Chapters Transcript Video 2026 ASCO Kidney Cancer Highlights The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the kidney cancer clinical updates With that, um, we will move on to our, uh, last session. These are kidney cancer updates from the ASCO annual meeting 2026. I'll be joined by our discussing Doctor Tony Shuweri. Um, first, we'll discuss a couple of exciting abstracts in. Kidney cancer, and this is a slide that we've brought up a couple of times at these conference highlights where we know that adverin Pembrose is standard of care for patients with intermediate or high risk clear cell kidney cancer. However, there have been a number of studies in the space that have not shown the same. Um, disease-free survival or overall survival benefit that we saw in keynote 564. And so the last of these studies to be reported is the Rampart study. This was a study led out of the UK, an international investigator, uh, an investigator initiated phase 3 trial, um, which compared, um, patients with high risk, uh, resected kidney cancer by the Leibovich score. So again, a little bit different than the criteria. Used in keynote 564, um, it randomized patients in a 3 to 2 to 2 fashion to either active monitoring the monotherapy durvalumab or combination durvalumab plus tremoliumab, and this study initially launched a number of years ago and aims to enroll over 1700 patients, but because adjuvant Pembroke became approved and this um was impacted by COVID-19, the study actually, um, ended early and, um, This is the first report of the durvalumab data. So, um, notably, patients on Rampart, about 85% of patients did have clear cell, but 15% of patients had non-clear cell disease. There were a small number of patients, less than 5%, who had M1 NED, so, Um, resection of a metastatic lesion, um, after resection of their primary kidney tumor, and they did include, um, you know, about 20-25% of patients with PT1, PT2 disease, although a majority of patients over 70% had PT3 or T4 disease. And the study, um, the data that we saw presented at ASCO 2026 was that Durvalumab did not improve disease-free survival with a hazard ratio of 0.74 relative to active monitoring. We had seen data previously that Durvalumab. Plus tremilimumabb did improve disease-free survival with a hazard ratio of 0.65. Again, you look at the three-year disease-free survival rates with active monitoring, 72%, 78% with DUB monotherapy, and 80% with DUB plus TRMI. And what we know from the DUB plus TREMI subgroup was that the patients with the, at the highest end of risk seem to garner the most benefit from Both PD1 and CTLA uh versus active monitoring with a hazard ratio of 0.52, whereas the analysis that we saw for devalumab alone showed that, um, there was no benefit whether the patients had intermediate or high risk disease after resection. And we see um no improvement in overall survival in either the alumab monotherapy or the draumab plus tremumab relative to active monitoring. Again, excellent 3-year overall survival rates in all three arms. Um, the Dervalumab did have, um, higher rates of grade 3-4 adverse events relative to active monitoring, but less grade 3-4 adverse events relative to Derva plus Tremi. I think our takeaway from Rampart is that, you know, even though Derva plus Tremi did improve disease-free survival, there was no improvement in overall survival, and the Derva monotherapy arm didn't improve. Free or overall survival, and was associated with higher rates of immune mediated adverse events. Question as to, you know, why was this study negative, whereas um 564 was positive, you know, potentially inclusion of patients who had lower risk disease with PT1T2, including patients with non-clear cell RCC, which we know is a very, um, much more heterogeneous biology. At least, you know, at present, there's no role for anti-PDL1 or CTLA inhibition. Um, in adjuvant clear cell or non-clear cell RCC, again, our standard of care is, um, uh, uh, is a year of adjuvant Pembroke. Um, but the question has to be brought to us is, you know, is there a way that we can better refine who actually needs to be, who are the patients at highest risk, and who, you know, really does require potential intensification of therapy for, um, patients with high risk resected clear cell kidney cancer, and so, um, with, uh, this next abstract was presented by Doctor Shiweri, which looked at CTDNA analysis for patients treated with adjuvant Pembro and the keynote 564 study. Again, as we all know. This was um for patients with high risk resected clear cell kidney cancer randomized to a year of Pembro or placebo for 1 year. This study met its primary endpoint of PF of disease-free survival and overall survival. And when they looked at CT, the CTDNA valuable population, they found about 75% of patients did have CTDNA that was valuable across treatment arms. And when they looked at the exome-based CTDNA status, Either by 16 plex cTDNA or 64 plex cTDNA, we saw a relatively low detection rate of about 5% on the 16-plex and 8% on the 64 plex. Um, we did see higher rates of cTDNA positivity, um, in the high risk versus the intermediate high risk subgroups, and then, um, maybe a modest rate of cTDNA detection in M1 NED population, probably reflecting the heterogy. The heterogeneity of that subgroup, and we know that baseline CTNA DNA positivity was associated with a poor prognosis, and again that was with other patients were on the Pembro or the placebo arm, whether they had the 16 plex assay or the 64 plex assay, again, wide, um, Differences in the Kappelmeyer curves here, and then we looked at CTDNA clearance, um, was higher with Pembro, relative to placebo, so you see on the left-hand side on the 16 plex, 60% of patients had CTDNA clearance with Pembro versus um just 20% with placebo, um, and then 55% on the 64 plex with Pembro versus 36%. Um, on placebo, um, again, interestingly, um, we know that patients who, uh, on the right-hand side, we know patients who were negative and stayed negative, they had the best prognosis on Pembroke. Those patients who were positive and stayed positive, they had the worst prognosis in the graph on the bottom, and then those patients who were positive. And then turned negative, they had a kind of intermediate prognosis, um, in terms of disease-free survival. And again, we'll call your attention to the patients on placebo. We saw 9 out of 25 patients, so 36% of patients actually converted from CTDNA positive to negative, and that was just on placebo without any active treatment. Um, so again, some of our takeaways, um, unfortunately, CTDNA has a low sensitivity using either the 16 or 64 plex exome testing. Um, we do know that despite that limitation, patients who are CTDNA positive, um, had a higher risk of, um, of recurrence of disease relative to those who are CTDNA negative, and that conversion from positive to negative was associated with a better DFS than patients who remained positive. I think unfortunately, there's, um, currently no role for exome-based CTDNA as a test. Minimal residual disease and clear cell kidney cancer, although, um, there's much more, uh, evolved technologies in chem1 that I think are exciting to potentially use in this space. Um, we also saw, um, a new update from the White Spark O22 study, so this was, um, again for patients with high risks clear cell kidney cancer, randomized to either Pembrolizumab plus Belzutifan or Pembro alone. Um, we know this study met its primary endpoint and now is FDA approved for patients with high-risk resected clear cell kidney cancer, so certainly another option for us to be discussing with our patients in clinic, and, um, we have now added that to our, our list of standard of care options, um. And we also have the strike Trey strike strike trial open, so this is um led by Doctor McGregor and um then through Alliance, which um is testing either a year of pembrolizumab versus a year of Pembro plus 6 months of TiVo, um, aiming to improve disease-free survival. We have a number of um neoadjuvant studies, so there's pre-Noshift, um, and the Neoshift, which is underdevelopment, and again trying to improve outcomes um for patients with a, uh, a high risk clear cell kidney cancer prior to surgery, and, um, and you know, trying to um follow Proteus and follow some of the um data that we've seen in, um, bladder cancer, that the neoadjuvant approach, um, in kidney cancer, um. So, the um next study that we'll go through is the radical study. This was an investigator initiated trial, um, led by Rayna McKay and um senior author, Doctor Shuri here at Dana-Farber. And this is based on an understanding that we know patients with kidney cancer and bone metastases, unfortunately have a worse overall survival, worse quality of life, and that there's some data to tell us that using a radioligan therapy. Radium 223, which is an alpha emitter in combination with cabozantinib, may improve outcomes. And so there was a smaller pilot study that was run by Doctor McKay and Dr. Schwri, and then this is the larger phase two trial, um, that, that built on that preliminary data. This took patients with any histology kidney cancer who had any untreated bone metastasis, KPS greater than 60%. And osteoclast targeted therapy was, um, was, um. was used unless contraindicated, and patients were randomized to either cabozantinib plus radium or cabozantinib alone, looking at a primary endpoint of symptomatic skeletal event-free survival. And what we saw from the 98 patients who were enrolled in the study was that they were predominantly clear cells, so over 80% had clear cell disease, about 20% of patients had liver metastasis, about 60% of patients actually had had a symptomatic, uh, prior symptomatic skeletal event, and, uh, about 90% of patients had had prior therapy, uh, predominantly with EFTKI therapy and or PD1 therapy. And what we saw was that the median exposure to the VEGFTKI was different between the two. So we saw cabozantinib and arm A was about 30 mg um relative to 40 mg on arm B, the cabozantinib alone, and that the median number of radium cycles given in the intervention arm was 6, with about 50% of patients completing all 6 doses of radium 223. And unfortunately, this study did not meet its primary endpoint, so we saw that the stratified symptomatic skeletal event-free survival, um, was not improved with the addition of radium to cabozantinib with a hazard ratio of 1.24. You see actually the, um, the curves do flip at about the 9 month mark, and, uh, because of this, uh, the study was stopped early due to futility. Um, we, uh, looked at other endpoints, so stratified progression-free survival, again, no difference between the two with the median progression-free survival of about 10 months in both arms, and interestingly, the, uh, overall survival, you do see a flipping of the curves at that 9 month mark and And perhaps a longer median overall survival with radium plus Cabo at 29, 28 months, relative to Cabo alone at 19 months with a hazard ratio of 1.4. Again, small numbers and you know, a lot of follow-up and, and censoring, so, um, caution needs to be taken there on overinterpreting that result, but, um, but certainly, you know, um, a potential benefit to radium seen later on than early on, um. What we see in time to first skeletal event, again very similar between arms, response rates similar between treatment arms, and time to subsequent therapy again, very similar between treatment arms. Um, we did see Slightly higher rates of hematologic toxicity, so anemia, uh, low white blood cell count, low, uh, lymphocyte count with the addition of radium to cabozantinib, but overall a pretty well tolerated addition to cabozantinib. And so unfortunately, uh, radical did not meet its primary endpoint, but it was relatively well tolerated with low rates of grade 34 adverse events or dose reduction. have to ask the question of, you know, would better patient selection have made a difference, whether it was using patients just with clear cell or non-clear cell, limiting extra osseous disease or potentially incorporating radium with now our standard of care immune therapy, would that have improved outcomes? Um. And you know, I think this is one of the, the first shots at radioIA therapy for patients with bone metastases and kidney cancer and really an area of unmet, unmet need. Um, I'll also call out that, you know, another attempt has been made, um, this is the laser study. By Doctor Praffel Rabi, which is using lutician, which is highly expressed on the vasculature of patients with kidney cancer. Um, this study did meet its, um, primary enrollment goal, and I look forward to seeing results from this soon. Um, the last is, uh, we'll discuss a couple of novel therapies and refractory clear cell kidney cancer, and this was actually a, a poster that was presented. Um, this was a phase one study of HC 7366, which is a potent activator of GCN-2, and at least in vivo has been shown to, um, Decrease HI signaling and decrease cell cycle progression, and so the hypothesis is that this drug may be a good partner for um for Belsudofan in patients with clear cell kidney cancer, and so this was a small phase one study looking at both monotherapy of this GCN-2 activator and combination with Belsudafan and a dose escalation. Uh, cohort, um, the monotherapy cohort, um, uh, and the combination, they had a median number of prior therapies of 2 to 3. Again, a majority of patients, um, in the monotherapy had gotten prior TKI and Belsudafan, and then patients, um, in the Belsudafan combinations had not gotten Belsudafan. And um what we see from the tolerability was that um the GCN2 activator um had a rather modest rate of grade 34 adverse events of about 40% and then in combination with Belsudafan, we actually do see an increase in. 34 adverse events, and then on the bottom, you see, um, the adverse events of note of anemia and hypoxia, again, higher in the combination and higher, um, but, but it did not appear to be related to the dose of HC 7366. Um, when they looked at responses, they, um, saw no confirmed objective responses in the monotherapy cohort, but then they did see a response rate of 26% in the 40 mg combination cohort and 37% in the 60 mg combination cohort. Again, they kind of include light spark 005, the Belsudafan monotherapy, uh, historical control of 22%, um, again, small numbers, so I don't want to overinterpret these, um, but at least, um, showed that there is some, um, some activity to the combination relative to the monotherapy. And interestingly, they did see that uh they did on um on um, on protocol biopsies at cycle 2 day one, and those patients who were treated with the combination, they saw. Decrease in RB in tumor cells and decrease in KI 667 in tumor cells, again, supporting the preclinical hypothesis that there may be some additive benefit to using these two agents. And so my takeaways from this is that, you know, this GCN2 appears to be a Uh, well-tolerated drug, and it shows some early efficacy, early safety data, again, really small numbers, phase one, but at least, um, some, some pre-clinical and now some early clinical evidence that this combination may be, um, may be a benefit to, um, potentially using just HIF2 alpha as a monotherapy. I will note that we have several studies that are investigating HIF2 or angiogenesis targeted. Agents. So this is the um PE one study, which is for patients with clear cell kidney cancer post IO randomized to either caststatapam plus Cabo or placebo plus cabozantinib, trying to see if early HIF2 inhibition improves outcomes with VEGFTKI therapy. And then we also have the ARNT molecule um out of, uh, from BMS which is being investigated in the phase one protocol led by our own Stephanie Burke here at Dana-Farber. So, um, with that, I will close and invite Doctor Shaarian for our discussion. Yeah, no, thank you. Thank you for the. 14 people that stayed, you know, adjuvant therapy and clear cell RCC is being redefined. Do not use what's commercially available for CTDNA because your sensitivity is low, so you're going to miss on folks and give them false hope. There are better tests we're working on for CTDNA. That are not going to only look at SMVs, but they're going to look at structural variant, at phase variants that are more common in renal cell cancer actually, and these are common, but you know, now it's rather probably Uh, not use it if you have someone borderline, you really don't want to give the drug, but the patient really want it, you could really do a CT, a DNA, knowing that if it's positive, then probably you have to act on it. Rampart, um. I think if Rampart was a larger study, single agent or volumab for a year, it would have been a positive study. It's a large study, but when you compare head to head the combo or the single agent versus the control arm. Which was observation, the power drop in a significant fashion. And why it's negative, you know, PD1 and PDL1 inhibitors are different. There isn't a single study with Pembro that was negative. There is one, so it's 1 out of 1, and there were Is not Pembro. These are totally different drug. It's like saying sunnitinib and sorafenib are similar. They have more similarities than differences, but they're not similar. That's my view. Radical is a labor of love that Reyna started, I believe, when she was here was the concept, you know, it builds on a phase 12 that Reyna and I did with at that time pazopanib, the newest standard of care coming where if anyone With renal cell cancer, first line pazopanib bradium, second line sorafenib bradium. The study showed that they're combinable. There was some interesting bone biomarkers, so we took it to the next step with cabozantinib. that trial suffered from accrual that was suboptimal because of the immune checkpoint inhibitor, you know, I can't say much except that. Combination is tolerated together, but nothing more. And finally, That she see and activation. I wouldn't say much of it. Yes, pre-clinically this is on target, what you would expect, but the response rate is not what I would think. It's not different than single agent HF2 inhibitor. If we don't have much going on and there are scientists. interested in this pathway pre clinically, yes, but there are, you know, different and I would think probably more interesting thing to do, such as what Stephanie Berg. is bringing with the ARNT, the HF1 beta degrader, that's the partner of HEF2 alpha. And that's it. We're on time minus 1 minute. Excellent. Well, again, thank you, Tony, for your commentary. Thank you all for, uh, for staying till the end. Um, we will send out slides and links to these and look forward to seeing you all after uh ESO in the fall. Bye guys. Thank you very much. Bye everyone. Good job. Bye bye. Published July 1, 2026 Created by Related Presenters Michael Serzan, MD Medical Oncology View full profile Toni Choueiri, MD Medical Oncology View Full Profile