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 GU ASCO 2025. Highlights in this video include:
• COSMIC313 Triplet therapy improves PFS however no OS benefit in first line ccRCC
• KEYMAKER-U03 investigates novel immune and targeted therapy in refractory ccRCC
• KIM1 shows promise as a prognostic and predictive biomarker predicting immunotherapy benefit in ccRCC
We'll move on to kidney is certainly not last but not least. Um, and so in kidney cancer at a glance, um, we saw a lot of interesting data, both in the first line, clear cell kidney cancer and in later lines of therapy. Um, one of the highlights for me was looking at, um, Kim one as a novel biomarker, which was presented by Dr. Vincent Chuu. And so, um, we'll go into all of this data. And try to get everybody out on time this evening as well. So, um, the first study we'll look at was a updated um outcomes on the checkmate 9 study. As many know, um, checkmate 9 was Cabonibo versus sennitinib for patients with first line metastatic clear cell kidney cancer. This study has, um, was positive for response rate, PFS and OS. Benefit favoring Cabonivo and so what this study was looking at was some of those longer term outcomes, um, and a final overall survival analysis, again, just by, uh, just to review about 20% of patients had favorable risk, about 60% of patients intermediate risk, 20% of patients with poor risk, standard, um, frontline frontline clear cell kidney cancer population. And again, the primary endpoint looking at PFS and the ITT population favored the combination with the hazard ratio of 0.58. I will note that these curves continue to decrease over time, and it's uncertain as to whether or not there is a plateau on these curves relative to what we see with Nevo plus IPI. And um and in overall survival again we see a maintained benefit supporting the use of Cabo Ebo relative to senitib with the hazard ratio of 0.79. When we break down these patients by IMDC risk categories, on the right hand side you see in favorable risk, patients with favorable risk on Cabo Ebo had high response rates, 6. 6%, 16% CR rates, that translated into an improvement in progression free survival on the left hand side. However, when we look at overall survival, we do not see a benefit for the combination relative to syne, and I think that this is um really calls into question um the use of this regimen for patients with favorable risk. However, for patients with more aggressive disease, um, with IMDC intermediate or poor risk, again we see that enrichment in higher response rates and the statistically significant improvement in PFS and OS over that has been maintained over time. So what are our takeaways from Checkmate 9 again in the ITT population clear benefit to Caboniva relative to ceitib, whereas in favorable risk, certainly tumor response improvements with ORR and CR benefits and complete response benefits. However, the OS benefits seems um more attenuated than what we see in the intermediate and poor risk groups. So clearly patients with more aggressive disease may may benefit from intense of therapy, which transitions really well into our next study, which was the Cosmic 313 study. This study was, has been reported and published. However, this is, um, our first look at overall survival, or our final look at overall survival on this study. Um, uh, cosmic 313 was for patients specifically with intermediate or poor risk clear cell kidney cancer randomized to the com the triplet combination of Cabo, if. Nevo relative to Ipievo. This is the first triplet trial and that the first randomized phase three to use Ipi-Nevo as a modern comparator control. Again, all of our previous studies used the previous standard of care, um, Cenitinib. So, uh, a lot of first in cosmic 313. Um, again, 75% of patients had intermediate risk, about a quarter of patients with poor risk disease. And when we look at the updated um PFS in the ITT population again that PFS benefit is maintained with a hazard ratio of 0.82 in favor of the triplet relative to IPO. However, when we look at overall survival, we see no benefit of the triplet versus the the hazard ratio of 1.02. When we look across IMDC risk groups, again in the top left you see in uh PFS was maintained in the intermediate risk, however, patients with poor risk, there was no benefit in PFS and then on the right hand side, obviously no benefit in overall survival, whether patients at intermediate or poor risk at baseline. Um, one of the things we obviously have to think about with triplet therapy is, um, does the triplet get in the way of dose intensity? And what we did see was a lower median dose of Cabozantinib at 22.4 relative to 3035. In the placebo group. We also saw uh lower use of all four doses of ipilimumab with the triplet relative to the Ivo doublet. Um, and we also saw higher rates of grade 34 adverse events with the triplet at 75%. Again, lots of, uh, liver toxicities associated with the triplet. Um. Uh One of the things that we're always looking for biomarkers. Is there any, um, any biomarker that can enrich for a response from the triplet therapy relative to the doublet therapy, and what we, um, looked at was, um, what we found was uh the M2 macrophage population appeared to be prognostic, so patients with high levels of M2 macrophages appeared to have, um, worse overall. Survival. But then when we add the combination of the triplet, those kind of patients seem to benefit more from the addition of eje targeted therapy than the Ipievo combination, and this was maintained both in PFS and overall survival. Those patients with M2 like low, um, there was no difference between the two, the two treatment arms. So what are our takeaways from Cosmic 313? Again, Cabo Ipievo showed a sustained benefit in PFS relative to Ipievo. However, there was no difference in response rate, um, complete response rate, or overall survival. What's more, the triplet was associated with high risks of grade 34 adverse events that may have limited drug exposure. I think it's intriguing to look at the biomarker of M2 high macrophages that may enrich for benefit with the triplet relative to the doublet. However, at standard of care right now is really still deciding between IOIO or IOTKI. Obviously there are some triplets that are under investigation. And we see one of these charts every time that there's new data that comes out from one of these large phase 3 studies. Again across the board, we see IoTKIs continue to have high high response rates, high PFS rates. Um, however, we do see a gradual increase in those hazard ratios for overall survival, suggesting Perhaps resistance to therapy, perhaps cumulative toxicities associated with VFTKI therapies. I think all of this tells us we need to be doing better for our patients. And obviously, there are many, many different studies underway in first sign clear cell kidney cancer, um, using triplet therapies. There's the Merck triplet, which is fully accrued. There's the adaptive pedigree study that We participated, that's also fully accrued. We're waiting on those studies to come out, but also incorporating novel agents, um, incorporating SPRT multimodal therapy. I think as we use more drugs, we're trying to be more creative and understand how to best select patients for the optimal first line therapy in clear cell kidney cancer. And I think that works, um, that transitions really nicely into a discussion of biomarkers, and this was uh a slide from Doctor Vincent Chu's presentation at ASCO last summer where, um, not for lack of benefit, we've looked at a lot of different biomarkers in clear cell kidney cancer. and while they seem to enrich for benefit, when we look retrospectively, when we try to apply them across different data sets, um, none of these have been validated and therefore are not yet available to use in clinical practice. um. Not to be deterred, Doctor Chuu has been working very hard on evaluating Kim one as both a prognostic and a predicted biomarker, and he took this analysis to the Checkmate 214 study, which was again first sign clear cell kidney cancer patients with Ipinivo or senitib, and evaluated circulating Kim1 as a novel biomarker here. Um, we look, they looked not only at Kim1 at baseline, but then also looked at Kim one after 3 weeks of therapy to see how did the level of of Kim one associate with some of our longer term outcomes both on Nivvo plus IPAR and Cyninib. What we found was, um, CIM1 was highly prognostic. So we saw that patients with baseline high levels of CIM1 were associated with a worse overall survival and progression free survival. On the left hand side, our overall survival curve, and patients with CIM1 and on the blue curve, um, a clear separation of low, medium, and, um, highIM one. And then on the right hand side, perhaps a, a more modest uh difference in progression free survival, but certainly Kim one appears to be a promising biomarker of uh a promising prognostic biomarker. And then when we looked at the change in CIM1 from baseline to 3 weeks, we saw that patients who had an increase in CEM1 seemed to have a worse PFS and OS in the IP evo arm. So on the left-hand side again, overall survival on the bottom in purple, those are patients who had an increase in CEM1, those patients did. the worst. Um, but then on the top, in red, patients who had a 30% decrease in CIM1, those patients had a marked improvement in overall survival. And again, on the right hand side, that was capitulated in progression free survival. So, again, suggesting that CIM 1 may be a predictive biomarker of response to, uh, of long-term. response to Ibo. Put another way, this is looking at the um 30% decrease where we see an improvement in response rate PFS and OS on the IPO arm relative to patients who had a CM1 increase where we see saw much lower response rates, much shorter PFS, and much lower overall survival. And so what are some of the takeaways of CIM1 and Checkmate 214? Again, I think it's a really encouraging biomarker, both of prognosis and predictive of response to immunotherapy when we analyze at the baseline and 3 week marks. This data, I think, um, fits nicely inIM1 has been evaluated as a biomarker of minimal residual disease in the adjuvant setting and has benefit from immunotherapy in that setting. And so I think that there's um a lot of interest in biology to be worked out and certainly looking towards prospective studies to validate CIM one as a biomarker for clear cell kidney cancer. Now, moving on to the later disease setting, um, what's next for second line clear cell kidney cancer, and again, this is from our NCCN guidelines where there are currently no Preferred regimens for patients with clear cell kidney cancer, although there's a whole host of options to consider, it almost kind of reminds you of the, um, of the prostate cancer setting where you've got an embarrassment of riches, um, but it really does kind of come down to, um, uh, trying to, trying to select the optimal, the optimal regimen for each individual patient. Um, the keymaker. one study. This was an umbrella study of patients who had had progression of disease on prior PD1 therapy, and then investigated several different agents, um, several different combination regimens in this setting. So there were, in total, 6 arms, um, 3 with targeted therapies, 3 with immune-based therapies. Of the targeted therapies, there was a 1. Vatinib plus Pembro arm, Pembro plus belzutaphan, and a lenvatinib plus belzutaan arm. And then in the immune therapy arms, there was Pembro plus a CTLA4 inhibitor, Pembro plus LAG3 inhibitor, and Pembro plus a ILT inhibitor. And this again was a, um, an umbrella study looking at, uh, primary, um, endpoint of response rate. Again, a majority of patients or uh about a majority of patients were in the heavily pre-treated setting, so about 80-90% of patients with greater than 2 lines of therapy, and about a third of patients across the targeted therapy arms have received prior CTA4 inhibitors. In the immunotherapy arms, again, about a third of patients receiving anti-CTOA based therapy, again, rather heavily retreated. And so this, um, graph puts together not only what was presented, but also what was presented on the podium, but also what was presented in a poster. And what we see. in the immunotherapy arms, and the addition of PD1 plus CTLA actually had a pretty modest response rate of 30%, medium progression free survival of 5.5 months with a pretty favorable grade +34 adverse event profile of 25%. However, When we added a LAG 3 or ILT-4, we saw no responses, very short PFS, and very low toxicity. And so this suggests that we should not be um uh using some of these in some of these novel checkpoint inhibitors or immune targeted therapies after progression on PD1 therapy, they may be better served in earlier disease settings. When we look at the bottom three in the targeted therapy options, we see that lenvatinib plus, Premro or Belzofem plus Pembro, when you look at those response rates, those PFSs, those are rather similar to what you would expect to see from a HIP inhibitor alone or on vaib alone. However, when we look at that combination, we see a bump in response rate of 47%, and improvement in median progression free survival, and perhaps not surprisingly, a higher grade 34 adverse event. Profile, um, I think that really stands out as probably the most promising regimen that was investigated in this umbrella study. So again, what are some takeaways in the targeted therapy arm when whenbatinib plus Pembrose appeared to have the highest response rates, although it did have more toxicity associated with it. Um, I think it the Belzudofan plus lebatinnib arms, um, probably, um, the benefit was more due to the targeted therapy, and then COA actually did show a modest response rate and favorable adverse effect profile. And um we have to put this study in the context of the two large randomized phase 3 studies TEO 2 and contact 03, which showed that continuation of PD1 after prior progression on PD1 um was not associated with benefit relative to TKI monotherapy. Last but certainly not least, um, we'll talk about a novel HI inhibitor called Cataopan from the ARC20 phase one study. Um, we know that, uh, belzudophan is currently approved as a therapy in later lines of clear cell kidney cancer. Um, Catadophan is a novel HIP-2 alpha inhibitor, and on this phase one study was investigated in 3 different dose cohorts looking at primary outcomes of, um, of adverse events and DLTs and then secondary outcomes of response rates. What we know about patients on the study was a majority of patients were heavily pre-treated with both veg FTKI's and Anti PD1 therapies, and what we saw was response rates in the 25 to 33% across all different dose um levels, and we saw low rates of primary progressive disease at 7 to 19% again in a rather, uh, a rather heavily pre-treated patient population. Or cast adopan, I think really makes a difference is it appears rather well tolerated. So lower rates of grade 3 adverse events than we may have expected with things like Balsuopan, rather modest rates of hypoxia less than 10 less than. 10% grade 3 hypoxia and only two patients discontinued therapy due to adverse events. So Catadophin may be differentiating itself as a better tolerated HIP2 inhibitor, although certainly requires further investigation. So, um, this Catadoin is um coming to a center near you, um, where, um, the peak one study will um investigate. Uh, in a 2 to 1 fashion, Catapan plus cabo relative to Cabo alone for patients who have had uh prior anti-PD1 therapy and are hi to alpha naive. Um, without further ado, we will invite Doctor Shuaran as our discussant for our kidney cancer abstracts. Oh, thank you to the force, uh, good job, Mike. Uh, you know, listen to, uh, all of us, uh, to the force. Nothing to add in checkmate uh 9. I yes, I would give it in favor if I have to because you have the PFS, the response rate, the all, the CR, none of these, um, agent improve, um, you know, overall survival in the population. Of patient where, you know, the event gonna be slowed down. Even, even NOIP has a rationale for OS less than 1. 313 was a major disappointed, uh, disappointment uh for myself. I still don't believe the result. I think it is toxicity, but I'm not sure that even if half the patients come off. Um, for toxicity, you should not have OS. I'm not sure of that. I think I perhaps does not combine uh well with TKI and everything else. I'm very disappointed. I don't know if um that biomarker with. Presented them to microphage it's gonna pan out in other studies. So far I don't wanna be overly excited. Besides game one, kudos to, you know, the team, uh, with Vincent and others, um, so far all the biomarker has been, you know, not able to be validated like the. Clusters and others, and they tend to be uh therapy specific more than anything else. I think CIM one currently is the biomarker to test. We're trying to get those samples and those trials for uh uh Vincent from the adjuvant setting, especially the CTDNA is uh quite poor and the sensitivity is low in renal cell cancer. CA uh maker UO3 didn't teach us much, made me worried. That La Bell is not as efficacious as I thought. 47%. Um, I expected a bit more. Um, it was in line a bit what we, what we've seen with what Laurence presented with Lan Bell, but that could be a single agent Cabo with a PFS 10 months on contact 3, etc. So is that why Light spark 0 11 is delayed? I, I don't know. And I think, uh, uh, just going back to our uh to Kim one before discussing R20, uh, 1 of the thing with Kim one that Vincent answered with one of our uh postdoc urologist, uh, scientist, and Clara Steiner here, uh, is if Kim1 get get affected by poor kidney function. As you know, metastatic RCC at least half of the patients have an EGFR less than 60. That's per IMDC uh criteria. And the answer, you look at creatinine, EGFR, etc. it does not. That makes it a way more powerful, um, you know, uh, biomarker. And finally, we need, um, you know, uh, other HIF2 inhibitor here. I don't know if, uh, Catayan gonna be better than Balzuttifan, but uh comparing at least PD as best response, it seems to have a low rate of. on the phase 3 trial, light sparkO05 PD rate is 34%. Now this is phase one, but as you know, we have that study open with CAS, single agent with multiple combination. PD1, their PD1 ZIM, as well as CaO and CAS gonna be part of Pe one, but also a study in the first line will be one of the first, uh first-line studies that are TKI free. Uh, with PD1 CTLA4 plus minus F2. So it's here to stay. Let's see if it plays well with other drugs, and that's it. Excellent. Could couldn't have said it better myself. Thank you for your, uh, succinct discussion points and, and thank you all for joining us this evening, um, to highlight, um, um, ACOGU 25. Um, stay tuned for our next, uh, discussion, which I believe will be after AACR in April, and then obviously we'll be back for, uh, ASCO in, in June. So again, thank you all and, um, have a good evening.
