. And I think this is a useful slide. Again, look at the reassurance. So transaminitis levels of less than eight times the upper limit of normal continue on drug. I'm not sure how many in people in the room are not interrupting after five. Certainly historically that's what we've been doing. This suggests that yes, we should be monitoring regularly, but we should also have confidence that we are able to do this safely. If it occurs in concurrence with a raised bilirubin, the situation is somewhat different. And obviously if it goes above eight times the upper limit of normal, interrupt. If it is going to occur, it will happen in the first 12 weeks. Interrupt, restart, and you can restart safely either posopenib or an alternative agent like sunitonib. So this is the patient who I was treating. And actually I, at five times the upper limit, I don't interrupt this patient. This was treated some time ago. I think the message is keep calm and carry on to a point. But obviously close observation is very important. I'm not stopping the paracetamol at this point is wise. I personally did it. I'm not sure there's any evidence it helps. So what I'd like to just conclude if I may is to say that specifically for this hepatic part of the talk, let's be really clear this is not liver failure or liver toxicity. It's a transaminitis. It's very different from the child-pew score. It's a transient event which is occurring in the treatment course that requires monitoring, re-challange is possible and safe and it's usually okay. CTC criteria again unfortunately here I think being counterproductive in my opinion. And we probably should work together to work out a better way of doing this. And yes we need a lot more data in this area because I think it will be helpful for the community. Thank you very much indeed.