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 ESMO 2025.
We'll discuss, uh, some really exciting data from phase 3 studies, as well as, um, a lot of practice informing, uh, studies. I think we'll probably have just as robust a discussion about kidney cancer, um, perhaps at our, our next meeting after GE Rasco. Um, but you know, three themes that I saw. We're, you know, certainly building on the legacy of admin Pembro using period operative approaches for clear cell kidney cancer, innovative approaches in first line metastatic clear cell disease, and then the best of what's around and not to the Dave Matthews Band for I refractory clear cell kidney cancer. So, as we know, admin Pembro is standard of care for many of our patients with high risk resected clear cell kidney cancer based on DFS and OS benefit. We also note that there are 3 similar studies, um, done with slightly different patient populations, slightly different drugs, different designs. All of those studies were negative for DFS and OS. Um, the last of these studies um was the Rampart study. This was an investigator initiated trial led out of the UK which randomized patients with high or intermediate high risk kidney cancer, um, by Leibovitz score. Again, this did include not only Clearasil but also non-clear cell. Kidney cancer, randomized patients in a 3 to 2 to 2 fashion to active monitoring, RMB Durvaluab alone and RMC durvalumab plus tremoloumab. The data we saw at ESO was focused on this RMC. I will note that originally this study was supposed to include about 17, 1700 patients, um, given the COVID pandemic and difficulty with growing due to the approval of pembrolizumab, um, that target sample size went down to 750. Patients included on rampart, about 16% of patients, again, we're in that non-clear cell subgroup, about 5% of patients have M1 NED and about 3/4 of patients were PT3. Um, rampart was a positive study. It showed that Durvalumab plus two doses of tremoliumab uh showed an improvement in disease-free survival with the hazard ratio of 0.65 and a P value of 0.09 relative to active monitoring. The 3 year DFS was 81% in the dervi Treme arm versus 73% in active monitoring. When they break down subgroups, those patients with high risk disease, which is about 50% of the patient population, we see an enrichment in that DFS hazard ratio of 0.52 relative to the 50, 45% of patients who are low risk, where we see that hazard ratio diluted down to 1.19. Safety, again, not surprisingly, the derby Tremi arm had higher rates of grade 34 adverse events at 40% relative to 8%. About a third of patients required high dose steroids, and there were treatment associated deaths including myocarditis and high rates of treatment dis continuation, again not surprisingly for PD1 CTLA combination. Again, many of these adverse effects were consistent with what we see with PD1 plus CTLA with high rates of diarrhea, um, LFT abnormalities, adrenal insufficiency, etc. What are our takeaways from Rampart? Well, again, the Derba Tremi arm did improve DFS relative to active monitoring and that Benefit appeared to be enriched in this high risk patient population. However, in the adjuvant setting, there were deaths notable on this CTLA plus PD1 combination. Ultimately, I, I think where this lands depends on that third arm that was not presented, the durvalumab monotherapy, and then maybe there is a role for CTLA plus PD1, um, and when we, when we look at those non-clear cell subtypes, trying to see is the benefit seen in those as well. I will note that the Light Spark 022 study, um, was at a year of adjuvant Pembro versus Pembro Popellzudaan in the Light Spark 022 study. This is a study that we ran here at Dana-Farber, and we saw a press release about two weeks ago, noting that this was a positive study for DFS. We have not yet seen data on this, but it'd be very intriguing to see how this, um, is integrated into the um adjuvant kidney cancer space. I'll also note that we currently have opened the strike study, which is again for patients with um keynote 564 criteria, a year of pembrolizumab or pembrolizumab plus 6 months of the TKI tavazumib. The study is open, being led by none other than our own Dr. Brad McGregor. And then when we think about, um, immunotherapy in the neoadjuvant space, we think about what can we learn from melanoma. We know that the neoadjuvant approach, um, appears to be superior to an adjuvant only approach in melanoma. Can we try to translate that into kidney cancer, i.e., with the tumor in place, do we get a better immune response than taking the tumor out and then giving adjuvant immunotherapy? A lot of what we know about adjuvant neoadjuvant studies in kidney cancer comes from small phase 2 studies in the 1st 4 examples here. And then the last study was a large cooperative group, Prosper, which really only gave one dose of uh nivolumab prior to surgery. So maybe not giving enough neoadjuvant therapy to really see that prolonged benefit. Again, a lot of these um small phase 2 studies, um, but certainly hypothesis generating, um. The phase two study that we saw presented at ESO was the NSCoreti out of study of the Netherlands. This took patients with clear cell kidney cancer clinical stage T1B with grade 4 features, T2B with grade 3 or 4, all the way up to node positive disease, but with resectable disease and Randomized to 1 to 1 to 1 to 6 weeks of nivo, 6 weeks of Ivo, or 6 weeks of nivorela prior to nephrectomy, and then patients would continue to be followed. The primary endpoint of this study, again, a small phase two, just looking for signal, was looking at pathologic response, which was uh less than 50% of viable tumor on pathology pathology response. There was um Simon's 2 stage to ensure that Um, you know, each, um, arm would would proceed. Baseline characteristics of patients on NSCO. Again, there were about 15 or 14 or 15 patients on each arm. Uh, a majority of patients had T3 disease, about 20-30% of patients had N1 disease. Actually, 75-80% of patients actually had a grade 1 or grade 2 on biopsy, and the median tumor diameter was anywhere from 10 to 12 centimeters. In arm one, the iO1 arm, we only saw one pathologic response at 7.1%, but in the Nevo IB arm and in the Nevorela arm we saw two pathologic responses in each of those, so five total pathologic responses out of the 42 patients who were enrolled. When it comes to safety, it looks like this was a feasible approach and that, um, surgery was only delayed and, um, one patient due to nephritis. There were 2 deaths on study, however, one was prior to surgery not related to Nevo, one was after surgery, again, not related to Ipivo. And on the right hand side, again, we see higher rates of immune-mediated adverse events in the Nevo, hippy arm and the Neborela relative to Nebo alone. Radiologic responses, the majority of patients, again, after 6 weeks of treatment, saw we we saw a stable disease. So 40 out of 42 patients had stable disease, one patient in the bevo arm had a partial response, one patient in the nivo alone arm had progressive disease. When we look at event-free survival again, small phase two study, limited follow up only 21.9 months, but Iyevo in the green appears to have better event-free and recurrence free survival. Again, small numbers, I wouldn't put too much into this. This data will need to be followed over time. However, those 5 patients who did have pathologic response, none of those patients have had recurrence of disease, again with limited follow-up, relative to those 36% of patients who did not have pathologic response where we did see more um recurrence of disease in that population. What are our takeaways from NSCO? Well, again, I think it showed that neoadjuvant IO led to a limited number of pathologic responses and virtually no um radiographic responses. It was feasible, did not delay surgery. Is there anything we can learn about those five patients who had response, and then ultimately, is pathologic response a reliable surrogate for recurrence-free and overall survival? Much of the neoadjuvant space and clear cell kidney cancer remains an area of active investigation. Um, I will note that the NeoShift study is an NCII study, um, being developed by our own Dr. Tony Schweri, um, where patients are randomized to one of 4 arms, Pembro, Belzudaan, or the combination of Pembro plus belzudaan or a nephrectomy followed by surgery and adjuvant pembro. Um, again, this is something in area where we're very invested clinically, but also looking at some of those, um, those translational end points as well. The second, um, uh, uh, the second theme that we saw was innovative approaches for first line clear cell kidney cancer. As many of us who treat this disease know, we do not have biomarkers to help us choose among our very effective first line regimens, whether they're IOTKIs or IOIO therapy. One of the biomarkers that's being investigated is um an RNA seek based approach. This is from the Emotion 151 study where patients are assigned into one of 7 clusters. Clusters 1 and 2 are angiogenic, clusters 4 and 5 are T effector or proliferative, and then clusters 36, and 7 are broadly classified as other. Um, one of the groups out of Vanderbilt is investigating, can we use this RNA seek based approach to assign patients into different clusters and then assign treatment based on that cluster. So in clusters, they presented data from the angiogenic clusters where they were assigning patients Nebo cabo and comparing it to a historical control. They, um, initially screened about 100 patients and ultimately ended up um assigning 27 patients to cluster angio with Cabonebo. On the right hand side, you will notice that there was a difference between primary and metastatic lesions and that a majority of primary lesions were angiogenic, whereas metastatic had more of a distribution of IO versus those with excluded clusters. Again, in these 27 patients with angiogenic-driven tumors, or angiogenic RNA clusters, um, a majority of patients had favorable or intermediate risk disease. No patients had sarcomatoid heart cystology. 80% of patients had prior nephrectomy, and we saw a preponderance of lung, pancreas, and adrenal glands, again, consistent with this angiogenic phenotype that we know. They did see a response rate of 76% in clusters 1 and 2. No patients have primary progressive disease. All patients had a decrease in tumor burden. Again, immature uh follow-up at only 11.1 months, but perhaps showing an enrichment of benefit when, um, when, when using this RNA seek based approach. Um, again, this is just the depth of response that they showed. Um, as they went along, the, the time from consent to cluster got shorter. So, um, the 1st 150 patients, it took about 36 months, and they cut that in half and then it stayed at about 20 days, um, afterwards. So, I think, you know, what do we take from Optic, I think it shows that this RNACH The approach is feasible. Probably biopsying a metastatic lesion is better than primary uh tumor. We're going to have to continue to follow this data over time, seeing what about that IPO for clusters 4 and 5, and then ultimately, what do we do for those patients who aren't assigned assigned to one of these clusters. Um, some of the work that we're doing using biomarkers to select therapy here at Dana-Farber, we're developing the Chimera trial, which is based on work led by uh Vincent Chuu and Brad McGregor, where we're using Kim one as a marker of response to IPNevo and then those patients who are Kim one high randomizing to Zanza plus PB1 or Ipivo and those patients who have are Kim one low, um, who have a good response to Ivo just continuing on IPevo, looking at a primary endpoint of PFS. Um, another approach that, um, we're taking for clear cell kidney cancer is intensifying with triplet therapy. We know the results of cosmic 313 on the left hand side. We know that cabo plus Ivo improved PFS relative to IPO, however, was limited by toxicities, and the stellar 002, Zanza plus ivorela, um, really didn't have the robust response in ORR or PFS, uh, relative to Zanzaivo. Um, so the keymaker UO1 study was presented at ESO. This was investigating a number of different combinations, um, building on lenvatinib plus Pembro. So this was again for patients with clear cell kidney cancer treatment naive on the bottom, Lenvatinib plus. Pembro is the reference and then as we go up, it's Len Pembro plus Belzudaan, one Pembro plus Merck's CTOA inhibitor, and then a digit containing arm and a lag 3 containing arm. Again, small study but really trying to look at response rate and which of these seems to be most promising to develop in the future. Um, baseline characteristics you see across these different arms, again, they were enrolled at different times. There's different numbers of patients in each arm, but broadly across them we see maybe about 25% of patients with favorable risk, uh, a little more than 50 to 70% of patients with intermediate risk, maybe a slightly lower percentage of poor risk patients than we typically see in our phase 3 studies. Um, and when we look at the primary endpoint of response, on the left hand side, you see that the lag 3 and the tidge containing arms had relatively lower response rates in the 40 to 60% range, whereas on the right hand side you see that the Len Pembro plus Belzudoin or Len Pembro plus CTLA, those response rates were anywhere from 70 to 80%. Um, I will note that the Len Pembro plus Belzutain had a complete response rate of 12%. And that the tidge containing arm actually had a relatively high primary progressive disease at 15%. Um, when we look at, you know, duration of response, PFS OS, these were Non-comparative studies looking at the CTA containing arm versus just Len Pembro alone. We don't see much of a difference in duration response PFS or OS. I will note for many who give CTOA, we're really trying to look for the tail on the curve, so we'll have to see if this data continues to mature. The I will say in the triplet of Glen Pembro Belsudafan, that duration of response PFS NOS um actually looked more favorable than just Glenn Pembro alone. Again, small numbers, um, but certainly a signal that this triplet may be promising to pursue in the future. Um, adverse events again consistent with what we know about the one Pembro, um, perhaps with um higher toxicities in the CTLA component containing arm relative to the reference control, um. And so what do we take away from Teammaker UO3? I think building on Len Pembro seemed to be feasible. Again, these were, uh, you know, really a signal finding study, um, but we'll we'll have to see how the addition of Bellzuderan to when that and Pembro ultimately plays out. The good news here is that this combination is being, uh, has been actively investigated in the light spark study, um. And we did see, uh, we did see a um a press release that this study was positive, although we don't know yet the details. I think certainly we'll we'll pay attention to this hopefully to be presented at a future meeting and discussed here on our platform. Last but not the least, um, the best of what's around for IRO refractory clear cell kidney cancer. And, you know, we're really left with our NCCN guidelines for patients who progress on a really highly effective IOIO or IOTKIs. We have a smattering of different drugs, but we don't really have any randomized studies to tell us which approach is best. We have lots of data that Cabox antonym of that of Eyus give us a response rate anywhere from 20 to 40%, PFS anywhere from 7 to 14 months, but again, all of the cross trial comparisons um and limitations apply. At ESMO we saw a phase two study, Lencabo, which randomized patients with clear cell kidney cancer who had prior anti-PD1 therapy. Randomized to either lebatinib pluseverymus or caboxantinib. Again, a very practical study of two regimens that we commonly use in refractory kidney cancer. I will note, uh, you know, a majority of these patients had intermediate risk disease at initial diagnosis, about 50-60% of patients had no prior bed jet targeted therapy, and about 70% of patients received Ipivo as their first line treatment regimen. Lencabo was a positive study. It showed an improvement in progression free survival with um a medium PFS of 15.7 months on Levain plus Eus relative to 10.2 on Cabosaninib with a hazard ratio of 0.51. When we look at response, response was higher in one bat nib plus Eyus said 52% relative to 38% on Cabosantii. Primary progressive disease rates largely similar between the two groups. This study was again only 90 patient studies, so immature, not conclusive, um, so really can't draw too much on OS between the two, but um, no, no OS benefit for whenever Lymus relative to Cabo. When we look at adverse effects, we do see higher rates of serious adverse events, higher rates of grade 34 adverse events, and double the rate of treatment discontinuation with one everyus relative to Cabos antonib, um. Again, a lot of those were fatigue, protonuria, hypertension, higher in Leev relative to PPE and mucositis, which were higher in Cabo's Antony. What are our takeaways? Again, when wheneverymus did improve PFS relative to Cabo alone, although it did come with significantly higher rates of adverse events and no benefit in overall survival. So, Um, I think some of the questions that come are what are the contribution of component parts, the VEF plus MO inhibition, and is combination therapy better than sequencing? Um, I will note another study out in this space is the Light spark 011 study, which was when Belzudaan versus Cabozantinib, and at this, we also saw two weeks ago that this is a positive study with an improvement in PFS. And so again, we'll have to see the nuances of the data again, hopefully to be presented. at a future meeting and discussed here. And then in this space of post PD1 therapy for patients with kidney cancer, we also have the P1 study which is soon to open where we're investigating Cataan the novel HIP2A inhibitor plus carbo versus Cabo plus placebo. With that, I'll invite our uh discussion and again scientific co-chair Doctor Tony Schweri for his comments. Hi, hi, thank you so much. You spend the most time on uh kidney and that is the, I would say the least exciting GU but you love kidney, I don't blame you. So, um. I think just uh one minute on the adjuvant neo adjuvant space natio or NECU is a proof of concept that people, um, you know, outside Dana-Farber can do neoadjuvant studies, we can't, uh, sadly, we will be able to change that with Vincent, Brad, our urologist, and everyone, uh, but, uh, we have to be able to do these studies. They're proof of concept. They're important. We give um. You know, uh, the tissue and rely on people like this guy here who visited me, Elian Allen, cause we're going together to dinner to ask important questions. In part, I want to look at the paper more. I'm on the steering committee despite not open in the US, there is a signal and non-clear cell. Uh, so I don't know what that's about. It's good we have another positive study. Could that be older Valloab for a year, a better drug than Etizo? I don't know. It's not gonna change standard of care together today. Um, first line clear cell RCC, uh, optic study is based on, uh, these clusters. They tend to change by who look at them, Doctor Salibi. I know was on the call, calling all the way from Yale showed that they could be prognostic. They repeat the biology, but they're not, um, you know, predictive of a certain, uh, therapy. And if you see the response rate and higher is higher in all, how much you gonna, you know, uh, enrich to enrich. Uh, so I think it's good, it's doable, the signal that patient with metastatic disease may have a different. Uh, biology is um quite uh interesting. Um. By the way, keymaker UO3, uh, which we were involved with, but they told us, I don't know if someone from Merck here that we have too many uh MRC studies, so we can't open it. Uh, uh, you know, I was disappointed that the CTLA for arm didn't perform as well as I thought. Uh, in the duration of response. Finally, uh, I think the triplet was the HEP2 inhibitor, quote unquote numerically did the best, and that is the more interesting thing on 012. So it gives 012 a life. It seems so far Belzotifan has 3 out of 3 positive trial. You know, adjuvant, second line, and single agent refractory. And if you add VHL 4 out of 4, all of this was not randomized. So we'll see. Now, Len Cabo, I congratulate my our folks, our friends at MD Anderson, able to do that. Will it change a small randomized phase 240 patient each arm and also oncology standard of care. And make us burn through len and Arolimus second line, maybe for the patient that need an immediate response. Uh, otherwise, I would still use cabozantinib, at least, at least for people that want one drug period based on the level of evidence, it's Lee, but there is no OS response and PFS. It's a good study. Uh, I'm glad that they were able to do it because we were never able to do acitinib versus everolimus post nitinib, right? So we did that. So it's good to have that, and that's it.
