Chapters Transcript Video Advanced Renal Cell Carcinoma (RCC) Management Back to Symposium Hi everyone. Uh, no, I don't, I, I know there's not that much new grade data in kidney cancer like we've seen in, uh, bladder and prostate space. Um, so, uh, today in my talk, I'm going to be discussing some of the known treatment options and I'm going to discuss more about, uh, what's new, uh, in the, in this field, and, uh, and then I'm gonna touch a little bit on the non-clear cell data. Um, and so, uh, this is a summary of, you know, the space, the frontline space for metastatic RCC, which has actually not changed a whole lot in the past 4 to 5 years. Um, you know, the first column, uh, reflects the Checkmate 214 trial, which is the IPO versus Senate. And then, uh, the next three columns represent the IOTKI trials, the keynote 426 with Pembro AC, um, and then Checkmate, uh, 9ER with, uh, nivolumab, Cabozantinib, and Clear with Linvatnib and Pembrolizumab. And what I really wanted to highlight here is that in all of these studies you can see that, uh, you know, compared to Sunitib, which is a control arm, the immunotherapy based regimens in general do better. And then, uh, I wanted to point out the overall response rate. The overall response rates are much higher with IOTK combinations compared to Checkmate 214 where the response rate was lower. Um, and you can also see that the rate of primary progression is very minimal in patients receiving, uh, IoTKI therapies in the frontline setting. However, on the flip side, we know that in patients who receive, um, dual checkpoint inhibitor in the frontline setting, they have a higher chance of having, um, a complete response and because of the tail of, uh, at the end of the curve. And so there is a role of that as well, um. And here I wanted to show you the, uh, you know, updated data we have, uh, with 9 year follow up for Checkmate 214. And if you look at the trend for hazard ratios, you can see with increasing follow up you still see that the hazard ratios for overall survival are maintained at 0.68, 0.69, which is really good to see that the data holds true after so many years of follow up, um. In comparison with the IOTTI data, as you can see in the at the in the top table, it represents the data for keynote 426 with Pembrolizumab and exit net. The hazard ratios do tend to get a little bit, uh, bigger over time, and the same can be seen for Kabuzi nivolumab. It started off with a hazard ratio of 0.6, and over time the hazard ratio has increased to 0.79. And then clear, this is the the final analysis data with the with the hazard ratio was 0.7. How about for favorable risk patients? So we know that for favorable risk kidney cancer patients, uh, in general we have been, uh, you know, advised to use IoTKI regimens in the frontline setting, but we do know that with the extended follow-up data with nivolumab and epilimumab, that, um, even though the progression free survival of the Epivo combination was not greater than CENITIP. We, uh, we do see that, uh, among the favorable risk patients there are some patients who have a complete response. There was a 13% CR rate and patients getting epinevo, um, and, uh, you know, based on that in the most recent NCCN guidelines, you can actually see that I ilumab nivolumab is included as category one in favorable risk patients. And so in patients who receive frontline treatment for metastatic kidney cancer, this is one cool FDA pooled analysis where they pulled randomized data from Checkmate 9 with Cabonivo, uh, Javelin renal 101 with Eveluab and exitib Checkmate 214, and Keynote 426, and they modeled the 36 month overall survival data based on how patients did at the 12-week imaging, the first scan. And it was interesting to see that patients achieving a greater than 60% reduction at the first scan, the 12 week scan, at a 75% probability of 36 months survival in the patients in the IO group. And so we know that deep early responses really matter and they predict for longer survival. Now, in the subsequent lines of therapy, um, there has not been that much addition and there is a real need to, to develop newer drugs in the space, but essentially the common treatment options in the second line setting would be a different, um, TKI, uh, like Cabozantini. Or Lenvatni Evrolimus and Belzan Tewazoib, these are really the available treatment options. And so what I, uh, you know, what is new, where is this field headed? And so in the next few slides I'm going to discuss some of the newer data we have and where the field is moving in the clear cell RCC space. So recently at ESO there was data for the Lencabo trial. So the purpose of this trial was really to sort of inform maybe the sequencing of how we may go forward. The trial included patients who had received 1 to 2 prior lines of therapy and were randomized to receiving lenvatinib everolimus versus cabozantinib, and the primary endpoint was progression free survival. It is to be noted that a majority of these patients received ipilimumab nivolumab in the frontline setting. And almost 60% of patients had not seen priority KI. The data from the study suggested that so on the top is a curve for lenvatnib Elius, uh, and in the bottom is a red curve represents, uh, Kabuzatib, and there was apparently a progression free survival benefit, uh, for patients receiving Len F, uh, in the first before, uh, in the second or third line setting as opposed to Kabuzantym, but really the overall survival data really matters in this setting and, and that data is still immature. So, uh, other trials that are looking at escalation, de-escalation strategy, we still await the results of this pedigree trial in which patients receive, uh, epilimumab, nivolumab, and then depending on their outcome, whether They have a CR, they continue on nivolumab alone. If they have progression disease, they switch to Cabozantib, and if they have a partial response or stable disease, then they get randomized to, uh, either receiving nivolumab plus cabozantib or nivolumab. And then now the field is moving towards combining TKIs with HIP to alpha inhibitors. Um, so the first two columns represent data we know from Kabozantib contact 03 trial and the, uh, Bellzoan trial. But, uh, the, the third, the other three columns represent the com the face to single arm data for TKI plus Bellzuropan trials. And you can see that the overall response rates are about 30 to 40%, but remember this is with the with with an active drug like lenvatinib orcabuzantib. And so we really need data from, uh, randomized trials. The last column represents one of the novel, uh, HP2 alpha inhibitors, R20, that is still under, uh, being developed fully. So Light spark 011 is one example of an ongoing randomized trial in which, uh, patients who have previously received ION TKI based regimen are randomized to receiving a combination. Of Lindvatnib and Belzopan versus Cabozany. What about other targets? Are there other targets that are being studied? So this is data from ESO with the Keymaker, uh, trial. It had multiple arms. These were patients who had previously received IO and TKI, uh, actually this is in the frontline setting where, uh, patients. Uh, were randomized to receiving one of these four, regimens and so there are some novel drugs here. The QMA represents an anti-CTLA 4 drug. Um, the, uh, FAI represents, uh, lad 3 inhibition, and then, um, a digit 1 inhibition based on the Vibo. We stole the map. Um, and, uh, in this study, these were not meant to be compared head to head, these different arms, and they had an arm with pembrolizumab lenvatnib which was supposed to be the reference arm, and, um, the results of of these were presented at ESO, and you can see that the Pembrolizumab lenvatinib Belzuropan arm had uh and the uh QMA, which is a CTLA 4 inhibitor, Pembrolizumab and lenvatinib. Had overall response rates that were comparable to Pembro and Lenvatnib and so the company is now developing this further in the light spark 012 trial. This is in the front line setting where patients are going to be randomized to Pembrolizumab, then Vattnip or one of the two combinations that I mentioned earlier that were potentially more active. So, uh, besides these, you know, rearrangement of drugs and combination of drug strategies, uh, you know, what else is there that is novel in kidney cancer? And so, um, I find the biomarker stuff to be interesting. Um, and, uh, you know, recent, uh, this, this trial that is the optic RCC trial is taking advantage of these RNA-based clusters that we know about, uh, in kidney cancer, and patients, uh, would be randomized, uh, patients in the cluster 12, which represent the immunogenic clusters, uh, um, oh sorry, the angiogenic clusters would be, would receive, uh, IoTKI combination with nivolumab and Cabozantinib. And then the cluster, uh, 45 which represents uh patients who are more immunogenic uh signature would be receiving illiumab, nivolumab, and then the last cluster has uh those are very small groups and those are excluded from the study. And the data for the first cluster was, uh, presented at ESO where the overall response rate was, you know, 76%, but these are small, uh, groups this this arm only had about 25 patients in it, uh, but it would be an interesting future direction where we we would be able to identify which patients should be receiving IOTTI versus IOIO. Uh, another biomarker of interest is CIM one. Kim one is a, a kidney injury molecule, and this is, uh, based on, it's a circulating, uh, molecule that can be measured by a blood test. It's a transmembrane protein which is expressed in kidney cancer. Uh, and it, it has been consistently, uh, been shown to help in early detection, risk stratification, and disease recurrence. So in, in the Checkmate 214 trial, uh, you know, it was found that baseline levels of CIM1 that were in patients who had higher levels, they had worse outcomes in both the epinevo and in the senateneb arm. Um, and, um, but one thing that is to be noted is, uh, that in the IOIO arm, if you follow the levels of CIM1, then, um, you know, patients with a reduction in CIM1 levels after receiving, after the first three cycles, uh, did much better than patients who did not have a significant. reduction, but this, this pattern of uh following the CIM1 levels was not very robust in the patients receiving TKI alone. So for patients with receiving IO alone, you can use CIM one to monitor their disease, and it would be interesting to see how this develops over time. And then lastly, I wanted to touch base on the uh carbonic and hydrase uh 9 targeted thenostics, which are really hot and popular right now. So carbonic and hydrase 9 is very commonly expressed on kidney cancer cells and uh. Currently, there are peptides which, uh, target, uh, carbonic anhydrase 9 and, and then deliver, uh, radioactive, uh, treatment into inside the kidney cancer cells. And this is another area that is hot and we see a lot of, uh, development in this space. So I'm going to briefly touch in the next few slides about non-clear cell RCC. So having, uh, you know, sarcomatoid variants, we still know based on the Checkmate 214 and the IPNEO data that patients with sarcomatoid RCC, uh, do much better with this combination, uh, and have a chance of having a CR of almost 23%. And so that is still my treatment of choice in patients with sarcomatoid RCC metastatic frontline setting. Um, and then, um, you know, in the non-clear cell, uh, population, uh, what, what other options exist, and now we have moved away from the single agent TKIs that were used before to combination of IoTKIs and, uh, we have data from these, uh, uh, you know, trials and the the best data that we have is for Pembrolizumab and lenvatnib based on the keynote, B61 trial in which, um, And overall response rate of almost 50% was seen, um, in patients with non-clear cell RCC, which is the best we have seen. Uh, the SUNY forecast trial was a randomized trial with IPO versus Synib, um, and in that, uh, the, the response rate was not as high, although it was a positive study. And then in the same, uh, keynote, B61 study, if you look at the breakdown based on the histology type, you could see that response rates of about 50% seen in papillary, but even in patients with chromophobia RCC had a response rate of about 25, 28% and in the translocation RCC, the numbers are small, but we do see, uh, some activity. And here are some of the ongoing trials in non-clear cell RCC. So now trials are comparing TKI versus IO plus TKI. We don't have that many non non, not that many randomized trials and non-clear cell RCC. So it would be interesting to see these results and see how they compare against TKI alone. OK. So with that, uh, you know, although there has not been a significant change in the frontline setting. The field is currently moving towards combinations of, uh, bells, uh, HIP2 alpha inhibitors with TKIs. We really need to develop, you know, novel drugs, um, that would, uh, enhance, uh, you know, the outcomes of our patients going forward. Thank you. Created by Related Presenters Pooja Ghatalia, MD Assistant Professor, Department of Hematology/Oncology Assistant Professor, Department of Hematology/OncologyCollaborating Member, Cancer Epigenetics
