Sumanta Kumar Pal, MD reviews the distribution of kidney cancers and explains clinical management of non-clear cell Renal Cell Carcinoma (RCC), with a focus on Papillary RCC.
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it's now my pleasure to introduce our next speaker, Dr Samantha Monty Powell. Dr. Paul is an internationally recognized leader in the area of genital urinary cancers at the City of Hope. Dr. Powell will be speaking to us on the management of non clear cell renal cell carcinoma. If you have questions you'd like to ask, please use the ask a question chat function, and we will collate questions for the panel discussion. Please, everyone Welcome, Dr Powell. Good afternoon. It's great to speak to you about a topic that I'm quite passionate about. Non clear cell kidney cancer. I'm a professor at the Department of Medical Oncology and Experimental Therapeutics at the City of Hope Comprehensive Cancer Center, and I focused primarily on kidney cancer therapy. These are my disclosures. So just as a little bit of background, and this is a slide that I like to show all the fellows that I work with when you look at the distribution of kidney cancer, you can see that about 70 to 80% is going to be clear cell, and then you've got this piece of the pie in the middle, which is green there, and that's going to be sarcoma toy disease that's probably in the ballpark of 10 to 15%. Maybe a bit more than that. Papillary kidney cancer, which is one of the main areas that I'm going to focus on, is actually a small piece of the pie constitutes about 10 to 15% of the disease. Chroma folk kidney cancer is about 5% and there's a smattering of other cancer types collecting unclassified and so on. Now, in terms of treating these diseases. One of the major problems is that we've really lumped all of these diseases together and treated them as one in the past, and I think that leads to a couple of different problems. Um, for instance, if you look at the ESPN trial, this was reported out in European urology sometime ago. This is a randomization between Senate nip and several amiss with cross over to the opposite arms that was done by M. D. Anderson as well as the Dana Farber Group and a couple of others. But it include multiple histology is it did include papillary, but it also included chrome Afobe, unclassified sarcoma, toyed translocation, all those subtypes that I've mentioned, and it included a total of about 108 patients. So at the end of the day, you end up with no significant difference. But I mean, it's more or less like doing a study that lumps together breast cancer and gastric cancer and stomach cancer and kidney cancer. And there are probably some diseases that are going to benefit from these therapies, but they may not necessarily benefit an amalgam. So I think that's one of the main issues with this study. When you look across these different cohorts, the numbers are really just too small. I mean, you really can't make any definitive distinctions between papillary kidney cancer when you only have 13 and 14 patients per arm. You look at some of the magnitudes of difference. For instance, in translocation RCC, you might say Well said it looks pretty good, but that's based on three patients. So the problem with these studies that just lumped together a bunch of non clear cell subtypes is that they're just really tiny. So what other data might potentially guide us in this setting? Unfortunately, we've kind of made the same mistake a couple of times here. There's the record three clinical trial, which is a study that lumps together both clear cell and non clear salt kidney cancer. It randomizes patients too sensitive and several MOUs with cross over to the opposing arm. So this was a mix of both clear cell and non clear cell. And then there's the Aspen study, which was a little bit more straightforward. This randomized patients directly to senator forever role in this, but none of these studies was really a clear win. I mean, all these studies really suggested that perhaps Senate Nip might edge out of a role in this, but it really didn't lead to any definitive conclusions in my opinion. And of course, that's a real challenge for us, as we are, you know, sort of proceeding down this path of trying to identify the best treatments for this disease. Um, so let's keep going here. So what can we do as an alternative? And this is really what I've been advocating for in my career. You know, I really want to see whether or not we can potentially take chroma, foam and sarcoma, toyed and papillary understand their biology and apply drugs rationally. So I'm going to show you how we have done that to at least some extent in papillary kidney cancer. Um, first, we examined a drug called Satellite in It, which is a putative met inhibitor. And this acknowledges quite generally, that when you're dealing with papillary kidney cancer, you have a lot of patients who have alterations in a gene called Met. This can be either altered mutated. There can be copy number alterations, and it can really happen in a range of different scenarios. But basically, you know, what I would propose is that papillary kidney cancer is really driven by these alterations and met by and large. So we have a drug called Savolainen that I've had some extensive experience with its a putative met inhibitor and basically satellite NIB works to really hit the proto oncogene and its product in a very big way. And what you see in this prospective Phase two study that we did a satellite nib is that outcomes seem to be markedly better amongst those patients who have met, mutate or met driven disease. That's the yellow line that you see here. This is data that we published in J. C. O about four years ago. Now, if you're met, status is unknown. Or if its independent, that doesn't seem to be that effective. There's another drug prison in which, you know many of you who have interest in lung cancer will be familiar with. And that's an agent that also has some inhibition of the Met proto oncogene. And this was a study called the Create Trial. So this took patients with type one papillary kidney cancer, where you have a lot of alterations in that, um, and it looked at those that were met positive and what you see in this case as a response rate of around 50%. But these aren't great numbers. It's just an around four patients or so. So I don't think it's anything that we can really write home about. But, I mean, these are encouraging results nonetheless, so perhaps worthy of further study. Um, the next agent that really might potentially have clinical utility in the setting is an agent called Cabos antonym. Um, I think everybody in the audience is probably familiar with cab, isn't it? In the context of clear salt kidney cancer, and this is really where a trial that I've been championing comes in so you know what we're doing in the context of the study is we are randomizing patients to either Senate Nip Cabazon. Banning chrysotile have been Savolainen so you can see that we're taking control arm of the veg F inhibitor in this case unit in in and comparing it against three Met inhibitors. This trial is an important one. I'll go through the details of this momentarily, but this took patients who had metastatic papillary kidney cancer. Irrespective of their histology, they could be type one or type two. I don't think that distinction is particularly meaningful. Um, it just mandated no prior therapy with Senate nib and these patients were randomized to the therapies is noted with the primary endpoint of progression free survival. Before we get into the details of that, I wanted to go through an even more ambitious study. This is the so called Savoie study, and the Savella study was interesting in the sense that it took patients with metastatic papillary kidney cancer and did something that we always talk about doing and diseases outside of lung cancer and ovarian cancer. It actually mandated genomic profiling in this setting, so patients with papillary kidney cancer had to have genomic testing within a 10 day turnaround time. They actually have the results given to them, and these patients were then randomized to receive either satellite or synonym. So, as I mentioned before, Savolainen is a very potent and specific Met inhibitor synonym, of course, just a conventional by Jeff directed therapy, and this study carried the primary endpoint of progression free survival. So I wanted to go through the results of this, and this has since been published in JAMA Oncology, in case you're interested in taking a peek at the results. But this study was an open label Phase three clinical trial. Now this study was an ambitious one again mandating that you have met. Profiling done in this population is difficult because they can often times have progressive disease. You know, patients don't want to wait for their genomic profiling to come back before they start treatment. So a lot of potential caveats in terms of the study design. But patients who had met alteration again were randomized to settle it. An abortion, it nip. Now there was a plan to have about 360 to 450 patients enrolled to this study. Um, and this was planned with the rate of Met alteration, which is roughly speaking somewhere in the order of 30 to 40% to allow for randomization of about 180 patients. What happened was this study. It accrued fairly slowly about 3 to 4 patients per month, and ultimately enrollment was actually closed. Now, even though enrollment was closed early on this study, I still think we can get some valuable insights from this trial again. Now published in JAMA Oncology, the study only randomized about 60 patients, so it got to only one third if it's a cruel goal again, with this randomization to Savolainen or Senate nip with the 60 patients analyzed here, what we saw was relatively, um, you know what I think is consistent with the real salt population distribution of patients? The median age was between 60 and 65. Most of the patients received their therapy for papillary kidney cancer in the front line setting. And when it comes to the Met driven assay done here, you can see some of the specifics below. But many patients in the study had gains in chromosome seven as well as just a smidgen who had met mutation of amplification. Mhm. So I thought there was something to this. You know, when you look at the Kaplan Meier curves for progression free survival, you can see that Savolainen actually did fairly well with the progression free survival of seven months. And this is versus 5.6 months with synonym. So the PFS for snitching was pretty much in range with previous studies. It's in range with studies that I'm going to discuss their forthcoming. So I thought that was a reasonable result. And, you know, even though this was non significant, you know, it certainly seems like there's a tail on that curve for satellite in, um so maybe it's relevant to consider biologically driven therapy. The overall, sir, I I actually thought was really interesting because here you can really see a distinction in overall survival between the two cohorts with satellite and really excelling beyond student and, um, there. So this is one of those studies that closed early due to a number of reasons, one of which may have been a cruel, you know, But one thing I will say is it would've been great to have gotten results here because there's some really, really encouraging trends. So, again, this is the summary of the data that was presented and now published in JAMA Oncology. You've seen the progression free survival, the overall survival. Take a look at the response data, also very encouraging response rate. With Seville, it nip was 27%. It was just 7% with synonym therapy. So again, I think there's something to these data, and perhaps in a Met directed population, there could be potentially some rationale to consider systemic therapy with Sevilla. But again only in those patients who are met altered. And I think this really speaks to a phenomenon that I'm quite passionate about. I'm really a big believer in genomic profiling across the spectrum of patients with non clear cell kidney cancers, and this gives you a little bit of a unique example of what genomic profiling can potentially do in this population. So these are patients that we profiled with papillary kidney cancer who had alterations in the elk gene. And again, this is the same L e m l for translocation that you're familiar with in the context of lung cancer. It's exquisitely rare. You see it in a percent of a percent of patients with kidney cancer, but perhaps some modestly higher fraction of patients with papillary kidney cancer. Um, and this gives you a sense of the timeline of the tumor dimensions on the Y axis and the clinical course of patients who received a whole slew of therapies. You can see on the left I had a patient that received his operative Savolainen. Several of this novel, um um Cabazon nib And this patient only really generated a meaningful clinical response when we transition them over to elective. These were long and durable responses. The same is true for the second patient that I've highlighted, who received travel it nip in the front line, setting again a specific met inhibitor. But maybe in this particular patient wasn't the target. Maybe it should have been email for alk. Um, And again, you see this fantastic response to therapy once you get gene directed treatment on board. So I thought this was quite impressive. Now, what about PT one and PT l one inhibitors and papillary kidney cancer? You know, I can't say at this juncture that we really have great data to support that approach. But I did want to highlight, you know, a handful of studies that are ongoing in the space of non clear cell disease, One of which is, I think, a very interesting trial that pairs devil a map with Savolainen. So again, you know drivel. A mob is a PD l one inhibitor Savolainen Iba. Very potent and specific Met inhibitor. Um, and there's some very compelling data for this. Um, And before we jump into the data for the combination, I'll share with you some data from keynote 4 to 7. This is a study that does substantiate, I think, the use of PD one inhibition and PD l one ambition and patients with metastatic non clear cell kidney cancer. Uh, in cohort B of this clinical trial. They looked at upfront therapy with embolism AB alone. And this was a sizable cohort, a total of 165 patients. Um, one of the things that we've done is we've looked retrospectively in a paper that we published at TMB. In this population, it's not particularly high, You know, you don't certainly don't see a lot of patients with micro satellite in stable disease or anything of that sort. But having said that, even with this particular approach, you know what we saw was some very, very encouraging results. Um, I'm going to highlight a combination study that we're doing right now with the combination of Cabazon nib with Tess Elizabeth. Um, and this particular study includes clear cell, non clear cell disease and multiple other cohorts. Um, and what we saw in the non clear cell kidney cancer cohort again I thought was quite impressive. And you see that patients who have non clear cell kidney cancer have response rates of up to 33% with a combination of Cabazon tonight with I o So you know, again something that I hope will move forward. These are the waterfall plots for Kazan with immunotherapy and again, you can see that on the bottom axis. Over here we have p designated papillary subtypes. Oh, designating other seed designating chroma foe Bob and you can see a handful of responses across each one of those categories. The swimmers plot also shows the durability of some of these responses. Although most certainly that warrants further follow up. Um, I wanted to give you a sneak peek at this data from Calypso, which is an interesting study that looked at Seville. It nip and drivel Ahmad and combination again. You know, very, very interesting data from this particular study that was presented some time ago at the Ask a genital Urinary Cancer symposium. And this study took 42 patients who received ultimately saville it with drivel a mob in combination. And what they saw here, in this case, was a response rate of 27% and previously untreated patients that rose to 32%. They saw disease stabilization and a healthy proportion of patients. So I think there is something to the strategy of dual targeting of both Met and PD one at the same time. And and we saw that in the context of my cab. Oh, Tiso data. We're seeing that now in the combination of Savolainen Interval a mob. This is the waterfall plot that highlights best change in size and what you can see here is that across these 38 patients over here you have about 54% having a decrease in tumor burden. So it's not, you know, definitely a fix for everyone. And we've seen waterfall plots far more impressive for clear cell kidney cancer with T K. I. And I owe combinations, but I still think this is a very interesting first step. Median progression. Free survival in this cohort was around 5.5 months, and interim overall survival actually looked very encouraging for this population, albeit with minimal follow up at the time of their interim assessment. So I've kind of been building up to this. You can basically forget everything in my talk up until now, because I truly feel that when it comes to non clear cell kidney cancer, this is kind of how we need to be doing studies. And the study on top of that really sort of sets the current standard for treating patients with metastatic papillary kidney cancer. This is the so called swab 1500. Some refer to it as the Pat Met study. This has really been a labor of love. I've been presenting this are developing this over the course of the past decade, and we just published this in The Lancet over this past weekend, and we presented the data at Asco Guo and I wanted to thank the scripts conference organizers for allowing me to update my slides with this information for you. Um, so again, I recall the design earlier in my talk here, but this took patients with papillary disease, and it randomized them to either synonym Cabazon nip present members of aluminum. And the primary endpoint in the study was progression free survival. So, you know, I've talked a lot about some of the, you know, sporadic data that we have across other, um, common small combinations. This is really the biggest randomized study, and I'll demonstrate to you in a moment that it really does have practical implications for what we do in the clinic. What's interesting about this study and you'll see that I don't focus on quite as much as the two arms listed there in Red Crescent and have been Seville it in it. And that's because we enrolled 152 centers across patient excuse me across 65 centers around the country. What we built into the study was an interim futility analysis. So we said that after we reach about 15 or 16 progression free survival events, we're going to close down the arms that are underperforming So we actually shut down the crazies out and have been Seville at Nab arms in the study, and we just kept accruing to the synonym and Kazantsev arms. And I think ultimately that was a very, very wise decision. And you'll see why in the data when it comes to the patient characteristics here again, fairly characteristics for a kidney cancer population. The patients had a median age of around 60. In this case, very few in this study actually had prior systemic therapy. I wasn't anticipating that I thought many patients may get upfront Checkpoint inhibitor. Many may potentially get an M tour inhibitor upfront based on some older data, but ultimately most patients were ultimately treatment naive. We made a lot out of the pathology assessment here. We were trying to do a characterization of type one versus Type two, and so we incorporated both a local assessment from your pathologist and my pathologist. And then we did an expert assessment, essentially with three pathologists that have a wealth of experience and looking at papillary kidney cancer. Um, so ultimately, um, you know, across the spectrum, the patient's largely had affected me about 75% in this cohort. We had many patients who demonstrated bone metastases, particularly as you can see there in the saddle that in the bottom of the trial and these are really the key results. So again, the main takeaway from my talk is probably this slide. So when you're treating metastatic papillary kidney cancer, which is the most common non clear cell subtype, I think it's important to consider starting with Cabins Avenue and my personal opinion. I think starting Kappa Sanibel alone is probably the way to go. But as you can see here, patients who received campus Sant nip in the upfront setting had a median progression free survival of nine months. Patients who sent and received sensitive had a progression free survival of five and 5.6 months. That 5.6 month estimate is exactly what you saw in the context of civil law and the Mets selected population. So I definitely feel that this is now the de facto standard for treating papillary disease. It's interesting. Savolainen and Chris had very meager progression free survival results ranging from 2.8 to 3 months. Um, but ultimately, you know, I just I really feel like the amalgam of data that we had from the study supported Cap Santa mono therapy. We did a detailed assessment of Type one disease versus type two disease. Again, the underlying interpretation here is that patients with Type one disease might have more in the way of that mutations, um, didn't really seem to have any bearing, though. We saw that there was a lack of concordance between type one and type two. But if you go to the table down below, no matter what way you slice it by local assessment or central assessment, it really looked as though those individuals who had who had received Cabazon minimum and that's what's being shown there seemed to benefit relative to sedative therapy in terms of response here. Ultimately, the response rate with Cabazon name was 23% and that was significantly higher than what we saw with Senate and just 4% with a two sided P value of 0.1 and you can see here 23%. Also within the cap. Santa bomb included two patients who had a complete response to therapy. So there's something very attractive about Cabot Santana in the disease biology of papillary kidney cancer. And what about overall survival? No real advantage here when you do look at the overall survival across arms. Overall survival was 20 months in the context of patients receiving capos antonym, and it was 16.4 months amongst those patients receiving students need therapy. Um, so you know, very different estimates across these arms, but ultimately no, statistically significant differences. And what about laboratory and safety studies? Um, you know, in the context of this data set here, you can see that the laboratory toxicities were nothing, uh, significantly different from what you would anticipate across your experiences with Kazan it and soon enough. Otherwise, you can see a decent amount of anemia and leukemia in this study. I don't think I have a slide included on the non human logic toxicities, but rates of hand foot syndrome, hypertension, etcetera those are all more or less akin to what you would expect. Outside of the context of this clinical trial, rates were very similar. So a couple of bottom lines from this presentation swab 1500 is the first randomized trial exclusively in patients with metastatic papillary renal cell carcinoma to complete a cruel cava Zana was shown to significantly prolong progression free survival relative to sensitive, and this meant this study's primary endpoint. With the hazard ratio of 0.6, Cabazon have also significantly increased response rates relative to Senate, 23% versus 4%. And Savolainen and Kasatonov Study arms were terminated prematurely due to a futility analysis. So just bear in mind, regardless of subtype classification, whether it's local review or central review, Cabazon appears to have a homogeneous effect across treatment groups. And in my opinion, it really should be the reference standard. Now for a systemic therapy and patients with metastatic papillary kidney cancer. This is again my studies have a bit biased, but the best level of evidence that we have for treating these patients in this setting, um, of course, there are many cooperative groups that actually participated in the study. Swag clog After and the Alliance and C. C. T. G. I actually put this slide up here for a different reason. Obviously, I want to pay homage to the patients and families who participated in the study, but I wanted to point out that a cruel to the study, remember, in total about 150 plus patients. It was really driven by two distinct entities, very distinct entities. One was through a major academic centers. So at City of Hope accrued 21 patients to the trial, and that was largely driven by support from folks like you who are referring from the community. The pen, Karmanos, Michigan. These other cancer centers did quite well as well. Um, but I did want to point out that when you look to the distribution of sites in the study, ours was really sort of a bit of an outlier, with 21 patients enrolled. About 45 sites actually have less than three Krul's one or two patients. And that's really what carry the study forward. So just underscores the point that, you know, when you look at that pie chart there, certainly, you know, we in the academic centers can potentially help drive these studies. But we really need a lot of help from our partners in the community. Um, and so if you're able to consider opening up these trials at your own practices, um, so just in conclusion here, I think I'm coming close to the 30 minute mark. I just wanted to highlight that One of the big issues that we faced in papillary kidney cancer and the non clear cell histology is in general is that we've lump them all together. And I hope what I've demonstrated today is that that's probably not the best strategy in those trials that I highlighted where we've compared pseudonym against every role in this, you know, we really are left with equipoise. We don't really have a best strategy emerging from them because what they've done is they've really sort of parsed out the various histology ease into very, very small subsets where you can't make definitive conclusions. So you know, what do we do for our patients with collecting duct carcinoma For patients with translocation disease? It's very hard to ascertain from the studies that have been done to date, and by and large, many non clear cell histology is outside of papillary are treated by a clear cell paradigm. But what should we doing be doing in the future? I think we've really got to Taylor studies to the biology of individual non clear cell subtypes, so we've really, for instance, got to do what we've done in the context of swag 1500 incorporate a look at Met and use Met inhibitors for a disease like papillary disease. And it's really paid off in spades in the context of our our study again, as I highlighted cabins and, in my opinion, really should represent a standard of care for patients with papillary kidney cancer based on available data. And finally, I would propose that combination strategies are incredibly encouraging amongst patients with, uh, papillary kidney cancer based on data from trials like Calypso. So I really would like to encourage you to consider and think about enrolling and supporting trials like Pat Met to. I didn't talk much about that, but that, too, is a clinical trial that's going to randomize patients to either the combination of Cabazon amenities, Eliza map or Cabazon to bologna. And again, I think that's going to be a practice changing study much like Patton, that one, Um, and we'll certainly need all hands on deck for enrollment. So again, please consider um, the apartment to clinical trial Cabazon of with or without immunotherapy. We're working it through the cooperative groups right now, and I'm very excited about moving that forward um, we really have a stellar team of individuals at City of Hope, led by our section chief Tanya Dorf, who sees prostate cancer and runs Do you oncology at our group. In addition to release Algeria, whose are phenomenal department chair, he's a specialist in lung cancer. We have a rich array of political trials within our group, but I certainly want to encourage any of you in the audience to reach out to me if you have any questions. Or if you want to just discuss cases available on Twitter, my email address is S p A l at c o h dot org. Um, and certainly I'm happy to discuss the availability of any research studies with you for our kidney cancer patients. Thanks a lot and enjoy the rest of the meeting.
