ASCO GU 2025: Latest updates in mRCC

Dr Bradley McGregor - Dana-Farber Cancer Institute, Boston, USA

Dr Stephanie Berg - Dana-Farber Cancer Institute, Boston, USA

Prof Viktor Grünwald - University Hospital Essen, Essen, Germany

Prof Roberto Iacovelli - Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

BM:     Well, hello, and welcome to this online round table discussion brought to you by ecancer focussing on the latest updates in metastatic renal cell carcinoma, focussing on the updates from the ASCO Genitourinary Cancer Symposium. My name is Brad McGregor, I’m a medical oncologist at Dana-Farber Cancer Institute, I’m joined by a great panel which I’m going to have them introduce right now, quick.

SB:      Good morning, afternoon, evening everyone. My name is Stephanie Berg, I’m also a GU medical oncologist at Dana-Farber.

VG:     My name is Viktor Grünwald, I’m a medical oncologist from the University in Essen, Germany and I’m also a GU expert.

RI:       Hello everybody, I’m Dr Roberto Iacovelli, I’m a medical oncologist in Rome, Italy.

BM:     So, yes, it’s great to be joined here together as we talk about this. We’ve been sort of spoiled in kidney cancer where I feel like every single meeting there’s been this practice-changing phase III trial. There was not that this meeting but there’s a lot of data that can really help inform our decision making and cover some of the nuances as we start thinking about this. So as we take a step back, I want to think of our interpretation of where are we in frontline treatment? We saw some really interesting data on long-term follow-up for cabo/nivo versus sunitinib as well as the OS analysis for cabo/nivo/ipi. So, as you put that all together, where are we now in the treatment of renal cell carcinoma? How did the recent data change your thoughts?

VG:     Maybe I’ll start. What we have seen even with the longer follow-up data from the different trials, the results seem to be quite steady, so they’re durable. Although numbers change, that’s something we have to admit, that with a longer duration of follow-up for TKI/IO combinations we do see different numbers in terms of the hazard ratios. But overall it’s durable and it’s very consistent. So robust data for the use of TKI/IO combinations.

RI:       Yes, probably I have the same vision. Also this data with 67 months of median follow-up confirms again the activity of the combination of cabo plus nivo. Finally, if we look at the hazard ratio, this was 0.79, this is exactly the hazard ratio reported by len/pem and this is probably very interesting when we have to choose between different combinations of tyrosine kinase inhibitors plus immunotherapy for the front-line treatment of mRCC.

SB:      I agree. I think it’s nice to see that there’s more follow-up and long-term follow-up for all the combinations. But I feel like it’s really going to come down to a provider preference of all this. We all have our own choice that we like to see, I don’t know how much difference Dr Iacovelli noted between the regimens, and they’re never going to be compared to one another and how we’re really going to… I don’t know if it’s going to change practice but I think it’s going to reconfirm a lot of what we do already.

RI:       I agree, this is great for us, this is great for patients because we have different options with a different safety profile and this may help us to decide based on the patient profile, what will be, and based on the presentation of disease, the tumour burden and IMDC prognostic category what will be probably the most OK treatment for patients we have to treat.

BM:     Yes, I would agree. I think we would all agree that IO/TKIs we have now extended follow-up but all of them all have benefit, most early on but that OS benefit maintains long-term. One of the things we were always hoping is with IO/IO we get this tail of the curve but this progresses best response around 20% is the way we can start mitigating that. So that was the basis behind the 313 trial which looked at adding cabozantinib to nivo/ipi, trying to give the best of both worlds, if you will. I don’t know, Dr Berg, if you want to comment about what we saw with extended follow-up from that trial?

SB:      Yes, I think it’s an ongoing story right from ESMO as well. It solidified that we’re not going to be using this triplet in the frontline, that’s something where all of us reading it and looking at the presentation. I really wanted to point out that the triplet got lower doses of cabo, they didn’t get as much ipi and it’s really tricky to know if this is going to be… what’s going to happen in the 011 with triplet. So I think it’s something we are going to be cautious about. Moving forward, I do have to commend the ELISA study for using a comparator arm like ipi/nivo, so I think it really reconfirmed my use of ipi/nivo in the frontline for that tail of the curve, like you said Dr McGregor. But it was nice to see all this data and really the biomarker data, I’m sure the others can talk about that. I found that really interesting with RNASeq and M2 macrophages, that was great to see that and live, along with the other data.

BM:     Yes, one of my concerns with the regimen is just the toxicity profile. I’m not saying triplets maybe are gone, I think that triplet is just quite toxic. We had a similar experience with different histologies and just the hepatic toxicity is quite, quite remarkable, as we think about that. So I do tend to agree with you that with no OS benefit in the extended follow-up and paradoxically the poorest patients actually did even worse with the triplet than with nivo/ipi, it really takes that regimen off the table for me as I think about options.

VG:     I think you’re absolutely right. What we have seen in the past five years or so is treatment intensification, moving from single to doublets but going beyond that, going for triplets, I think it makes it much harder. So there is more toxicity, how to get it right in terms of the balance between the outcome data and also the tolerability. That’s a great effort and with the other agents more suitable for that approach we will see, we’re curious, so stay tuned. Maybe next year or at the end of this year maybe we’ll know more, I don’t know. But I think that’s the way forward, to push for more intense therapies but that’s certainly not an all-comer approach, that’s something that we have learned from COSMIC.

RI:       Again, there is another strategy is a [Notch]-directed triple therapy, as investigated in the COSMIC and the LITESPARK trial. But I think the possibility to consider three drugs in a sequential way, as investigated in the PDIGREE trial, then for a patient who would not achieve a complete response or doesn’t have a progressive disease during the combination of ipi/nivo will be randomised in this trial to intensify treatment with cabo in addition to nivo or to continue with nivo alone. I think this could be probably a more safe way to combine ipi/nivo with cabozantinib. It’s just a different way by a sequential strategy more than a combination.

BM:     I agree. I think the PDIGREE trial, it will be very interesting to see how that plays out. But that trial, ultimately, patients are still getting four cycles of nivo/ipi before they make that decision point. There was some thought-provoking data on can we find out who those patients are who are going to progress even earlier than waiting for that first imaging, looking at dynamic changes in KIM-1. I found that data pretty compelling when they looked at the 214 analysis. I don’t know, anyone else have the same thoughts?

SB:      When looking at that type of serum marker that we’ve been all learning about, really, even since ASCO last year with Dr Albiges and Dr [Shiu] just really presenting this in the data. I agree it was really compelling. I mean, after one cycle of ipi/nivo to see those significant changes in this potential biomarker is thought provoking. I don’t know what we’re going to do with it yet but it’s something that we haven’t seen a lot in kidney cancer, to do a test. We don’t have ctDNA like urothelial cancer. So I thought that was a very, very interesting and thought-provoking presentation. More to come, right?

BM:     Yes, absolutely. It’s unique because it’s not just looking at… there’s not an absolute cut-off, it’s a dynamic change based on before therapy to on therapy. More timepoints, more to come, but it is sort of the future as we think about how we’re going to think about choosing the right therapy and that balance between IO/IO versus IO/TKI, how can we look beyond what we have right now to figure that out. As we think about it further, as we go through the frontline setting, we have a lot of different factors that come into play. But one of the things I always find challenging is the treatment of brain metastases. Patients present with brain metastases or develop them later on, most of these patients are excluded from the clinical trials. If we had some nice retrospective data on cabozantinib… There was phase II prospective data where we had patients, a small number, with untreated brain metastases treated with cabozantinib and close to 50% objective response rate and they seemed to be quite durable. Notably, there wasn’t that concern for bleeding or all those things that we always worry about potentially with untreated brain mets and VEGF TKIs. It builds upon the retrospective data that we’ve seen already with cabozantinib.

RI:       These data are not surprising, considering the previous retrospective experience. To be honest, also in my clinical practice when we have to treat these patients with brain metastases probably a combination based on cabozantinib – cabo/nivo, cabo [alone] – reported a good control of disease. I think these data are in line with previous retrospective experiences. Of course, we don’t know if cabo/nivo is better than len/pem for these patients, we cannot say that, but I think it’s sufficient for us from a clinical point of view to have a good option to offer for these patients. If we are increasing data for cabo/nivo, this is good for clinical practice.

VG:     I totally agree. I found it always useful to know numbers in clinical practice. So this is a benchmark study that gives you a threshold of what you can accomplish with cabozantinib in that specific scenario. It’s great for planning whether you need to have now local therapy, can you wait, can you start off with the medication first? These are questions that we have in the real world or in real practice and it just adds substance, it adds data towards this discussion. It’s really helpful.

BM:     To that point, I think this idea that when we don’t have clinical trials, so we don’t have clinical trials that prospectively looked at one TKI versus another for brain mets, for instance. But we don’t have trials versus IO/IO or versus IO/TKI. I think that real-world analysis can be quite helpful. There are actually some pretty interesting real-world data presented at the meeting just looking at an IO/IO versus IO/TKI specifically in those patients with poor-risk disease from Italy. What they showed overall was that really even the poor-risk disease they still developed a benefit from nivo/ipi although, as to be expected, objective response rates were lower with nivo/ipi versus the IO/TKIs although the actual median survival was slightly higher. I don’t know exactly how to use that data in the clinic but data like that is probably going to be the best we’re going to get as we start thinking about how do we do A versus B and this real-world analysis. How do others view data like this in the decision-making process?

RI:       I think this is probably interesting data because this is the question we have every day in our clinic to decide between a different type of combination, especially the main decision is about the double immunotherapy or combination immunotherapy plus a TKI. Specifically this work about colleagues from Italy that looks at patients with a poor prognosis, this is really frail patients but also really heterogeneous in clinically how they present. Some are symptomatic, some others are only humoural alteration. And then there is no just one way to treat these patients but we have to look at what is the priority. If it’s the control of symptoms probably IO/TKI will give us better results in the short time. And when we have asymptomatic patients we can look at double immunotherapy. But, of course, when we choose, especially when we look at retrospective data, we have to consider how we think about these patients and probably this may influence the choice. And finally the overall survival that was reported in retrospective data, I don’t know what you think about this?

VG:     Yes, I think it’s very difficult from real-world data. It’s great when you can fill up a gap, so things that are not being covered from clinical studies that are prospectively done, say phase III studies. But when it comes to really comparison, one regimen versus the other, I found it quite difficult, to be honest. So we presented also on real-world data from Germany, from a retrospective analysis of a couple of hundred patients with different combinations. Although we do see that in terms of efficacy we do have differences, when it comes to overall survival there are a lot of unknown confounders that are really playing a role here actually. Because we tend to break it down to what’s the intervention, which is some sort of medication that we use in specific combination, whatever it is, but in real world practice there are also comorbidities and there are many things to adjust for. It’s informative, definitely, but it’s not always that straightforward and conclusive.

SB:      Yes, I agree, I think real world is important for our community which is international to see how these drugs are doing in different populations, different people. And also side effect and safety profiles which I find really important – if there’s anything new that comes out or if there is anything we can delineate from certain subtypes if it wasn’t in a prospective, like we were talking about with different sites of metastasis. Or just how we generally know if they have a higher disease burden we want to control it more and, again, it just solidifies what we’ve been already doing based off clinical trials. So it’s great to see that this gap is getting filled with clinical trial to practice. I always enjoy seeing these every year.

BM:     Yes, 100%. As you think about the real-world data, it’s very much thought provoking and maybe just helps you put things into context. But it’s always tough to make a definitive decision based on that data. So I think we are right now at the end of this meeting where we’re sort of in a very similar spot to where we were before the meeting in that we know that IO/IO, IO/TKIs are both options with extended follow-up showing a benefit. COSMIC-313 gave us some nice long-term data for nivo/ipi actually with contemporary dosing which is noteworthy. But, unfortunately, as we move into the future we know that even with nivo/ipi and any IO/TKI a lot of patients will progress and we need to think about how we can treat those patients. So that’s where novel combinations are really coming up and novel drugs. Maybe not so novel anymore is the HIF-2 inhibitor, so that is certainly going to be coming earlier to a clinic near you with a lot of different data. We had a lot of data for belzutifan in combination, as well as some updated data for casdatifan, a novel oral HIF-2 inhibitor. So as we look to the future, how do you see this data affecting care going forward?

SB:      Brad, you were just saying about the KEYMAKER studies, it was great to see that we can use belzutifan perhaps earlier up front with combinations with lenvatinib, that was extremely compelling. What wasn’t compelling was the IO arm, that was a poster that B1, B2 and B3 and everyone else can comment about but line 3 had no responses, and I think the other one was a Merck, ILT4 had no responses post treatment. I feel like these LAG3 stories were something we want to work in kidney cancer and I’m a little hesitant now, even thought these are small numbers of patients, there are like only 20-30 patients. But I think the belzutifan/lenvatinib was quite compelling for that second-line therapy showing really nice response rates. Then if you use pembro/len up front, it’s going to be confusing but that’s OK, we don’t mind to be confused.

VG:     Yes, I think it’s important to do these studies and to understand resistance mechanisms and how to seek more efficacious combinations. I think it’s worthwhile to explore. Yes, it’s a small subset of patients that has been explored now, there is a signal, is it worthwhile to succeed? Yes, it is. I’m really curious to see how the larger randomised phase III study will turn out to be, whether it will be sufficient to overcome cabozantinib which is a common second-line drug. So I’m really curious to see – is it enough in terms of efficacy? Probably. Is it enough in terms of overall survival? Don’t know. So stay tuned, I would say.

RI:       Yes, I perfectly agree. This study, the KEYMAKER, probably tried to answer three questions previous studies tried to investigate – if immunotherapy has a role after progression to immunotherapy, if belzutifan has a role, especially in combination with immunotherapy or tyrosine kinase inhibitors. But what is the main message is that TKIs continue to work after progression to a previous TKI. This probably is very useful for our clinical practice but what we really need is to find the perfect TKI for second-line treatment in patients progressing to IO-based combinations.

BM:     Yes, I 100% agree.  Those numbers are small so we’re very excited about the lenvatinib/belzutifan data and the ongoing trial looking at lenvatinib/belzutifan versus cabozantinib. I would definitely take a step back when you look at that len/pembro data, that’s post IO, I would not use that to justify lenvatinib/pembrolizumab as a second-line combination after progression to immunotherapy, just because now we have two randomised trials showing that TKIs cannot rescue IO. So I think it shows the inherent issues with… These phase I datasets are certainly very exciting and they sure lay the foundation for phase III trials as we go to the future.

VG:     Yes, the len/pem data, that specific arm in the KEYMAKER study has been there only for reference. So in order to get a benchmark and see what’s the contribution of the different components in this setting. I totally agree, it’s not a common second- or third-line agent and we have learnt that subsequent exposure to IOs across different lines of therapies may not be a good choice, it’s nothing we recommend in the clinical guidelines actually. Something we looked at as well is the CLEAR study that is also transitioning from the first line into second line. We just wondered, because the exposure of len/pem in the first-line setting is about two years, so 22 months in total, and then overall survival is more than 50 months, so how does first line contribute to this overall survival benefit? Something we looked into is in patients that progressed and what we have seen is that patients that have a lower tumour burden seem to have a better outcome. And patients progressing on len/pem had about half of the tumour burden as compared to the baseline assessment, meaning that they are in a lower tumour burden state when they progress compared to when they started first-line therapy. So it’s just an observation but it’s interesting because it really translates or links the first-line towards the overall survival benefit that you may gain from combinations.

SB:      I agree and I think when you look at that first CLEAR data with that overall response rate of 70%, the less cancer you have the better you do and that just really makes this regimen for using in the first line one of my choices because in this really bad poster it really helped. I loved that poster a lot too.  I guess one of my other comments was with the len/belzutifan data what’s going to happen with len/everolimus and that was part of the CLEAR study as well. Dr Grünwald, you were part of the CLEAR study, I feel like with the new trials coming through, I don’t know where that’s going to land anymore. It’s always been an option for a lot of us, so with these belzutifan combinations it will be interesting if that’s even going to be a combination that we have anymore in the future versus a monotherapy. So that was something I was thinking about as well.

VG:     Yes, we’re now exploring novel combinations in second line. Is there room for improvement? Definitely there is. Let's see how it turns out to be. If len/bel, let's say, is less promising than initially thought then it maybe does not change our sequence. But if that’s very efficacious, I don’t know, maybe you have to rethink what you use in first line. But, for now, what I do is I use the best choice I have in each line. So in first line whatever is appropriate for the patient, that’s what I give and I don’t plan on sequencing because you never know. It’s like a bet because you think you make it to second line but some don’t. Some of those patients are a surprise for everybody that they don’t make it to second line but it’s clinical reality, it happens.

RI:       That’s the point because if we look at the COSMIC-313 or CheckMate-9ER, only 50% of patients received a subsequent line. We all agree that we have to choose the best for first line treatment and we consider what we have for second line for patients eligible to receive subsequent lines of therapy.

BM:     100%. Looking at those novel combinations, we had the len/bel versus cabo, there’s a new trial that they talked about looking at casdatifan with cabo versus cabo, trying to look at the role of HIF-2 and HIF-2 is obviously moving, this trial is looking at earlier in combination with dual checkpoint blockade or lenvatinib and pembrolizumab. So as we wrap this up, as we look to maybe GU ASCO next year, what trials are being done right now that you think really have the foundation to be the next big thing that changes the way we think about kidney cancer?

VG:     I don’t know who wants to start. I think triplets are something really worthwhile to explore, whether it’s sufficient in the overall population I don’t know. I’m happy to see advancement and if the price is more toxicity and it’s still tolerable I’m OK with that. But that’s our current direction that we head to.

RI:       I really hope we will be about to really understand if HIF inhibitors play an additive role to impart to VEGFR or if they’re simply heading the same way and the same pathway. This probably is an answer we will have next year with the LITESPARK results. And also casdatifan plus cabo may help in the definition of this activity of HIF inhibitors plus VEGFR.

SB:      I agree, I think that the Merck triplet trial is going to be really important to see when it comes out. Then right as second line for a new HIF inhibitor, casdatifan, that was interesting and there are trials coming out there. So it’s great that we have all of these options coming up and hopefully more data in ASCO or next year.

BM:     Yes, I absolutely agree. There are just so many trials in development and then we haven’t even talked about the development that we have in the perioperative space to try to prevent this discussion from ever being needed. So it’s really exciting where we are, moving forward in kidney cancer. Just the developments we’ve had in the past decade has transformed how we think about this disease. I want to thank everyone very much for listening and to the panel for this great discussion and we look forward to joining you again soon on a future round table.