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 2025.
So last but not least, um, for those of you joining us, um, we'll be discussing our kidney cancer highlights from the ASCO 2025 meeting. Again, we'll have Doctor Tony Shaweri join us for some expert commentary after we review our abstracts. Um, I thought a couple of themes of, uh, ASCO 2025 and kidney cancer, we saw some long-term follow-up and biomarkers in the adjuvant space in kidney cancer. In the first time metastatic setting, I really do believe that we are in the doublet triplet era of combination therapy, and we saw some long term efficacy of these triplets, of these doublets as well as a novel triplet. In the first time metastatic setting, and then something old, something new. So we have a next generation of HIP inhibitors, we've got next generation of cellular therapies where we saw some very intriguing data presented. So, first, again, many know the design of Keynote 564, um, but this was for patients with high risk resected clear cell kidney cancer randomized to either a year of pembrolizumab or placebo. We know that this data was positive for both a Um, a disease-free survival benefit and overall survival benefit. What this presentation highlighted was some of the long-term outcomes now with 69.5 months of follow-up. And what we see is a maintained DFS benefit for patients receiving pembrolizumab with a relative risk reduction in recurrence of disease by 30%, an absolute reduction of 10% at 6 years. I think these are figures that, you know, are, um, easily digestible and, and things that we could potentially bring back to our clinic to. Advise patients on the benefit of adjuvant therapy. When we look at overall survival, again, a relative risk reduction of 35% in the risk of death, and an absolute reduction of 7% at 6 years, um, so again, really speaking to the long term durability of adjuvant pembrolizumab in this setting. Um, Switching gears a little bit, um, there was some very intriguing biomarker data presented from a different adjuvant therapy, um, uh, study. This was the Emotion 010 study, which, as many know, was the phase 3 study of adjuvant slizumab or placebo for high-risk resected renal cell carcinoma. And what this abstract looked at are several circulating and tumor-based biomarkers to try to predict which patients may have benefited from A Teslazimab versus placebo. Again, this was a negative trial, so she had no DFS, no OS benefit, um, but really important to look at negative trials and try to understand, are there specific subsets of patients which may have benefited from adjuvant therapy. Again, many correlated studies were examined, both circulating uh biomarkers as well as tissue-based biomarkers, um, but really a huge effort in a negative study, um, to try to learn. And better inform how we care for patients with adjuvant, um, with high risk resected clear cell kidney cancer. Um, I think the biomarker that's most intriguing and the one that we've heard the most about at ASCO last year at GUASCO in the, in the winter and now again is, um, the circulating biomarker Kim one, which on the left hand side you see highIM one is prognostic, so it had a, um, increased DFS, um, Increased likelihood of disease recurrence relative toIM1 low, and it was also predictive of response to sallizumab. So you see the line in blue patients who received sallizumab had a prolonged DFS relative to placebo, whereas on the right hand side, patients who wereIM1 low, um, we actually see that those patients tend to do better long term. Um, however, we didn't see that same predictive, um, uh, benefit from a Teslazimab in theIM1 low subgroup. They tried to, um, what this analysis did was add TFfector signature toIM one to see if that further predicted benefit from a Tessab and again on the left hand side you see patients who wereIM one high and TFor high seem to have Even more improvement when treated with the Teslazumab with a hazard ratio of 0.59, whereas those patients were CIM1 high and TF effect or low, um, we saw a more attenuated difference between patients who received a Teslazimab versus placebo. Um, one of the tissue-based biomarkers that has received a lot of attention over the last couple of years is looking at RNAC and um seven clusters that um we assign patients into. Um, very briefly, clusters 1 and 2, you see those are patients with angiogenic driven tumors, clusters 45 and 6 RT effector or proliferative signatures, and, um, clusters 3 and 7 are either complement or snow RNA based signatures. And again, this was initially um uh developed in the Emotion 150 program and has been um kind of applied to other data sets as we've, um, as we've uh found more data and The take home here is that none of these signatures really predicted benefit for a Teslazab therapy. So again, you see the gene signatures, TF effector high or low, angio high or low, um, cell cycle high or low, none of them predicted benefit from a Teslalizumab therapy. Similarly, patients that are in seek um um clusters did not seem to predict benefit from adjuvanatetesolizumab for these patients. Um. I thought some of the most intriguing data from this presentation was looking at paired samples. So, um, so prior surgical samples and then biopsies of metastatic lesions after recurrence of disease, and when they compared those two, they saw a down regulation in MHC1 in patients who had recurrence of disease and an up regulation of immune suppression or myeloid signatures stromal pathways, cell cycle pathways. So perhaps suggesting that um the Um, the, the genomics are such that, um, patients who have recurrence of disease, um, may be enriched for a, um, a, a resistance to immunotherapy. Um, again, there's small numbers here, um, and certainly a bias to, um, having data only from patients who recurred, but I think some really encour um, um, intriguing biology to be worked out. So, um, in summary, again, adjuvant Pembra remains the standard of care for patients with high-risk resected clear cell kidney cancer. Um, we, I, I think the long term outcomes are really reassuring to see, especially in patients, um, where we're looking at disease-free and overall survival benefit, and that there's certainly more biomarker, uh, work to be done in this space to optimally select patients for adjuvant therapy. Um, we do have a phase 3 study open here at Dana-Farber, and this is the strike study, which is led by our Brad McGregor, same inclusion criteria as the keynote 564, except it's randomizing patients either to Pembrolizumab or Pembro plus 6 months of the eFTKI to Bozinib, um looking for improvement in disease-free survival. So we certainly look forward to putting patients on strike. Again, this is open and um growing patients rapidly. Um, the next data that we'll review are, um, is from the first line metastatic setting and clear cell kidney cancer. And I, I think, um, the Cheney 214 study is one of our landmark studies. It's one of the largest studies in clear cell kidney cancer that brought immunotherapy to the front line. And what this analysis looked at was 9.3 years of median follow-up. Um, again, as many know, this is patients with clear cell kidney cancer randomized to Ipivo or the previous standard of care sunniib. And we know that um this study met its primary endpoint with improvement in progression free and overall survival in the intermediate and poor risk population. At 9 years of follow up, we saw a median overall survival of just short of 4 years at 46 months. 30% of patients were alive, 25% were progression free, and 50% of those responses were maintained in that intermediate and poor. Group. So again, I think these are high water marks that, you know, we're certainly going to be looking towards these long-term outcomes in future studies. I thought very interesting to look at the favorable risk population, um, which about 20% of patients on the study were favorable risk. And at 9 years follow up, we saw a median overall survival of 77 months, 35% of patients were alive, 17% per free and 36% of patients had their responses maintained. I'll call your attention to the overall survival on the left hand side where we see a flip in those curves. Initially, sunitib outperforming Ipievo, um, but then the flip and the um sustained separation of those curves showing that Ipi evo is an act is indeed an active regimen for patients with favorable risk disease. Um, the duration of response again, patients who had a response in the ITT population, about 50% maintained that response at over 8 years of follow-up. Importantly, when we look at long term toxicities of Ivo, again, many of the immune-mediated adverse events occurred within the 1st 2 years of therapy with very low rates of immune-mediated adverse events um at later time points. This has changed guidelines, so now Ipibo is listed as a preferred regimen for uh patients with favorable risk disease, although it does not have category one recommendation as our IOTKIs do. Um, and when we look at other IRTKIs in this favorable risk disease, it's clear that these patients have a protracted disease and, um, and we see the overall survival for IRTKIs somewhere in the 0.9 to 1.1 range. Um, and so I think, you know, what to do for this, um, this patient population is really an outstanding question. Um, and certainly, um, calls into question should we be using Ipiebo um for patients with all risk disease, um, based on the data, long term data that we saw for, um, from Checkmate 214, um. The next study what we'll go over is the pedigree study. This was a cooperative group study, um, through Alliance led by Dr. Tian Zhang and Doctor Tony Shaweri and our group. Um, this took patients with metastatic clear cell kidney cancer with intermediate or porous disease. Step one of the therapy was standard ipilimumab plus iboliab induction for 4 cycles, and then based on response to therapy, if patients had a complete response, they would continue Nivvo. Alone, if they had progression of disease, they would go on to Caboxaninib. But for all the patients in the middle who had either stable disease or, um, partial response, they'd be randomized to either nivolumabalone or ivvo plus caboxantinib. Um, this study was powered to look for overall survival in that subset of patients. While we don't yet have that data, we did have the analysis of patients with, uh, who were treated on step one with Ivo. And what we saw was that there were a total of over 1100 patients enrolled into step one. About 2/3 of patients actually moved on to step two, and a third of patients withdrew prior to step two. The most common reasons to withdraw prior prior to step two were due to either adverse events of therapy or primary progressive disease. When we looked at patients who did move on to step 2, we saw there were fewer patients with poorous disease who Um, enrolled in step 2, there were fewer patients with bone metastasis, really suggesting that these patients, um, are at high risk of either early progression and, and certainly in an area of unmet need. Um, I'll also note this is a cooperative group study, so we did see a, a rather large number of deaths of, uh, for patients on step one, primarily related to progression of disease. We did see a number of grade 5 events as well. And so I think, you know, um, perhaps lay some caution to our previous statement that we should be using more Ipi-bo in the frontline setting, um, that Ipibo may not be the best treatment for all patients with clear cell kidney cancer. Um, next up, we'll discuss a novel triple therapy and first sign metastatic clear cell kidney cancer. This was the stellar 002 study that investigated Xanzalitinib, which is a novel vegFTKI therapy similar to Caboxaninib, however, has a much shorter half-life than Caboxantiib. And so this was the phase one study combining Xanzalitinib plus nivolumab. And zanzalitinib, nivolumab, and relatumab, the Lag 3 inhibitor, really just looking at um at the um safety and efficacy of this doublet and triplet combination. Um, about 25% of patients had favorable wrist disease, about 75% of patients had intermediate or poor risk disease, then 80 patients in total, 40 in each arm. Um, the first in the doublet, Zanza plus Nivo, we saw a response rate of 63%, a low rate of primary progressive disease, and median progression free survival of 18.5 months. I would say that's vastly on par with some of our currently approved IoTKI doublet regimens. However, when we look at the triplet therapy, we see a rather lower response rate of 40%. low rate of primary progressive disease and perhaps a little shorter, median progression free survival in the triplet relative to the doublet. Now this is a phase one study, so not powered to compare between arms, but certainly intriguing to see, um, uh, a shorter lower numerical response rate and potentially shorter PFS and the triplet versus the doublet therapy. Um, when we look at adverse effects of the doublet versus triplet, we saw similar rates of treatment-related adverse events, similar rates of dose reductions, um, where I think Xanzolitinib differentiates itself as relatively lower rates of um hypertension, ALT, AST and PPE relative to what we would think about with caboxaninib, and so, Um, you know, in summary, again, I think Ipievo, um, really showed, um, to borrow from our previous presentation, took a victory lap and chose, um, remarkable, durable response at over 9 years of follow up. Um, in pedigree, we saw patients, um, treated on step one, about a third of patients actually came off of therapy. Either due to early progressive disease or treatment-related adverse events, highlighting that patients with poor risk and bone metastasis, certainly in an area of unmet need, and then, um, obviously we're looking at, uh, novel vegFTKI combination therapies and the stellar protocol. Um, at the end of the day, I still think that our Treatment decision for patients with clear cell kidney cancer is between IOIO or IOTKI largely taking into account the disease, the patient, the treatment factors um that we consider between these two regimens. I will highlight that we do have the Architect study open for patients with first sign metastatic clear cell kidney cancer, randomizing patients to a next generation CTLA inhibitor, Botinilimab plus bowelsilimab or Ipivo as standard of care. We've, um, had about half patients, um, enroll in the study, and it's, uh, currently ongoing enrollment at Dana-Farber. Last but certainly not least, um, we'll discuss novel next generation therapies in the treatment refractory setting. Um, first up, we'll discuss the ARC20 study. This was a phase one study, and for those who are at GUS, we saw the monotherapy data for Cadataphan, which is a novel HIF-2 alpha inhibitor. What this data presented was the combination of cast. plus Cabozantinib. I will call your attention. We did this study did use full dose Catapan 100 mg daily and full dose Cabozantinib 60 mg daily. And what we were looking for is the primary efficacy and, and safety of this regimen. Um, about 40% of patients in this safety population, um, received Veja TKI plus IO. About 60% of patients received IO only. And what we saw was a response rate of 46%, a primary progressive disease rate of only 4%. Uh, 1 patient had progression of disease. I will also note that this is rather early follow-up, just 5.3 months of follow up, um, on this study. Again, as you see from those, um, the responses, many patients are um continuing on therapy, 19 of the 24 valuable patients remain on therapy, so we'll continue to see this data mature over time, but certainly intriguing to see the combination. Um, and only one patient with primary progressive disease treated. Um, when we look at grade 34 adverse events, 48% in the combination, um, but relatively lower rates of anemia and hypoxia than maybe one might expect with the HIP2 alpha inhibitor, especially hypoxia, only 7% of patients with grade 3 hypoxia on the castaan. And then, Um, as, um, we've seen some promising data with this combination, this is being brought forward in the phase 3 trial for patients with, um, who have had prior anti PD1 therapy, randomizing patients to the combination of Catadoan pluscabozantinib or Caboxatinib in the peak one study. So this um study is open and, um, You know, certainly look forward to putting patients on and seeing some outcomes here. Um, last but certainly not least, we'll discuss CAR T cell therapy in clear cell kidney cancer and the AO 316, which is a CAT CART against CD70, um, that, um, That was evaluated in the traverse phase 1B study. Um, patients received standard lympho depletion day -3 to 5 to -3, and then received infusion of CAR T cell therapies on day 0. This was a phase one study again looking at the tolerability early efficacy of CAR T cell therapy. Um, this was a pretty heavily pre-treated patient population, so a median of 4 lines of prior therapy. All patients had received prior anti-PD1. Over 50% of patients had received CTLA inhibitors, um, and many patients received more than one TKI therapy. And what we saw was, um, the grade 3 adverse events were somewhere in the 50 to 60% range, um, with the CAR T cell. Um, on the right-hand side, you'll note, um, rather modest rates of CRS and ICANs with this CAR T cell therapy, although that Grade 3 infection rate of 36%, um, rather high for a CAR T cell therapy. However, there were no grade 5 related adverse events and again many of the treatment-related adverse events were related to the lympho depletion that was used prior to the CAR T cell therapy. Um, when they looked at responses in the overall population, they saw a response rate of 21%. However, when you break that down by patients who had a CD 70 TPS greater than 50%, you saw a response rate of um 26%, whereas patients who had a CD70 TPS less than 50%, we actually saw no responses. So perhaps suggesting that TPS, that CD70 TPS may be a biomarker of response to this CAR T cell therapy. Um, of those patients who had a TPS greater than 50%, 44% of patients had a reduction in 30%. Um, of the uh baseline target lesions, and many of those, uh, many of those responses seem to be prolonged in duration. And when they looked at, um, the reduction in CD70 positive host T cells, um, and persistent persistence of CAR T cells, we see again, um, uh, the prolonged benefit of patients who do have a response to this CAR T cell therapy. And so, um, well we see some responses for patients who express CD70 at a high rate. Um, we did see rather high rates of grade 34 adverse events with neutropenia, relatively low rates of CRS and ICANs. And so I think some intrigue in biology here and certainly um some promise in the CAR T cell space where we have not had as much success as we would have liked in refractory kidney cancer. I will highlight two studies that we have open. Um, the AB 2100, which is an integrated circuit T cell consisting of autologous T cells modified by CRISPR. This is, um, efforts being led by Dr. Vincent Chuu here at Dana-Farber, and then we also have an NK cell therapy, um, which is up and running as well. So certainly welcome referrals um for patients for these two protocols. Um, with that, I'll welcome Dr. Tony Shuwean for expert commentary on kidney cancer abstracts. Yeah, no thanks, uh, Mike, great. I think, uh, this is a great overview. Um, for first, for the adjuvant, uh, keynote 564 adjuvant Pemb is standards. It's amazing after the 69 months follow up to see the overall survival, um, remaining, there'd be one more um OS, uh, that's the end of the study OS which will be um positive uh for sure at this rate. Uh, the biomarker, I think it's kudos to Rosh who, you know, immediately does biomarker studies. The practice in forming. It's very interesting. Uh, there is nothing counterintuitive, uh, but, uh, how, I think they found the population where Etizo might work, that's the Kim one high population, maybe more aggressive, and they need more aggressive treatment, and they justified that by high effective. So, like you. I was quite intrigued with uh the subset, and I think this alone can be a huge uh undertaking, uh, because we don't have data on pre and post and renal cell cancer. And this trauma and proliferation gene signature at progression and decrease in MH MHC1 signature at progression uh make a lot of sense. We've seen that in the melanoma, but loss of mutation more than progression, it's along the same lines. So this is, uh, this is great. Uh, Checkmate 214, what can I say? 5 year survival was 5% when I just was an instructor. Some time ago, now you have 9 years survival of 34% when you add the favorable risk. This is, this is amazing. Now you go 5 years earlier into the SER Medicare, SER database, you see a 5 year survival of 17, 18% only, but then it was less than 5% in the past. And I'm not sure stellar or to uh that combination gonna go forward. Um, I'm not, it doesn't, as you see with PFS of 18 months from single arm. This is not gonna cut it, but at least they're, uh, tolerated together. They're doing it in renal cell, perhaps the combination will find home and renal cell or other, um. Other, um, indication of No Zanza just recently with Akio showed an overall survival benefit against regorafenib in colorectal cancer. That's big for colorectal UCOS. I look forward to see the data, um, perhaps at ESO, but that was, that was big. So that's a, and Zanza has a shorter half-life than Cabo, and it's the kind no wise target. The same, the same, exactly the same knasas, uh, at the same level. The penetration in the tissue just by pure luck serendipity, is a bit different, uh, from, um, um, you know, um, tumoral tissue to normal tissue. The ratio is different. I think based just on the pH and acidity, that's why talking with scientists. There at Exelis and pedigree presentation was a simple presentation just what happens uh in the first step when we give people NOIP before we randomize them, 30% um people come off therapy. It's just unacceptable, but that's the nature. Normally, no one come. Everyone will get, you know, almost everyone second line treatment, but these are people that moved that decided no, that they didn't want to be on trial. So when you have a, you have to be careful when you have a two-stage trial, you know, you give one and it. Uh, you have to probably plan for power purposes, especially if your endpoint is uh on the second randomization, your primary endpoint. You have to not uh plan the 5, 10% loss in patient, but the 30, 40%. And finally, I think if two inhibitors are here to stay, I'm glad we have another one. The combination is active, and be tested in peak one. The toxicity is less, I think, just because we know how to manage anemia and hypoxia and not put any patient. I think that's the main reason. And um glad that Vincent is leading the charge in kidney and bladder with cellular therapy. These drugs are active, but we need our uh hospital, the 300 bed hospital, because all these patients have to be hospitalized, and that's another reason, and they're only getting better. And I've seen other data with other uh cellular therapies that actually uh in a uh in a population that is completely, um, completely, uh, targeted for the biomarker showing 20 to 30%. This is one infusion. If there is no death on study, you know, this, this gonna be big and uh and this is something we need to invest as an institution, um, and as much as possible.
