 Tom Hudson from Dallas. Thank you for being here. Thank you. And you will be discussing temporal iris and what is the best patient for an mTOR neighbor to write? Certainly and and it's hard to to match Bernard and his last slide there but we'll try to do this. I have to be honest with you when I got this invitation I wasn't sure if I should believe this topic. I thought it was a joke. Who is the ideal mTOR patient? You've already heard from three speakers eloquently about VEGF inhibition. Certainly those the VEGF inhibitors seem to be the most generalizable drugs out there so most patients we see are going to be candidates for that but I think what you will see is that there are subgroups that are probably ideal for mTOR inhibition alluded to already by my colleagues. Poor risk being the one that we're most common with but you know what we're looking for in kidney cancer is really predictive factors for targeted therapy and and we really don't have any validated predictive factors yet and I just remind us that we have a variety of different biomarkers that we're using in cancer management but the ones that are most important for us that we have at least some preliminary data needs to be validated as prognostic and predictive biomarkers and in some regards some pharmacodynamic biomarkers and I wanted to review the data that supports the role of mTOR inhibition as a viable cancer option for selected patients with this disease. I think right now clinically many of you in the room would agree with me that the factors that aid in selecting agents between the classes VEGF and mTOR are shown here you got VEGF inhibitors we generally think for good performance status patients who need rapid responses in certain comorbidities whereas the mTOR inhibitor class sometimes under recognized as an important class in this disease has been left to poor risk disease patients which it really should represent 10 to 20 percent of our practice in the frontline setting patients that have had prior VEGF inhibitor i.e. second line or refractory setting a non-clear cell histologies is often pointed to as a reason to use mTOR inhibitors so these three bullet points here are probably the main subgroups that we're going to explore as potential roles for mTOR inhibitors. So let's start with TEMSARLIMUS which was the newest or excuse me the oldest of the mTOR inhibitors that really heralded the the class as an viable cancer strategy. If you remember back to Gary Hudes New England Journal paper this was a plenary presentation at ASCO the same year Sutent was presented was a trial that was done in predominantly poor risk patients in fact it's the largest trial done in a poor risk patient population the only of only agent which documented overall survival as a primary endpoint in a randomized phase three trial in as you recall the modifications that occurred in the poorest features to allow the trial to complete enrollment but these are generally the acceptable acceptable poor risk features and there was a benefit in favor of single agent TEMSARLIMUS with the median survival of 10.9 months. You heard from my colleague Dr. Hawkins about Pozopinib he shared a trial where there was an overall survival in with Pozopinib and poor risk patients of approximately five months so clearly this seems to be a group of patients that may benefit from mTOR inhibition. We've had some modern trials of trials done within the past few years that have been read out using mTOR inhibitors this is an intersect trial you'll hear more about that coming up it was a negative trial per se for the primary endpoint and in this trial similar to what had been reported by Jan Dutcher from the pivotal trial there was a benefit seen in non-clear cell histology in fact it was the only benefit when looking at hazard ratio that did not cross midline so one would say it's non-clear cell histologies although not centrally path reviewed but the idea of non-clear cell histologies being a subtype that may benefit from mTOR inhibition seems to be validated by the most recent modern trials. Interact which was a combination trial of TEMM versus BEV Bernard mentioned suggesting there was benefit with Bevacizumab I will say the trial didn't really add anything into the knowledge based on is there a group of patients that respond to TEMS Rolimus but this is a trial that included TEMS Rolimus in patients remember with good and intermediate risk too and so what we've outlined so far is that TEMS Rolimus may be unique in patients with poor risk so what is the basis for this activity is it just a clinical trial phenomenon or do we have any basic science evidence that would back up its its activity and poor risk well I think you know data coming out of UCLA by Allen Pantuck Bob Figlin when he was there suggested that that phospho S6 was a strong predictor for survival and localizing and metastatic disease high nuclear phospho AKT expression was associated with a favorable prognosis whereas high cytoplasmic was associated with a poor prognosis in multivariate analysis included at their institution showed that there were several poor prognostic factors including activation of what we now recognize as being the p10 mTOR pathway so high expression of mTOR pathway components has been identified as patients a subgroup of patients that may benefit from mTOR targeted therapy and it show it in it correlated with patients who were deemed to be poor prognosis so patients who had other features of poor prognosis that we clinically recognize hypercalcemia poor performance that is we're also those same group of patients that had high expression of mTOR pathway as is shown in this slide so you can see a difference in disease specific survival when one looks at the mTOR pathway components that are over expressed versus those that are not and then more recent reports coming out of cancer in 2011 was looking at cancer specific survival associated with activated mTOR pathway so if you were fossil mTOR negative you did better you live longer if you were fossil mTOR positive you did worse and and again the thought is that the majority of these patients that are positive with mTOR are what would be considered the hang or moat or porous patients by clinical features and so another way to look at this is is predictors of response this is more of a basic science where they took 20 specimens looked at express in a phosphoresics and fossil AKT and this was able to correlate with what we thought from the previous studies with response to temporal limes so when there was over expression of these mTOR pathway components and porous patients they seem to respond better to temporal limes okay so it seems based on the clinical science data that there is a rationale to use mTOR inhibition and porous patients that has been substantiated now by several clinical trials of temporal limes and hence it has an NCCN and ESMO EUA category one designation in that group of patients you know there's other biomarkers that you can look at you know once people are starter on mTOR inhibitors there's been thoughts that may be pneumonitis maybe a marker of patients that will go on to benefit from from this other kind of pharmacodynamic biomarkers that have been looked at lipid elevation hyperglycemia occurring did not seem to pair out as being a predictor of ongoing response to it and then some of you may be familiar with LDH of looking at patients before starting looking at those patients that have increased LDH again a marker for porous patient if you had increased LDH you were likely to have benefit from temporal limes so again supporting the activity of the temporal limes and porous patients so hopefully I've established there that it appears in front line setting porous patients that there's a unique role in patients for mTOR but what I can't say universally is that that's going to be for all porous patients you've seen that there's some activity of the VEGF inhibitors in this same group but again the bulk of the data supports temporal limes as a standard of care in that setting if we move into the refractory patient where we're in our my other favorite drug Everolimus and if you believe that there is a difference between the two mTOR inhibitors this is why you know here is the AUC curve of IV injection where you reach a peak and then you quickly decrease down to a trough level versus continuous oral daily dosing where you're maintaining an AUC at a higher level and so you know we've I know many of us have been asking for data to really support that there is a difference if there is it would be this that maybe having a higher AUC is associated with greater effects on the phospho S6 kinase and so that has again as far as I'm aware never been validated as to be true but there is some theory though that there's a difference between the agents in the trial that was the pivotal trial that resulted in approval of Everolimus as an agent in the refractory setting is the trial by Bob Mozart shown here you're familiar with this and we saw an advantage to Everolimus with the PFS updated of over five months versus placebo which was under two months and it established it as a standard option in the refractory patient population but now that we've gone through and we have other agents to give in the second line setting and beyond we've scrutinized the data from record one and we realize that really the role of mTOR is actually in the second line and beyond when the majority of patients in this record one trial were actually in the third line or beyond so it appears that there is a role for mTOR inhibitors that isn't deemed absolutely second line but is in a refractory patient population so second third fourth fifth line there appears to be a role for mTOR inhibitor in that setting in fact most people would consider using an mTOR inhibitor as a standard therapy and patients at some point in the second third or fourth line again if we look at is there any benefit it seems like from this particular trial compared to placebo all subgroups benefited from Everolimus so it appears that it's a generalizable drug there have been new modern trials looking at Everolimus unfortunately they have been negative trials I think there's a session looking at negative trials and why they're negative and Tim gets to I think champion that here in the next session but again evidence that bevacism may have some activity but certainly the combination did not appear to be better than interfere on combination and then the record three crossover as you know didn't really meet its primary endpoint either either so it appears that just as a generalizable drug using an mTOR inhibitor in all comers and the frontline setting is probably not optimal we've heard that we have VEGF inhibitors that are probably more optimal in that setting and mTOR inhibitors in the frontline setting are probably most suited for the porous patient or the refractory patient so just to end there have been some attempts to further understand this looking at pharmacogenomics etc and this is from the memorial group by by Martin Voss he looked at patients with advanced RCC who were determined to have long-term or short-term responses to mTOR inhibitors so they're kind of the ends of the spectrum and try to analyze analyze their cancer related genes to see if you could find certain predictors there looking for mutations either gain a function or loss of function and what he was able to show is there was a variety of different mTOR missense mutations or TSC1 mutations that may have put some patients at benefit for mTOR inhibitors and it looked like that there were some genomic determinants of long-term response to Everolimus for instance in this setting so that brings us some hope that maybe with further study we will be able to do some type of genetic testing on tumors that would allow us to at least identify group of patients that may benefit for mTOR inhibitors so in conclusion we certainly are in search of biomarker development it's challenging when you've heard three VEGF inhibitors because we know most of our kidney cancer patients at presentation are hip dependent so it's it's hard to do biomarkers when a drug works in 80% of patients to identify that group but certainly in a situation of porous patients or patients that have mTOR activated pathway components you could imagine that would be a group of patients that may be very easy to to do biomarker development and so I encourage pharmaceutical companies and independent people to continue to support this research we need validation of what I've just told you for mTOR inhibitors and I think the future is going to be in biomarkers and selecting and individualizing treatment so to conclude I think mTOR inhibitors do have a role they'll be in kidney cancer for the years to come I think the established role as based upon evidence is mTOR inhibitors as a frontline option in those minority of patients that have porous features and then mTOR inhibitors as a refractory option sometime along the lines of second third or fourth line in those patients thank you thank you very much