Doctor Galia will talk about all the cool updates in kidney cancer. She has been a co-author on some seminal work on Bel Zoo of Fan and uh looking forward to her talk. Hello everyone. Um I'm going to be focusing mostly on the updates this year in some of the existing trials already published once and then also the Bell zero and trial as Dan alluded to. Um So, uh as everyone in this room probably knows front line treatment for metastatic kidney cancer uh for favorable risk, it's typically a combination of IO plus TK I so exit plus pembrolizumab, CBOLA Nevo, then vat plus uh pembrolizumab and for poor and intermediate risk patients. Uh The combination includes a combination of I ipilimumab nivolumab as well as one of the added indications. Um And the IM DC risk score is basically uh involving one of these uh prognostic factors listed on the left, which include uh the time from uh diagnosis to need of systemic therapy, performance status. And then laboratory parameters like hemoglobin, calcium neutrophil count and platelet count. And based on those uh prognostic factors, patients are classified into one of the IM DC risk groups and having a good uh risk group patients live much longer, 3 to 4 years compared to somebody who is poor risk with a much worse overall survival. And so, uh lately, we have had uh updated results from some of these uh combination trials that I wanted to go over. So the checkmate 214 trial, as everyone knows, included patients with untreated, untreated metastatic kidney cancer randomized to uh IVO versus uh SUNItinib. Um And then we have, you know, other trials including the keynote 426 with Pembrey versus SUNItinib. And then the Javelin trial with a vab exit versus SUNItinib. The checkmate nine study where um Kono was compared against Sunni Nib and then the clear trial which included Pembrolizumab, LIN VTB versus LVAT Nib hero Imus versus SUNItinib. And so we have all of this data and now we have some updated results from all of this data. Uh So to sort of com uh you know, these tri these trials, even though we have put them next to each other to try to make a comparison. They were not really exactly the same kind of population. For example, the Pembrey, the keynote 426 trial had a lot more favorable risk patients compared to the other trials listed here. Um And uh for example, in the checkmate nine trial, they had, you know, 20% of their patients were poor risk compared to a lower percentage in the checkmate 214, keynote 426 and clear trials and even the inclusion of sarcomatoid uh patients was different in these studies. So they cannot really be compared, they're not exactly the same patient population. Um But as a clinician, when we need to make decisions, it would be nice to sort of have this sort of available data. Um So cross trial comparison of response in these I TT populations in these four trials that I've listed at the bottom uh really showed that uh for patients in the clear trial, the Pembroke lastly, that trial really had a very high response rate of 71% with about 16% patients achieving AC R um versus uh you know, in checkmate 214, we had lower response rate of 39% and AC R rate of 11%. However, if you look at the landmark overall survival data, comparing these four trials, they were quite similar uh across all of these combinations with about uh 70% overall survival rate at uh 24 months for these uh experimental arms. But recently we had, we have more mature uh follow up data for checkmate 214. And what I wanted to highlight here is in red, you can see the hazard ratio for median overall survival uh for uh IVO was quite stable over five years. Uh staying at around 0.63 to 0.68. So not much lower. But if you look at the same thing with the keynote 426 data, for example, over time with increasing follow up, you see the hazard ratios are increasing over time um which you know, as I said in checkmate 214, we didn't see that kind of increasing hazard ratio over time. And similarly for checkmate nine, you also see a similar trend with slight increase in the hazard ratio from 0.6 to 0.7 with greater follow up with uh in the clear data as well. Uh The with the la latest uh overall uh follow up data at 49.8 months, you can see the hazard ratio is slightly higher compared to what it was initially presented. Now, uh some of the other kind of interesting things that we have in this year is that uh we have more data for favorable risk patients. And as we know that IVO is not currently approved for uh metastatic patients who fall in the favorable risk IM DC criteria. And that's based off of the fact that the patients in the comparator unit NIP arm had a higher response rate like 54% versus 29% in the VO arm. And similarly, the PFS and OS were not really too different with the Iine versus sunt NIP arm. But if you look at the uh F so this is just looking at the favorable risk patients, you can see that even in the Pembrey, Nevo Cabo and Pembroke and VTB arm. The hazard ratio when you compare it against Synod NIB was not significantly greater. And recently, there was an FDA pooled data analysis from these IOPS TK combination trials. Um and you, you can see specifically in the favorable risk patients where on the left side, on the left uh graph, you can see the top two curves represent favorable risk patients where you're combi uh comparing the combination of IOPS TT I versus SUNItinib. And there's not that much different difference in overall survival. Now, this may be related to limited number of favorable risk patients, lower number of events as these patients live much longer. And they may also have a chance to receive more second line treatments. But this is something interesting. Uh Now, if I had a favorable risk patient in clinic, I would probably still give them one of the IO plus TK combinations. But this was interesting data based on some analysis that, that came out this year. Another interesting group of population that we see in clinic are patients with sarcomatoid RCC. And uh as you can see here, you know, uh I had ac R rate of 23% with sarcomatoid RCC patients. Recently, data from Pembroke RCC, especially patients who are young and who we are trying to get a long duration of response. I still try to give IVO. Um Now how about for a non clear cell RCC? Like papillary RCC or Chromophobe RCC. So I just try to try to pull the data together from various retrospective and phase two trials. Looking at how about TKIS alone. So in pa patients with, with papillary RCC, giving them TK I therapy alone like Cabozantinib offers them a response rate of about 25%. Um and for chromophobe RCC as well, a single agent, TKI like Cabu Aib or Lenvatinib Berly are pretty reasonable treatment options. How about IO alone for these agents? So for papillary er CC giving them IO alone um has a response rate of about 20% or so depending on which study you look at. But in Chromophobe RCC, single agent I OS not really good response rate. So I wouldn't choose a single agent IO for Chromophobe RCC. But this year there was data that came out for several IOTK I combinations, especially looking at non clear cell RCC. And as you can see for papillary RCC with an IOTK a combination, you can get a response rate of about 50% not that much lower than the regular clear cell RCC. So I think this is a reasonable option for patients with metastatic papillary RCC and IOTK a combination. And for chromophobe, I still think that IO doesn't have a great role in Chromophobe RCC patients. So moving on to some additional data that came out this year that looked at uh trying IO plus TK in patients who have received IO before. Um so in this clinical trial, they compared a TZ O plus cabozantinib versus cabozantinib in patients who have previously received immunotherapy. And uh the progression free survival was not that much different. And so based off of this study, we don't have great enthusiasm of giving patients immunotherapy combinations again, in somebody who's already received immunotherapy, but this is just one trial and we have some additional data from other trials that may steer us towards the other direction. Recently, there was also data looking at triplet therapy. So how about VO plus co and so in this clinical trial, cosmic +313, they specifically included intermediate poorest patients because that's where VO is approved and randomized those patients to the triplet vo plus cabo versus VO alone. And the primary end point of the study was PFS. So you may the curves they may look separate and it may look like the triplet therapy did much better than the uh doublet therapy of vo with a hazard ratio of 0.73. Um but the cr rates were not so different, the cr rate was only 3% in um both arms. And uh the problem with the triplet therapy was toxicity as I will outline in the next slide and about 58% of patients got all four doses. So about 40% of patients in the triplet therapy did not even get all of the uh initial induction vo doses. And uh 45% versus 25% patients had to discontinue treatment due to treatment related adverse effects in the triplet therapy. So you can see here in this uh table here, the grade 34 treatment related adverse effects were almost double uh in the triplet therapy compared to the doublet therapy. And so even though the data was positive in terms of PFS, it has not really led to a lot of influence in the clinical uh oncology community to use triplet therapy in our patients with metastatic kidney cancer. So switching gears to uh Bel Zohan versus Alius. So as you may know, Belz Ofan is a hip two alpha inhibitor, one of the newer drugs that is not a TK I or immunotherapy drug in kidney cancer. Um and recently data from the Light Spark oo five trial was presented at Esma. So this trial included heavily pretreated patients with metastatic kidney cancer who had progressed on several lines of treatment and were randomized to receive Bel Zoen, which is an oral drug versus Lymus. And the primary and part of the study were PFS and OS. Uh what I, what I wanted to highlight here are the uh balance in the favorable risk and patients between the two arms and also the intermediate risk, very balanced between the two arms. But look at the number of lines of therapy. So about 45% of patients in each of these arms had received pre three prior lines of therapy. So this is truly a heavily pretreated population. Now, the PFS uh looks like in there's an initial drop down where a lot of patients progress. And then over time, the curve seem to separate out and the PFSW has a ratio was about 0.74. So this was really a positive study. Um but we had really hoped more from this drug than we actually see here. And overall survival is not yet mature, but they seem to be sort of overlapping here. The response rate from Bell Zan was about 20% and olly is 3.5%. And the two main toxicities of interest for Belsen as we know are anemia and grade three anemia was seen in about a third of patients on the study and then hypoxia, which is seen in about 15% of patients. But these are both very manageable toxicities. And uh in clinic, we find that giving bells to patients really gives them a break from TKIS, especially if they have a lot of toxicity from that drug. So where is this field headed? Um combining TK I and Belsen and moving it forward. And so recently, um there is some information that has come out for Bel Zoen plus Cabu Zant nib. Um So in this clinical trial, they included patients who had received uh you know, about two or less lines of prior treatment and cohort one included treatment naive patients where they combined Bel Zuro Fan plus Cabu Zant and cohort two included patients who had been previously treated with immunotherapies who also received the combination. And now we have data from both of those cohorts and at least in the treatment naive cohort combining Belsen uh plus cabozantinib really had a overall response rate of 70%. Now, this is a small study with only 50 patients. Um but it definitely makes one want to push these drugs a little bit in the earlier line of therapy combining with Bel Zura Fan. Um And in the cohort two, also in patients who had received previous immunotherapy plus or minus uh prior targeted therapies. The response rate was about 30%. This is a very small study with only about 24 patients combining Belsen plus Len vib. But once again, the response rate was about 50%. This trial also included patients who had previously progressed on IOT. Uh So recently, there have been other drugs like Zanolli, which are other veg of TKIS that have shown some excitement, especially in the recent IP CS uh conference. And then um some drugs that are targeting carbonic anhydrase, the lutetium 1 77 7 geron tim um some other dual checkpoint inhibitors. And then recently, a combination of immunotherapy plus bar inhibitors. So in conclusion to summarize uh the different points, I try to make your IO plus TKI combinations and IOIO they remain standard front line treatments for metastatic RC CIO IO with a longer duration of response and stable has a ratio over time and in favorable risk patients, IO TT combinations did not significantly improve overall survival compared to TKI. With the caveat of these being retrospective subgroup analysis. Um In Sarcoma RCC patients, IOIO really offers a good cr rate. And in papillary RCC patients, we should consider I OLA TK I combinations. That's what we have right now. That's the best. Um IOTK I post IO Thera doesn't seem to be too effective and then triplets are really too toxic right now to be able to use in clinic on a regular basis. Um And Bell Zoran, the H two I find that we have right now seems to be active and will likely be com combined with other agents and move to earlier lines of therapy in the future. Thank you for your attention. Yeah.
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