 I think the Kidney Cancer Association Planning Committee for the opportunity to present today. So I wanted to address a couple of questions related to toxicity in the context of metastatic renal cell carcinoma. And I have a little bit of a game plan in terms of this 10-minute time limit here. So I'm going to very briefly go over what comparative data exists to date. And what I'll suggest is that we really don't have enough comparative data as it stands right now to really address therapeutic selection. So then I'll move on to the next portion of this talk to discuss who will develop toxicity. Whether or not these toxicities can be prevented. And finally, whether or not there are certain settings in which toxicity considerations might be more relevant. And then we'll wrap up by talking about whether or not certain toxicities are associated with response and whether or not dose adjustment, which Dr. Vaishan Pye highlighted to some extent, is actually relevant and can potentially optimize therapy. So the first question at hand here is what comparative data exists? And I'll suggest that in the context of clinically relevant decisions at hand, we really have one trial that addresses this. And this is the Kampars trial. We're all familiar with this design and treatment naive patients. Patients were randomized to receive either synitinib or posopenib therapy. There were several toxicities. For instance, hepatotoxicity that favored synitinib. We saw several toxicities, 50, can foot syndrome, et cetera, that favored posopenib therapy. So I actually find this data somewhat useful in terms of counseling patients from day to day in the clinic. Now what we need, I would propose, and these are the NCCN guidelines, are trials that really address relevant comparisons that we also face from day to day in the clinic. For instance, in the first line setting, we really don't have toxicity data putting posopenib and buvacizumab side by side, for instance, and in phase three trials. And perhaps even more pressing, we actually don't have comparisons in the second line setting. For instance, between exitinib and neverolimus. And this is certainly a decision that we still struggle with. We do have, for instance, the 404 study comparing seraphinib and temserolimus, but I'd argue that those are distinct agents. So that's what we need. And what we will need down the line is actually the data emerging from ongoing clinical trials that were highlighted earlier today. Dr. Gore presented the randomized trial comparing everolimus and nivolumab. Dr. Chewary presented the Meteor trial comparing everolimus and kabalizantinib. I think just as important as comparing efficacy across these trials, if we can potentially do that, we really need to take a long, hard look at toxicity. So again, I've suggested here that we don't really have enough comparative data to guide therapeutic selection right now in the clinic. So in light of that, what can we turn to next? Well, how about prediction of toxicity? Who will develop these toxicities in the clinic? And for that, I would suggest the preponderance of research to date has focused on single-ducleotide polymorphisms or SNPs. I've highlighted this very nice paper from Jenny Kim and colleagues from when she was at the Cleveland Clinic in which they looked at 63 patients with metastatic renal cell carcinoma treated with synitinib. They identified one VEGF SNP at position minus 634 that was associated with the prevalence and duration of synitinib-induced hypertension. I'll suggest that this particular SNP was not associated with clinical outcome, although they did find a pairing of a VEGF SNP and a VEGF R2 SNP that was associated with overall survival. I'm giving you a bird's-eye view here of several relevant studies that were done associating SNPs with certain toxicities. I've summarized several trials here looking at toxicities associated with SNITinib and various SNPs in both clear-cell metastatic kidney cancer patients and just patients. We see several distinct SNPs, I'll point out, associated with hypertension, others associated with hypothyroidism. In the context of bevacizumab therapy, relatively large cohorts assessed with breast cancer and renal cell carcinoma, where again we see distinct SNPs associated with hypertension. In the context of seraphonib therapy and amongst metastatic renal cell carcinoma patients, we see that UGT1A9 polymorphisms can predict the onset and frequency of grade grade and are equal to 2 diarrhea. So a heterogeneous array of agents have been assessed across a heterogeneous array of diseases for a heterogeneous array of outcomes. So right now I don't think that SNPs are really ready for prime time for prediction of toxicity in the clinic. So we can't predict toxicity. How about preventing toxicity? And very oftentimes when I get referrals from my community based oncologists surrounding me, the question center around management of SNITinib related toxicities or seraphonib related toxicities, and there are just outstanding peer reviewed articles in the literature right now that propose how we might actually address some of these toxicities from day to day, many written by some authors sitting here in the room right now. But in terms of toxicity prevention, I really don't have a lot of great resources. So I wanted to just throw out a proposal that we're working on at City of Hope that might potentially address this issue and perhaps other studies may come in the same fashion down the line. So Dr. Porter and colleagues have put together a really outstanding piece. This was an expert consensus panel that convened to address toxicities related to everolimus therapy. I'm throwing up here a table from their outstanding piece related to management of mucositis. For grade one mucositis, for instance, they've proposed using non-alcoholic mouth washes or saline solutions. For grade two through four disease, they've proposed using topical analgesics, corticosteroids and antimicrobial agents. So one thing that we're actually working on at City of Hope is actually using some of these regimens in a prophylactic fashion. I'm working with my breast cancer colleagues on a concept in which we'll randomize patients in a two by two design to either no prophylaxis, to budesonide, neural corticosteroid, minocycline or neural tetracycline or the combination of these agents. And our primary endpoint in this study is the incidence of stomatitis of two months. This actually comes from that same piece from Dr. Porter and identifies that the bulk of these toxicities actually occur within a two to three month span. Okay, so if we can't prevent toxicities, how about identifying settings in which toxicities are most relevant? Dr. McKay actually presented an outstanding case earlier of an older adult with metastatic renal cell carcinoma. I think many of us would agree that that's a setting in which toxicities related to therapy are particularly relevant. Also those with extensive comorbidities, we've had some presenters here today outlining cardiac toxicities. I'd also argue that toxicities are also very relevant at the extremes of therapy. Our patients with localized disease who are contemplating adjuvant therapy and those individuals who are heavily pretreated. So I just wanted to throw out a couple of examples of data in this regard. I presented this at the KCA meeting last year and it's since been published. This is an institutional series of 220 patients with metastatic renal cell carcinoma. What we observed is that patients above the age of 75 actually did far worse than those patients below the age of 75 in terms of overall survival. And I wanted to highlight one particular element of this report in that patients age greater than or equal to 75, discontinued therapy less frequently due to progression and actually more frequently due to toxicity. That's highlighted in this table here below. I had some communications with Dr. Haas and I think this is a great reminder of the relevance of toxicity in the adjuvant setting. This is the Assure trial in which patients were initially randomized to synendobitful doses, seraphonibitful doses, or placebo. And as many of us are aware who participated in this study, these doses actually had to be modified due to poor tolerance in the adjuvant setting. Patients ultimately received synendobit 37.5 milligrams seraphonibit that actually halved the standard dose and they were escalated if they didn't incur toxicity after two cycles of treatment. I think this is gonna be especially important as we really sort of take on this barrage of adjuvant clinical trials that are ongoing. So far we don't have efficacy data from any of these studies outside of a riser which was presented at ASCO this year. But as these studies emerge, I certainly think it's gonna be important for us to weigh in efficacy data but also consider toxicities associated with these therapies given the lower threshold in the adjuvant setting. In the last couple of moments here, I wanted to turn my attention to whether or not there are certain toxicities that are associated with clinical outcome. We've seen a lot of really outstanding data over the past couple of years relating systolic and diastolic hypertension to clinical outcome in patients receiving VEGF TKI therapy. What I've highlighted here are two studies looking at synendobit and tyrosinib. These are two amongst many that have associated systolic hypertension with benefit and progression-free survival and overall survival. We see that with synendobit and tyrosinib, two studies here identify a similar benefit in progression-free survival and overall survival amongst individuals who incur diastolic hypertension. But rather than focusing on hypertension, I wanted to just call to some other side effects that we don't focus on too often in the context of these sessions. First, hypothyroidism. Dr. Donskow, who's in the audience today, has participated in a study associating hypothyroidism. Associated with synendobit-treated patients with clinical outcome, progression-free survival seemed to be higher in this population of patients. In a series of 770 patients receiving synendobit therapy, fatigue was actually associated with improved progression-free and overall survival. Certainly this may simply be related to longer drug exposure. In the same series of patients, hand-foot syndrome was related to clinical outcome. Overall's response rate improved in the population of patients developing hand-foot syndrome as did overall survival. Turning our attention to mTOR inhibitors, what we see is that in a small series of patients, the subset of patients who develop pneumonitis actually had a lower rate of progressive disease's best response. And what I thought was a very well-done study based on the pivotal temporal misdata, cholesterol increases seemed to be associated with longer survival and progression-free survival. So a couple of toxicities that we don't traditionally focus on that may potentially be associated with clinical outcome. So if certain toxicities are associated with response, can we actually dose-adjust to optimize therapy? And Dr. Vaishanpayan actually hit on this earlier, so I'm not gonna spend too much time on this topic. Dr. Renian colleagues have taught us a lot through the AXIS trial. These are the criteria for dose titration within AXIS. And ultimately we saw that 17% of patients were titrated to seven milligrams BID, 23% of patients to 10 milligrams BID. And ultimately what we saw is that patients who were at higher doses of exitinib and lower doses of exitinib had relatively similar progression-free survival, certainly this may be a phenomenon associated with the AUC of these agents and patients that were titrated upwards. I think Dr. Vaishanpayan hit on some of that data. This is one example amongst many of studies that are ongoing to assess the effectiveness of dose titration. I wanted to highlight a study done by my colleague Dr. Bjarnsen at Sunnybrook. This is a really innovative trial being run at 11 centers currently with 56 patients enrolled. He's randomizing patients to receive varying schedules of synantinib therapy. And in patients who don't incur toxicity, they may actually be titrated upwards to 75 milligrams on a 14 day on, seven day off schedule. So we've taken aim at a couple of questions related to toxicity and metastatic renal cell carcinoma because of this very stringent time limit. We really haven't gone over toxicities with some novel agents, PD-1 inhibitors and vaccine therapies. We really haven't delved into the biology of toxicity as much as I'd like. And we haven't talked about some patient preference designs such as in Pisces or Gemini. But nonetheless, I hope we've provided some framework in which to assess toxicity in the context of therapeutic decision making. Thank you.