JP: Hello, welcome. Thank you for joining us in this online expert panel discussion as a part of the ecancer educational programme entitled Latest in Metastatic Renal Cell Carcinoma. As you know, the treatment of metastatic cancer patients has dramatically changed in this disease for the last ten years as many drugs and combinations have been approved for different strategies, even in Europe and all over the world. I’m Javier Puente, I’m a medical oncologist at Hospital Clinico San Carlos in Madrid in Spain and it’s my pleasure to participate in this online debate focussing on the management of patients with kidney cancer held just after the ESMO 2022 in the city of Paris when important therapeutic approaches have been taking place. So in this debate we have three outstanding medical oncologists with a great expertise in the field of metastatic renal cell carcinoma. Let me introduce all of them before we initiate the discussion. First, Professor Bernard Escudier, thank you for staying with us, from the Gustave Roussy Hospital. Congratulations for your recent award.

BE: Thank you.

JP: Dr Viktor Grünwald from Essen in Germany, thank you for joining us.

VG: My pleasure.

JP: And finally Stéphane Oudard for the hospital here in Paris, the Georges Pompidou in Paris in France, thank you for joining us.

SO: Thank you.

JP: So the key objective of this debate is trying to review the most important data that has been presented during this ESMO in metastatic renal cell carcinoma, in the first line treatment – how do you consider this data in your daily clinical practice in the future and how it could affect subsequent lines of therapy. So we have selected four abstracts, enough time to discuss the awaited study of the COSMIC-313 trial, the updated analysis of the CLEAR study, the PIVOT-09 trial and the combination of a new anti-HIF inhibitor plus cabozantinib. So let’s start with the COSMIC-313 trial, please Bernard, could you give us a brief summary of this trial before the discussion?

BE: Yes, of course. COSMIC is a rationale trial because we started with nivolumab ipilimumab as the backbone for this trial and we tried to add cabozantinib in a randomised trial where nivolumab ipilimumab was added to cabozantinib or to placebo. So the question needs to be answered and the goal, for me, of this trial is to improve overall survival and complete remission. That’s what we should try to get. The primary endpoint for the study was PFS and we know that it reached a PFS endpoint. That’s good because if it was not the case that would be a very dismal to add cabozantinib, so it makes sense that it’s going to increase PFS. So the question will be, when we see the data fully, is it able to improve complete remission and cure and is it able to improve overall survival. I know that at that point it is probably not the case. So that’s going to be a big problem because we are going to give a triplet which is much more toxic, and we see the data, and the improvement is probably not as good as expected.

JP: So what is your expectation with the trial? Are you looking for a prolonged PFS or more overall survival compared with the classic nivolumab ipilimumab scheme?

VG: I would say prolonged PFS is a given. If you add a third component, and TKIs are very strong on PFS, it needs to deliver on PFS. It has been released, it met its primary endpoint so that already happened. So my question would not be so much on progression free survival, because I really would like to see mature overall survival. I think it’s more important in that specific study.

JP: Just because when you are using the nivolumab ipilimumab combination obviously you have great results in terms of the tail of the curve in PFS and the overall survival benefit. But you are looking for something more where you are using a triple – maybe increase the response rate, maybe more complete response, maybe prolonged PFS. How do you see this data, Stéphane?

SO: Yes, if you look at the comparator arm with the placebo you know the median PFS is around 12 months which is in agreement with the CheckMate 214 study. So the comparator is strong. Now we need to know if we can prolong the PFS, also complete response as Bernard said, because if you don’t have a complete response leading to a plateau then it’s  not useful to use this triplet because what are you going to give later on in the case of progression?

JP: This trial has the strong rationale of adding the anti-VEGFR to the combination of IO/IO but also we have the rationale to include ipilimumab to the classic combination of the cabozantinib nivolumab. So what is the role of the ipilimumab for this combination? Is this a good drug for combining with the winner of the CheckMate 9ER trial?

BE: Probably we all agree that ipilimumab is the most important component to induce complete remissions. That’s the drug which, when it works, induces complete remissions. So that’s why it’s a good drug. We don’t know how many doses we should give and probably we heard from the Presidential Symposium that one dose might be enough in some tumours. The big question is if you look at cabozantinib PFS after nivolumab ipilimumab it’s in the range of ten months, 9-10 months. So if we increase PFS by 20 months I would say that’s impressive. If we increase by 8-10 months I would say that’s just an additive effect; we’re adding also a lot of toxicity.

JP: What about toxicity, Viktor? This is something, a weakness of this combination or not?

VG: Yes, it’s a weakness of any combination. It’s always the balance between efficacy and then getting the dose right and having toxicity. So if you overdo it, if you’re too intense, you compromise the type of therapy and then you don’t deliver on the different drugs and you have a lot of discontinuations and therapy pauses. So it really is something that is a problem for any combination and in particular for that one. I think we have to have more insights into the data and really how it paid off.

JP: More follow-up?

VG: Yes. 

JP: Yes, absolutely. And what about the subsequent lines of therapy, Stéphane?

SO: But, about toxicity, I felt that in the abstract in around 12% of the patients they needed to stop all the drugs in the triplet arm so what are you going to do in the case of no further treatment for those patients? So sometimes the patient has a high toxicity, especially at the liver level, so what are you going to do? You need to… And, as you know, the half-life of cabozantinib is quite long so you need to wait for a long time and this is a problem so far because without drug what is going to do for the patient later on? For subsequent therapy it’s a good question because what are you going to use? It’s a hard question.

JP: A hard question, yes.

SO: I asked some people yesterday about what they are going to do, maybe pembrolizumab, lenvatinib or whatever, or changing class of therapy, I don’t know, experimental drugs. But if you don’t hit the tumour the first time what are you going to do later on? So this is a question.

JP: So, in summary, we need more follow-up with this study to incorporate these alternatives of treatment in the future in guidelines, for example.

BE: For me, in summary, the study is probably going to be negative. If we don’t see a big signal in OS and a big signal in complete remission, I think I would conclude for myself that the study is negative.

JP: And you agree with him? Do you think that it’s going to be negative?

VG: I do, I do totally. Let’s say you increase intensity so you have more toxicities; you compromise treatment procedures which is giving the therapy. If you don’t have overall survival then why would you do this kind of complicated therapy? Then the landscape is quite competitive, [inaudible] also performed quite well and I think the big elephant in the room is really why not use cabozantinib nivolumab? Why adding ipilimumab? These are the questions that we have to answer.

JP: They’re very good questions. Absolutely. Okay, let’s move to the second of the presentations that have been related – the updated analysis of the CLEAR study. Viktor, can you make a brief summary of the presentation that was made by Camillo Porta?

VG: Yes, the CLEAR study has been a study that also recorded in the first line space and is quite similar in regard to the patient inclusion criteria to other clinical trials. Selection is a bit different, we have a higher proportion of patients selected for favourable risk. It’s a study that investigated lenvatinib plus pembrolizumab but also lenvatinib everolimus, we don’t speak much about that arm but it’s also part of that study, and it compared it to sunitinib. This is a very reasonable approach, it’s a huge study, and the question would be what’s the winning strategy and it turned out to be lenvatinib pembrolizumab at the end of the day. 

JP: So the data are impressive in terms of response rate, again. How about the complete response, Stéphane, because nearly 17% of complete response is something.

SO: Yes, it depends. When you look at the complete response in the article, if you go to the supplementary data it’s 10%, if you look at the primary article it’s 17%. If you look at the sunitinib arm it’s 4% so I did not see so many patients having complete response with sunitinib, but nevertheless. So it’s quite a high frequency of patients having a complete response which is great, which may lead maybe to a plateau in the future, I don’t know. But the data are very impressive but, as Viktor said, you have around 40% of patients with favourable risk group so we know for those patients that you’re prolonging OS. 

JP: Yes, absolutely. And, similar to other trials with the combination of TKI plus IO, the hazard ratio is increased over time and the reduction in the risk of death is modest in contrast to the beginning. 

BE: Yes, with all IO/TKI regimens we have seen this phenomenon that the hazard ratio is increasing which probably means that we are not going to have such a big plateau. Probably nivolumab ipilimumab is the regimen where there is a kind of plateau that we see. The big question is we always over-treat our patients with kidney cancer. Pembrolizumab lenvatinib is a great regimen, I’m sure, but probably a lot of these patients don’t need lenvatinib, pembrolizumab would be good enough. On the reverse, probably some patients are not sensitive to IO and the BIONIKK trial for that, Stéphane’s one, shows that some patients don’t need IO. Giving pembrolizumab lenvatinib to all our patients is great but it’s too much for some of our patients.

JP: Yes, however, the combination of nivolumab ipilimumab has the same hazard ratio over time and this is something very [inaudible] for this combination.

BE: Yes, absolutely. 

JP: So let’s move to the third of the…

VG: Before we leave, I think it’s an important issue. What you say is when you use immune only, like the immune doublet, you’re very steady with your results. That also contributes because you have the immune response and that’s durable. TKI is a great way to treat for palliation and you prevent early deaths, early progressions, I think that’s what you see. So in the initial phase of the trial it’s very potent and then subsequent therapies kick in and so there are other factors that are driving, really, the OS curve.

JP: And for this reason I read things about this combination of lenvatinib pembrolizumab is a good combination for patients with high burden disease, liver mets, need to quickly respond.

VG: I think it’s quite potent. You have 72% of complete responders and Camillo also reported if you wait longer some of them shift from partial to complete remission. An additional four patients had really made it to complete response. It’s not unusual, if you wait longer you have better results. When you look into the subgroups, favourable risk patients do very well on that specific combination. So it’s the question but it should be restricted to a specific patient population or you should broaden it up.

JP: Yes, absolutely. Last question about this study is about the future of these combinations because obviously we are recruiting right now in the trials with the triple combination with lenvatinib, pembrolizumab plus an anti-CTLA-4 or plus belzutifan, sometimes highly toxic. How do you see these potential combinations with this combination?

BE: My view is that it is good to build on an active combination so that’s a good idea to add something. The question is should we do a large phase III and my point of view is that we should not. What we want to do is to higher the complete remission rate; we don’t need a large phase III to do that and we should do a good phase II, 50 patients, and if we have a high complete remission try to go to registration. But it’s toxic; we are in the trial, probably you are.

JP: Yes.

BE: And when you add three it’s quite toxic and we see with belzutifan, the combination. I think we just want to increase complete remission, not PFS.

JP: We do. Stéphane, the combination of belzutifan plus cabozantinib has been reported this year. It’s a very interesting study. It’s a phase II trial but can you comment something about this study?

SO: Yes, it’s a phase II trial and, as you know, belzutifan is an anti-HIF inhibitor. It has been presented this morning in VHL tumour disease and it seems to work nicely. With a longer follow-up you have nicer data and objective response rate in monotherapy. So it has been combined to cabozantinib which is also a TKI looking at inhibiting the VEGF pathway. So we have two drugs which are working on the same pathway. The objective response rate is around 60% and a lot of patients are having stable disease around 37%. So only 6% of the patients have progressive disease, which is not so high. So a great combination but I’m not sure, if you look at median PFS it’s around 30 months but in this study around 60% of the patients had favourable EMDC risk factors, so a favourable group of patients. So we’ll see. But in terms of toxicity, anaemia, diarrhoea, which is sometimes painful for the patient and, as we said this morning, how you are going to handle the anaemia – are you going to give [ipi or], which is not so easy to use in kidney cancer because you may promote tumour cells. I’m not sure that in the future this combination will be used. This is my point of view.

JP: This is a phase II with high activity, a median PFS around 30 months, it’s impressive. That is enough for that?

BE: I think there are two points. One, if you just look at the numbers you say, ’30 months? Woah!’ and then you realise that it’s a phase II, very selected patients. I remember when the first data from cabozantinib in second or third line was 70 months PFS, when Toni first presented the data. We know it’s not the case in all patients coming. So that’s the first thing and most of the patients were good risk patients so it’s probably select patients. Second, I don’t really see the rationale to add HIF inhibition to VEGF inhibition because that’s two ways to hit VEGF. Probably we are going to increase toxicity and the benefit is unlikely to happen. We did that with sunitinib plus bevacizumab; we did that with pazopanib plus bevacizumab; most of the time we had a lot of toxicity and benefit was not obvious. So we wait for more data but I’m not still convinced by the rationale of that.

JP: Yes. Many of the trials had combined this anti-HIF inhibitor with another TKI.

BE: I know, I know, and we do that with lenvatinib too and I’m not yet convinced either. Maybe you are Viktor, maybe you are.

JP: Please [inaudible].

VG: When you look for… is there a signal? I think that’s a clear yes. There is a signal for the combination. Belzutifan has a favourable tolerability profile, my answer would be yes as well. It does not have this broad grade 3/4 toxicity that comes along with the usual TKI use. So therefore it can be combined. Is it the best biological rationale? I don’t know, to be honest. I think it needs to be explored. Going back to your question, does it need to be a phase III? Probably not but if you think big you could score in this specific combination. I think it’s worthwhile to go for.

JP: Just the final abstract is related to the negative results of the PIVOT-09 trial that combined nivolumab plus the pegylated interleukin-2. Any comment on that? How have you seen this data? It’s an older study, obviously, compared with sunitinib or cabozantinib but the rationale of combining this pegylated interleukin-2 to immunotherapy…

BE: This raises a different question and Laurence Albiges is going to discuss this study this afternoon. One, why do we combine IL-2 to nivolumab? We had some data with nivolumab plus high dose IL-2 which was not convincing. So the rationale to do that is not very strong. Second, they started the study at a time where the CheckMate 214 has been released and still they used sunitinib as the comparator arm.

JP: Absolutely, yes.

BE: So two reasons to think the study design was not very good and the study is negative, just meaning that it confirms previous data. So not a big surprise for me but maybe for you?

JP: Same?

VG: Yes. I think it’s the same. It’s a problem, if you’re restricted to sunitinib single agent use, wherever you have combinations available you would not participate in such a study. Something that struck me is really when you look into the nivolumab BEMPEG arm it’s 29 months of overall survival. That really is not what we expect nowadays from a modern up-front first-line therapy. So it’s disappointing.

JP: However, the trial again makes some signal about the possibility to treat them only with one PD-1 inhibitor in some patients.

BE: Sure, sure.

JP: It could be a possibility in the future to treat them.

BE: I think that’s certainly something that we need to know – who are the patients who just need nivolumab or pembrolizumab monotherapy as first line? And we have some patients in the BIONIKK or in the pembrolizumab phase II that David McDermott presented. So we know that some patients just need pembrolizumab as well as some patients just need probably a TKI.

JP: Absolutely, yes. 

SO: We showed this morning by looking at the process and then an analysis looking at [?? 20:01] structure that you have a small [?? 20:05] into the tumour you can really increase the rate of objective response rate and PFS and having less oligo-progression of the patients. So it’s not so complicated, it’s not immunochemistry and immunofluorescence, you can do that in daily practice in the future. So really this is a first step of a biomarker that will help you to design either to go for monotherapy or combination.

JP: Hopefully we can make this kind of trial in the future. So we don’t have enough time to do so thank you so much for your very grateful insights. I hope that all of you have enjoyed this debate and see you as soon as possible. Goodbye.