MS:     Hello, and welcome to our discussion of updates in kidney cancer brought to you by ecancer. My name is Dr Michael Serzan, I’m a medical oncologist at the Dana-Farber Cancer Institute and I’m joined by a panel of my esteemed colleagues from around the globe to bring you the latest updates in kidney cancer and how it may influence our practice. If each of them introduce themselves and then we’ll go to our discussion.

JP:       Thank you. I’m Dr Javier Puente, I’m a medical oncologist. I’m currently the Head of the GU Cancer Unit at the Medical Oncology Department of Hospital Clínico in Madrid, Spain.

GdV:  Hello everyone, I’m Guillermo de Velasco. I’m also a GU medical oncologist based in Madrid at University Hospital 12 de Octubre.

AR:      Hello everyone, I am Alessandro Rametta, also a medical oncologist with a specialisation in GU cancers in Milan National Cancer Institute.

MS:     Fantastic. So we’ll start with the adjuvant setting. We obviously have a lot of data supporting the use of pembrolizumab in the adjuvant setting. We saw an update on that data with over five years of follow-up on the KEYNOTE-564 study. What did you find most insightful in that discussion and how are you going to take that back to the clinic on Monday?

AR:      Yesterday we were presented data about the KEYNOTE-564 that is the first study in the adjuvant setting in renal cell carcinoma that demonstrated an advantage in overall survival. The data presented yesterday with a follow-up of more than five years, I think 69 months, confirmed this advantage in overall survival. It was very important and in our clinical practice we have to use the pembrolizumab, to propose the pembrolizumab to our patients with a high risk of relapse.

MS:     So it’s certainly reassuring to see that disease free, that overall survival benefit maintained over five years of follow-up.

AR:      Yes, yes. All risk classes, among intermediate, high risk and M1 with no evidence of disease. So it’s very important to propose this.

GdV:  I think it’s specifically important to see, as you were saying, that it’s maintained, the benefit. We’ve seen that in the metastatic setting not always we can see how it’s maintained, the hazard ratio with longer follow-ups. So it’s extremely important to see that after five years we can still see that benefit in overall survival.

JP:       In addition, I think another important point is that with this long follow-up we don’t observe any additional toxicities. This is something important when we are talking about adjuvant treatments in patients that potentially cure only one surgery. So with this long follow-up, more than five years, as I mentioned before, no additional toxicity has been observed and this is something that is going to be important for daily clinical practice.

MS:     Yes, I really like that part because when you discuss this with patients you talk about some patients may be cured with no additional therapy. So what is the risk reduction and then also what are some of the potentially life-changing toxicities that they may encounter as a result of pembrolizumab? Moving on to the metastatic setting, I was really excited to see the CheckMate-214 study presented. This was our largest phase III clinical trial with now over nine years of follow-up. Could you walk us through CheckMate-214, the design and then what you took out of the presentation and how you’re going to bring that back to the clinic next week?

JP:       The combination of nivolumab plus ipilimumab is one of the standards of care in the treatment of kidney cancer. The CheckMate-214 trial is a phase III randomised open-label study comparing nivolumab plus ipilimumab versus sunitinib with a primary endpoint to demonstrate an advantage in terms of response rate, PFS and overall survival in the intermediate and poor-risk group. In this long follow-up, presented by Dr Motzer, we consistently see a very active regimen in terms of response rate. We have at least 12 complete responses with this combination at 9 years; we have also an impact in terms of overall survival with a median overall survival around 45 months, that’s impressive. And the duration of response is something impressive because the median duration of response for all these intermediate and poor risk groups is around 80 months. I think that is impressive. But something interesting in this analysis is potentially the activity of this regimen in the favourable risk group. This is something that is under debate and the most important guidelines have added this regimen in the favourable risk group. We have observed in the nine years of follow-up a trend in the positive in overall survival in this subgroup. So again we have something to debate between the medical oncologists about what is the preferred regimen in this group of patients. So I think that is very impressive data but again something to debate between the oncologists.

MS:     I think it’s a fantastic point, that favourable risk group, that when the data was initially presented in The New England Journal of Medicine 2018 the OS hazard ratio was 1.45 favouring sunitinib. Now with over eight years of follow-up we saw that hazard ratio is now 0.80 favouring immunotherapy. I completely agree, I think it’s very wise of our guidelines to now have that as an option and it’s something that I talk about with my patients as the regimen that gives us the best chance at a long-term durable remission. So I think it’s a fantastic point.

We also saw some data on a new combination in front-line and metastatic clear cell kidney cancer using zanzalitinib in the STELLAR trial. Could we talk a little bit more about that triplet therapy, what maybe the rationale was and then was it tolerated. Triplet therapy in COSMIC-313 we saw had a lot of toxicity to it, what did you see in STELLAR and do you think that’s a promising regimen we should be pursuing?

GdV:  I guess we are eager to see something new in kidney cancer. So I think sometimes when you are thinking about the rationale we are trying to find whatever is a signal we’re trying to put together to see whether we can use it and improve the outcomes of metastatic RCC. That’s something for sure. So now seeing the combination, what I think is clear is that the combination of tyrosine kinase inhibitor, even it’s a new tyrosine kinase inhibitor, plus PD-1 is still a really good combination. It’s solid, I don’t think it’s that different, as we’ve seen with other combinations. So I don’t think it’s giving something else. Especially when you are seeing the response rate with that triple therapy it’s not that exciting. So I think we were trying to put something else, LAG-3, how relevant is that? We’ve seen that in melanoma. Sometimes we try to compare melanoma and kidney but at the end of the day they are totally different solid tumours. So, yes, there is a rationale to use the different immune checkpoints. LAG-3 I don’t think we are really targeting the right point here with anti-LAG-3. In terms of toxicity it’s different; we’ve seen that as well in melanoma. When you are combining anti-LAG-3 usually the tolerance is much better as compared with CTLA-4. But I don’t think now we are at the point about deciding the safety profile, I think triplet combinations may be feasible, which is pretty good, but I don’t think that triplet combinations will have a really good future. That’s my perception.

MS:     Yes, I completely agree. I thought it was really interesting that the presenter did make the point that this was a phase I study so it was not meant to compare zanzalitinib plus nivolumab versus zanzalitinib/nivolumab/relatlimab in terms of response rate. Those response rates are pretty similar at 60%. The toxicity, I agree, was consistent with some of the IO/TKI combinations that we already have available to our patients. Certainly we’ll see where the triplet space ends up going for first-line metastatic kidney cancer.

JP:       Potentially I think that this kind of drug, zanzalimab and [??] I think that it’s going to be a very interesting drug in terms of toxicity compared with the classic cabozantinib. I think that obviously these lower half-lives could be helpful for the management in daily clinical practice. Sometimes we have difficulties to attribute was this toxicity due to the immunotherapy or the TKI and sometimes it is relevant for the medical oncologist to try to attribute these treatments and resolve the toxicity as soon as possible. So I think that it’s going to be interesting for that.

GdV:  Yes, but what I was thinking is the bar is really high.

JP:       Absolutely, yes.

GdV:  And how about the triplets, that’s what I was thinking. Even if it’s a small number of patients I’d like to see a really good signal there. It’s going to be really difficult to beat something such as lenvatinib/pembrolizumab or IO/tyrosine kinase inhibitor in terms of response or even ipilimumab/nivolumab in terms of OS with the data just presented. So unless you see really, really those kind of phase Ib – quite orientated to the specific pathology – unless you see something very clear, I don’t think that’s going to trigger a big investment in a big phase III randomised trial.

MS:     I like both your points. To your point, I did see that the rate of primary progressive disease with the triplet was actually quite low, less than 10%. I think that’s on a par with a lot of our current IO/TKI regimens. I think your point about the short half-life is super-important and really practical for the practising oncologists. How do we tease out LFT abnormalities, colitis if maybe we stop the zanzalitinib and it gets better sooner and can we withhold giving high dose steroids or other types of immunosuppressive therapies.

JP:       That’s a good example.

MS:     So a super-important point. Another space that’s just exploding within kidney cancer is the HIF-2α story. We saw data from the LITESPARK-004 study, this was the study that originally got belzutifan approved for patients with VHL-associated kidney cancers. Can you walk through a little bit about what you saw from that 4-year follow-up and what you think about not only the response but also the tolerability of that regimen over time?

AR:      The strategy to target the HIF-2α now in renal cancer is very important. I think belzutifan is the first drug that was approved but also now we saw data from casdatifan that is another one. I think it’s important to have more than one drug targeting the same target to compare them and to understand in which setting we can use them. For the VHL syndrome I think the data were very interesting this morning. The follow-up was more than four or five years and I don’t remember, it was very long. People with RCC localised, non-metastatic, receiving belzutifan could achieve an objective rate of 70%, that’s very high. This is important to delay or to avoid the need for surgery for these patients, that is very important. The rate of response was very high also for the other tumours with VHL syndrome like hemangiomas and 90% of response in the PNET. So a very interesting study, very important for the patients.

MS:     I think your point on the slide that they showed about the number of surgeries for patients with VHL syndrome before they went on belzutifan and after and you see it almost just fall off completely. Which is super-important – we know these patients have hemangioblastomas, they have pancreatic neuroendocrine tumours, and we see high response rates and they’re durable over time which is really a fantastic thing to see. So high complete response rates, I think it’s really a drug that has changed how we manage that disease. I like how you also brought up the idea of casdatifan which is a novel HIF-2α inhibitor which is now being combined with cabozantinib. Can we talk a little bit about what you saw from that combination and what you think about not only the efficacy but the tolerability of it?

JP:       I think that is another new HIF inhibitor with very interactive and very interesting activity in combination with cabozantinib in the phase I study that has been presented today. Obviously this new generation of drugs has been tested in a population that has been previously treated with an anti-PD-1 or PD-L1 and in this combination we have shown activity of around 40% response rate with similar toxicity that has been observed previously in another anti-HIF with anaemia, diarrhoea, etc. So these new drugs are another good news for these scenarios. I think that activity is encouraged with this phase II study and a phase III study has been opened right now, the PEAK-1 study, in patients that have been previously treated with an anti-PD-1 or PD-L1 inhibitor, randomised to this casdatifan plus cabozantinib versus cabozantinib. Remember that the phase I study of this HIF-2α inhibitor has demonstrated that the drug is still rated with a maximum dose of 100mg daily and could be combined with 60mg of cabozantinib. So it’s impressive because obviously the two drugs are given at the maximum dose without any problems in this phase I study. So we will see in the phase III study.

MS:     Yes, I think it’s a super-important point that cabozantinib 60mg, that’s a tough dose to tolerate as a monotherapy. We know cabozantinib/nivolumab, that combination actually the approved dose is 40mg in combination with nivolumab. So I think super-important. I was also very impressed by the low rates of discontinuation and I think that’s probably because the side effect profiles are so different, we can tease out the differences, dose reduce and get patients back on therapy to maintain that response.  The holy grail for kidney cancer has been trying to look for CAR T-cell therapies. I thought there was a really interesting abstract, a phase I study, the TRAVERSE study, with a CAR T, ALLO-316, targeting CD70. Can you talk a little bit about what you saw in that presentation? Is CAR T coming for kidney cancer? What are your thoughts there?

GdV:    CAR T-cells are all something tough. When you think about CAR T-cells you know that the main issue about that is toxicity. I’m always thinking that we were saying before how is the profile of toxicity with triplets? Can we get a triplet in the first line? You can get it, I think it depends on how is the benefit. So how big is the benefit of the treatment that will lead you to basically for any single toxicity? We are doing that in melanoma with TILs. If you’re doing TILs it’s crazy because patients will go to the intensive care unit for a month but it’s OK because you are curing, or you think that you may cure, those patients. So I think CAR T-cells it’s very solid in some tumours already, in [??]. I think having a target is pretty important. I think this is not going to be the first CAR T-cell in kidney cancer and I think it probably is not going to be… I don’t know if this specific CAR T-cell will be the future but I think we’ll be working with CAR T-cells. We know that there’s a lot of toxicity around, that’s something that we need to acknowledge, but it will not be a treatment for everyone. But we have a lot of experience, so we’ve used IL-2 in the past. I’ve not but some of us probably we used that IL-2 and we know that sometimes if the outcome at the end of the day is to double response but we need to think that we have ipilimumab/nivolumab. We were saying today that we have such long, durable responses for some patients that we need to obviously have a very good treatment but also we need to try to select which patients really need that treatment.

JP:       I am impressed by the results that were presented today because obviously it’s a very heavily pre-treated population. The median lines of therapy is 4. Obviously in general when you look at the data with the higher expression of CD70, the response rate is around 40%. Something that is very impressive. I don’t know how much is the duration of the response and what will be the PFS, we will need more follow-up. But something interesting. Obviously toxicity could be an issue, you have to make a lymphodepletion with fludarabine with cyclophosphamide so this is highly toxic. But after that we will see, we will see. I think that I am very impressed about that.

GdV:  Yes, so the data is encouraging, definitely, but I think we need to be cautious because in this kind of study usually you are selecting those patients with a median of more than 4 lines of therapy. Usually it’s bad but somehow it’s good. You have a bias because you are selecting those patients that may get to the fourth line. Not everyone can get that. And also I’m sure those patients were the best patients because they were able to go into CAR T-cell therapy. So that’s why I think it’s promising, I think we need to wait a little bit at this time, but I think it’s exciting. I will say that we are eager to find something else. We have very good drugs – IO, double immune checkpoint blockade, we have IO/tyrosine kinase inhibitor – very good combinations and we don’t talk about cure, even we are talking about nine years follow-up, but we are seeing amazing results for some patients. So I think for the other patients we need definitely new drugs and I think that’s the way.

MS:     You both bring up excellent points. Obviously we’re borrowing and we’re learning from other disease types where this is a standard of care. Melanoma, we’re learning about how to manage immune toxicities and cytokine release syndrome and to do that more effectively. I think your point about the target is super-impressive. I thought that was the most important datapoint we saw – patients who had the target CD70 had relatively high response rates, those who did not express CD70 had no responses. So I think clearly having a target that our CAR T can go after is super-important.

The second holy grail that I wanted to talk about is biomarkers and I was really intrigued to see all of the data coming out on different biomarkers – KIM-1, RNA expression profile, circulating biomarkers. What did you think were highlights from that session and where do you think we are in terms of trying to bring biomarkers to the kidney cancer field?

AR:      I think this session was really impressive, the session, but probably we didn’t find any biomarkers that could be used in the next five years, or something like that. But I liked a lot the presentation about the gut microbiome, the MAdCAM-1 protein that is a soluble factor in the blood that is like a surrogate of the gut dysbiosis. That’s very interesting, I saw something like that in ESMO with a presentation of the transplantation of gut microbiota. It’s a field that we should explore for renal cell carcinoma. The results that were presented yesterday showed that high levels of this protein in the blood was associated with a better prognosis. This data was used to see if with an IMDC score we can advance and have more precise prognostic IMDC, adding this MAdCAM-1. I think it’s very interesting as a biomarker, it’s too early but it’s interesting.

MS:     It’s certainly a field that’s exploding. I think Dr Renée Saliby, an internal medicine resident at Yale, presented this work on MAdCAM-1. I think it really nicely pairs all of the stool transplant studies that are being done, CBM588 which we obviously have some phase I data on in kidney cancer, I think it marries that really well together but certainly a lot more work to do to better understand how we could use that as a prognostic and potentially a predictive biomarker for therapies that modulate the gut microbiome.

AR:      Yes, exactly.

MS:     What stood out to you from the biomarker session?

GdV: So I guess I have three highlights for biomarkers. First of all, I think KIM-1 is a reality. I think we have seen not one but three different trials on the value of KIM-1 as prognostic and I think it’s really relevant, especially for the adjuvant setting where we are over-treating patients. We need to have something to select better patients and that’s why I think that’s a very good one and I think it’s feasible because it’s not that complicated. The second one is Dr Braun’s talk is going to be really important to integrate different biomarkers. So we are trying to focus in this protein RNA signatures, I think we need to put it all together to really select better treatments for patients. And the third highlight, I saw the presentation from David McDermott and it was awesome. So anyone who wants to know about an update in biomarkers should watch the talk from David McDermott, congratulations David.

MS:     So, as you said, KIM-1 both prognostic but also potentially predictive of immunotherapy benefit. I completely agree with your point on Dr Braun’s, this needs to be integrated. It can’t just be tissue and serum, it’s got to be all of those factors together to increase our power, I couldn’t agree more. I think Dr McDermott’s presentation was particularly important because it’s frustrating doing biomarker work, we learn a lot but then our drugs change and our technologies change. But I saw it as a call to action that we need to continue to do this work because it does advance our field, it does lead to new targets which we desperately need in kidney cancer.

JP:       I think that we have a lot of information about potential biomarkers but from the prognostic point of view. I fully agree with the vision of to be integrated, all this information, from the proteomic, from the genomic, from the [??], from all points of view. I think that the technology will help us in the future, I think that artificial intelligence could help us to integrate all these models and try to make an answer about these questions.

MS:     This is certainly a huge theme at ASCO this year – AI and how we can integrate that into our practice and our research is super-important. With that I’d like to thank each of my esteemed colleagues for joining us in this panel and sharing their expertise and I’d like to thank you all for your attention in updates in kidney cancer from ASCO 2025.