The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the kidney cancer clinical updates you need to know from ASCO 2024.
Thank you all for joining this evening for our as o annual meetings, uh highlights of 2024 starting with kidney cancer. I think before we dive into the data, it's important to look back over the last year and realize just how much progress we've made. Um some of the highlights. So since last, as o we saw overall survival benefit of adjuvant pembrolizumab and kidney cancer. This was a trial led and presented by our own doctor Shri. And um and so we're, we're, it's the first adjuvant PD one therapy to show and improve been an overall survival therapy. And so we're um encouraged to see that we also have a new FDA approval for Balzan, the hip two ALPA inhibitor for patients with advanced clear cell kidney cancer. And then we continue to see um prolonged uh benefit from checkmate nine and checkmate 214. Acknowledging our successes, we've also had a lot of setbacks. Um So the checkmate 914 study of Adjuvant Ebola A that was a trial that failed to show DFS benefit. Um And then we had the contact 03 study presented back in the fall which showed that for patients who had prior prior immunotherapy A tesol A tab plus Cabo was no better than Cabozantinib. So I think acknowledging both our successes and our failures, I think helps to contextualize some of the biomarker work that was done and really featured at as 0 2024. So these are um just four of the abstracts that we're going to be focusing our time on today. Um First, we'll discuss the role of Kim One as a circulating emerging biomarker in adjuvant therapy. Then we'll move on to um a lot of biomarker work that was done in our first line metastatic trials of one vat plus pembrolizumab and the clear trial which was presented by doctor and then the Exit plus pembrolizumab study of Keynote +426 where, which analyze it's a lot of similar biomarkers um in the first line metastatic setting. And then finally, we'll finish with um a emerging outcome known as treatment free survival. And this was data that was presented by once again our own Charlene mania um with data from the Checkmate nine yard study. So without further ado um this uh first abstract was presented by our colleague uh Laurent Salbi um from Gustave Roussy in France um which was analyzing uh Kim circulating Kim one as a biomarker on the emotion. 010 study. Um For those who may not be familiar motion 010 was a um a randomized phase three clinical trial in the adjuvant setting for patients with high risk resected kidney cancer patients were randomized to either receive a year of a Talab or placebo. And the primary endpoint of this study was disease free survival. Unfortunately, this trial did not meet its primary endpoint with a with no benefit in disease free survival. You see those curves are essentially overlapping. And what this abstract was seeking to ask was, are there any patients within that subgroup? Uh or are there any patients who may have benefited from anti PDL one based therapy with the Tesla NAB on this study? And so what they did was they um looked at a broad number of proteins, almost 3000 proteins um both at baseline and then at disease recurrence and tried to look for what protein may have been associated with uh disease recurrence. And what they found was that Kim One really stood out among all of the different biomarkers that were looked at and was enriched in uh disease recurrence. And so, uh a little bit of background on Kim one, this uh Kim one stands for kidney injury molecule one. And this has actually been studied um originally back at the Brigham for 25 years ago by nephrologists um and has made a resurgence over the last couple of years um and work led by our own Vincent chu um looking at Kim one as a circulating biomarker of both clear cell kidney cancer and papillary, kidney cancer. And so, um what this um with, with this circulating biomarker is um meant to do is look for a minimal residual disease after patients have had a nephrectomy. And so what the uh emotion 010 program did was they looked at baseline levels of Kim one, then, then looked at uh levels at cycle four and then at either disease recurrence or um or protocol cessation. And they found that in the Kim one high versus Kim one low groups, um there, the um baseline characteristics were matched between the two. When you look down at disease stage, you see about uh 83% of patients on either arm. And so there weren't any particular baseline characteristics associated with Kim one high versus Kim one low. Uh But what we did find was that those patients with Kim one high status at baseline that was associated with the worst outcome on emotional 10 So you see that a curve in, in um brown, you see that patients had a, a worse disease free survival than the patients were Kim one low at baseline. So this is a potentially a prognostic marker in the adjuvant setting. And then when we look at um a Talab and what effects treatment had on that PV uh on that km one subgroup. And on the left hand side, you see that those flip, those curves are flipped. So patients who got who were Kim one high and got a Talab. Those patients had an improved disease free survival relative to patients who were Kim One I and got placebo. On the right hand side, you see the patients in the Kim one low subgroup, whether they got placebo or a Telism that there was no difference in disease free survival. So again, perhaps suggesting that Kim 1 may be a predicted biomarker of relative benefit in the Kim one high subgroup when treated with anti PDL one therapy. Now, um those are baseline levels, then we look at um was there any difference in the change in Kim one from Kim one low to high or vice versa? From high to low? And so on the left hand side, when you look at those dashed lines, those were patients who um were either Kim one high or K one low at baseline, but then had an increase over time. Those patients had a worse disease free survival relative to patients who were either K one high or low at baseline and then had a decrease over time. Those patients tended to do better in the upper two lines. Um On the right hand side again, in placebo, you see that um that largely holds true as well that patients who were Kim one who had experienced an increase in Kim one while on protocol therapy, those patients um seem to have a worse disease free survival. And so some of the take home points uh that Doctor Albi uh spoke about was that uh post nephrectomy K one serum levels may be a marker of minimal residual disease. And that it appeared a Tesla lab showed an improvement in disease free survival for those patients who were Kim One high. Um In the discussion of this, uh Doctor Vincent Chu highlighted some of the work that he's been doing with Kim One and showed that not only in the emotion O and O study was this uh shown to be true, but also in the assure trial assure was a um an adjuvant study using Veg ftkis after a nephrectomy. And similarly, that showed a high KM one level was associated with worse disease free survival and overall survival among all arms. And then in the checkmate 914 study, again, this was an adjuvant study of Eliab plus Ebola. We saw that Hakim one was associated with worse disease free survival and potential benefit from immunotherapy. And so, not only is K one being investigated in the adjuvant setting, but it's also being used in the diagnostic setting. And I'll encourage folks to read uh Doctor Vincent Chu's uh JCO paper where we're able to differentiate between benign small renal masses and malignant small renal masses. Um As well as in the metastatic setting. We see that a decrease in KM one after treatment with immunotherapy with evola A is associated with a clinical response to therapy. So, um certainly a promising circulating biomarker and, and an area that we really haven't been able to, um, make much success in kidney cancer. Um, certainly a lot of other, um, outstanding questions that we have to think about. Um, are potentially those patients who are K one low after their surgery? Are they being overt treated with pembrolizumab? And if we think about things from the opposite perspective, if patients are Kim one high, are they being undertreated with pembrolizumab? And should we be adding either another checkpoint inhibitor or another targeted therapy? A hip T alpha um molecule on top of that. And then lastly, how do we incorporate this with other biomarkers that are being used in the adjument setting? So, looking at cell free DNA, looking at Turin tux a pet imaging um and other genetic markers, um I will highlight that we have a, a new adjuvant trial that's opening within the next three weeks here at Dana Barber, which is seeking to build on the success of adjuvant pli. And this is um a phase two trial using AM RN A vaccine plus pembrolizumab compared to P pembrolizumab alone um with placebo. And so this has been done in Melanoma and it's shown some really promising efficacy. And this is, you know, one of our um one of the ways that we're trying to advance advance um adjuvant therapy and kidney cancer. So, moving on, um one of the questions that I often get asked in clinic is um for patients who have progression of disease after adjuvant therapy. What is the standard of care? And you know, do our Ioioiotk I or the FTK I therapies work in that setting. Um And so this was a really intriguing retrospective analysis done by some of the folks here at the L Center um which looked at patients who had received adjuvant therapy and they looked at 76 patients, you see a majority of those patients were clear cell histology and received either anti PD one or PDL one therapy and were treated with a combination with different regimens including Ioioiotk I or BF therapy at one. And you see in the PFS and the OS curves uh in the top, right, there was really no difference in progression free or overall survival suggesting that all of our current standard treatments may be um may be options for patients who experience uh disease progression after adjuvant therapy. But largely this relate remains an admin need for patients in the clinic and in an area that we'd love to investigate in the future. Um Moving on, we'll discuss a little bit about biomarkers um in some of our front line kidney cancer trials. Um and this is uh stolen from a graphic in the eo education book again um published by Dr Selebi and doctor um Eddie said, and they highlight that while we've investigated a lot of n novel biomarkers and kidney cancer that have, tell us a lot about the biology of the disease. Unfortunately, none of the heat um have made their way to the clinic yet, in order to um select what is the optimal patient for the, what is the optimal treatment for the patient sitting in front of us? Um And so what these two abstracts uh get at is a deeper dive into the data and um and potential explanations for um for why um biomarkers have not yet been successful in kidney cancer. So, the first uh investigation was um presented by Dr Shri and this was biomarker analysis from the phase three clear study. Um As many are aware, the clear study was a front line uh kidney cancer trial, randomizing patients to lenvatinib plus pembrolizumab, lenvatinib plus alius or the standard of care at the time. Cit nib and one of the exploratory end points was looking at biomarkers specifically between the Lenvatinib pembrolizumab and the SIB, a similar study was presented right after doctors um from the keynote 426 study. And that was exit plus pembrolizumab again, compared to the standard of care cit I at the time, um we'll present these two together because a lot of the biomarker work does overall app and so um the questions that are being asked from these two abstracts are, is there, how can we identify any subgroups who may benefit from unit monotherapy versus the combination approach with Latin plus pembrolizumab or Axitinib plus pembrolizumab. We've looked at a couple different um, buckets. The first being PDL one expression. The second being, are there any DNA tumor mutations? And the third being, are there any RN A expression signatures which enrich for response in one group versus another? We'll start with PDL one. And there's certainly some biologic rationale there to support PDL one. If there's PDL one on the surface of an immune cell or a tumor cell, you would think that that would enrich her response to an anti PD one based regimen. Um But what we see across the board is that whether patients have PDL one or don't, they can still respond to these immune based combinations. And that was largely recapitulated in these two analyses. So, um we saw that patients with one vib plus pembrolizumab and exit plus pembrolizumab benefited whether they had PD one expression or did not relative to sin. The second analysis we looked at was, are there any specific tumor mutations which may predict benefit from cit nib versus the combination? And we've learned a lot about the biology that drives clear cell kidney cancer? We know that almost all clear cell kidney cancers have a mutation in the BHL gene on the short arm of chromosome three P and that they often co occur with other mutations such as said T two PB RM one B one. And that in some analyses that these co occurring mutations um are associated with that with response to either angiogenic based therapies or immuno immunotherapies. And so, what these analyses looked at was um all of these different co occurring uh genetic mutations. And they saw that whether patients had one combination or another patients benefited from combination therapy, whether they um had mutations or whether they did not. Um And that combination therapies really did improve outcomes across all different subgroups. Lastly, we'll look at uh RN A signature and, and so these are transcripted transcriptome signatures and stratifying patients into molecular subgroups to see again whether or not one group benefits more from vic monotherapy versus IOTK I. And this was work that was initially presented from the emotion 150 study, which was um sinit nib versus A tab plus bevacizumab. And that stratified patients into seven distinct molecular signature subgroups um in the first two subgroups, uh those are the angiogenic signature subgroups. And then in the 4th and 5th, those are the TF vector or the proliferative subgroups and then groups +36 and seven, those are driven by other transcript donic signatures. Um And while that was initially discovered in the Javelin in the emotion of 150 study, um that those subgroups did not necessarily um uh predict benefit from the Javelin Reno 101 the of value map plus exit. And so what, what we tried to do is look at, are there any particular patterns that we see with the two regimens that we analyzed? And we do see some differences. So, um for instance, on the left hand side, you see that patients who had a mic or proliferation signatures, those patients did not seem to respond well to sive whether on the clear study or on the keynote 426 study. Whereas patients with angiogenic or microvessel density, um those patients seem to benefit um from sid therapy. However, when we look across all the groups, um we see that there um there is no difference between the two and that none of these particular subgroups would argue to use veg E monotherapy versus combination therapy. But another way, um they do not justify denying a patient the potential benefit of an IOTK I combination relative to uh veg E therapy. One. And so again, well, I think we've learned a lot about the biology of kidney cancer, the DNA, the RN A, the protein expression. Um none of these have yet made their way into the clinic and, and uh are helping us to make decisions, although they are being used in a, into in a prospective fashion to try to assign different treatments to different patients. So, on the right hand side, you see the optic kidney cancer trial and this is getting a baseline at uh a baseline biopsy and then assigning patients in cluster one and two, which again are the more angiogenic driven tumors to an IOTK I or patients in the uh clusters four and five, which are more driven by immune pathways to an IOIO I that plus Ebola Ma. And so we await the results of these trials and, and uh and continue to see how we can drive the field forward with biomarkers and kidney cancer. I would be remiss if I didn't mention that there's some really exciting biomarker work being done here at Dana Harbor. And this is work led by the senior ready lab which is investigating um the role of regulatory T cells in the tumor micro environment. And this is work that's been published in CCR and by Doctor Cinder Red, as well as some very talented folks in her lab, which really seek to look at the ratio of regulatory T cells to affect their T cells in the tumor micro environment. And it's thought that these regulatory T cells are critically important to um as a resistance mechanism to anti PD one based therapy. And so if we believe that biomarker work to be true, and we're now bringing that into the prospective uh space. So there's uh our new front line kidney cancer trial, the architect study which is investigating a novel CTL A four inhibitor boin cell ANAB which selectively depletes regulatory T cells in the tumor micro environment and thereby hopefully improves the efficacy that we see from anti PD one based therapy. This trial is open and running here at data harbor. Lastly, but certainly not least again, we'll discuss the uh partitioned overall survival from the checkmate nine study. Um and this is was presented by our very own Charlene Mantia um and is um analyzing data from the Checkmate nine study, which was Cabozantinib plus Ebola compared to CIT nib, that's a front line uh kidney cancer trial. And um a lot of this work in partitioned overall survival and treatment free survival has been pioneered by uh MEREDITH Regan and the Biostatistics folks here at DF Harbor. And it's really getting an appreciation for when we have such effective therapies for kidneys, cancer, but also other types of tumors. It's really important for us to quantify how our patients are living on therapy. It's not just enough to say our patients alive. It's important to say, are they alive on treatment? Are they alive with toxicity or without toxicity? And so to dive a little bit further into this, when we look at this graph uh and you start on the bottom left, this is time when patients are on their protocol therapy. Um And then as we go up the graph, we notice that kind of purple shaded area that's on therapy with toxicity. And as we start to get into that blue area, that's where patients um come off their first protocol therapy and are what we call treatment free either with toxicity or without toxicity. And as we continue to follow that graph up into that area of gray, that's when patients are on a subsequent line of therapy and then ultimately may experience death. And so again, it's trying to analyze patients across the disease spectrum. And so with this analysis, looked at with patients on Cabozantinib plus Ebola on the left hand side compared to SIB on the right hand side. And as you see on the left hand side, patients are on Cabo plus Nevo for a much longer time or a bigger area under the curve relative to CIT nib. And then when we focus in on that area within the blue, we see that again, patients have a greater proportion of their time on with treatment free survival, both with or without toxicity. Whereas on the right hand side, you see patients with SUNItinib have a much greater area in that gray space where they're on subsequent therapy because they progressed um for sign sy. And when we put some numbers behind that cabozantinib plus nivolumab, the treatment free survival was 7.0 months compared to syin, which was 1.5 times or lower at 4.6 months. And so put this in the context, I think it's important to look at what are our other standard front line treatment options. And this was a, a paper published by MEREDITH Regan as well as Dr Mantia and several other folks within our group. Um And when you look at IPO IAB plus Ebola, you see that the area under the curve in that blue area treatment free survival again, is larger than SYN I. But when you put numbers behind it, treatment free survival among in the ITPT population with 7.8 months compared to 2.3 months, which is about 2.5 times longer, relative to what we saw with Cabot 1.5 times longer. Now, again, it are, we can't compare uh across trials but, but it is intriguing to think about um whether or not treatment free survival is different with an IOTK I versus an Ioio approach. So again, um a really intriguing set of data that um Doctor Mantia presented to us and really uh important way to look at how the patients do both on protocol therapy and off protocol therapy. Um And it's a patient centered endpoint and one that we're seeking to validate in um in additional trials in the future. Um Lastly, before we get to Doctor Sri's discussion, I do want to highlight some really brilliant work being done by a lot of our colleagues here at the L Center. There are too many to, to put on one slide, but these are just a couple of highlights of posters and presentations that I I think were um really brilliant and and um are really driving the field forward in kidney cancer. So with that, I'll uh I'll pause and allow Doctor Shuwei to come on for some discussion. Yeah. Thank you very much. I think uh overall uh you know, this overall um you know, Guis, but kidney specifically, there hasn't been much um you know, um exciting things that happened. Uh The signature are important um uh work that needed to be ha happening, that are not happening um in prior, in prior studies now, um uh now they're happening. Uh and that's important even though we have not changed the standard uh of care. So none of these signature or none of these um um work from clear and uh uh other study Pembrey um are relevant in my opinion to change anything instead of care, but at least teach us what, you know, probably not to do. And I'm a bit worried about those signature where trials are um being built on. Che one is interesting. It will be more interesting if we're able to replicate it in the uh with Vincent uh overall.
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