JP: Hello, welcome and thank you for joining us in this on-site expert panel discussion as part of the ecancer educational programme, entitled Latest Developments in Kidney Cancer. As you know, the treatment landscape of this disease has dramatically changed in the last 15 years, with the incorporation of new drugs targeting the antiangiogenic axis and also the mTOR inhibitors and PD-L1 inhibitors. I’m Dr Javier Puente, I’m a medical oncologist at Hospital Clinico San Carlos in Madrid in Spain. I try to welcome you to this round table discussion after the ASCO 2023 where important therapeutic advance has been taking place. Today for this discussion focussed in kidney cancer we have three outstanding and well-recognised experts in the field of kidney cancer. So let me introduce all of them before the discussion. First, Dr Cristina Suárez, medical oncologist at Hospital Vall d’Hebron in Barcelona, Spain, thank you for joining us.

CS: Thanks Javier.

JP: Dr Viktor Grünwald from the Hospital in Essen in Germany, thank you.

VG: Yes, thank you Javier.

JP: And finally Dr Stéphane Oudard from the Hospital Georges Pompidou in France, thank you for coming.

SO: Thank you Javier.

JP: So the key objective of this meeting is to try to make an overview about the different abstracts that have been presented during this ASCO 2023 and, most interestingly, how can these abstracts modify your practical changes in terms of the first line or also in the second line. So there are a lot of them but we can initiate the discussions with a trial that has been focussed in the first line setting. We have two important updates of the interesting phase III trials and practice-changing trials, the CLEAR study and the KEYNOTE 426 trial.  So, Viktor, can you make a brief summary of the CLEAR study and the updated analysis presented today?

VG: Yes, Javier. The CLEAR study is one of the studies that is most recent and it investigated the use of combinations in the first-line treatment of kidney cancer. It included clear cell carcinoma, I think that’s also important to distinguish, that we now acknowledge all the different entities in kidney cancer. It investigated len-pem as a combination versus sunitinib, I think that has been the main idea. It reported positive quite a while ago and it has very good efficacy outcomes. So what did we learn this ASCO? We have seen more mature data – we have four years of follow-up time so that gives you a bit more certainty about long-term effects in this particular setting. Efficacy-wise it did not change, which is not a surprise because data has been mature already with the previous report. So we have seen very good progression free survival data, 71% of objective responses. Complete responses moved a bit – up to 18% – which is naturally if you just wait longer tumours have a better chance to shrink and really reach that timepoint. So that’s not a surprise, I would say. Most interesting, I think, is really the overall survival data. With more follow-up what we see with all the trials, all the trials for the TKI/IO combinations, is really that the hazard ratios do shrink over time. So the difference is not as big as in the initial proportion of the follow-up time and that’s the major point that we have seen. So the hazard ratio is 0.79, which is different from the initial report, but it’s still positive in terms of the significance. It’s reassuring that the combination delivers also on long-term overall survival benefit.

JP: Maybe we can discuss together with the other trial that has been presented, the updated analysis, the KEYNOTE 426. Stéphane can you comment something about this abstract?

SO: Yes, we have an update also for the KEYNOTE 426 with five years follow-up. So we have mature data. As we know, we had a positive study at the first analysis regarding objective response rate, PFS and OS and now we have more mature data regarding the 60-month OS rate and PFS rate which is in favour of pembrolizumab plus axitinib. In terms of toxicity no new side effects, this is very important for the patient. If you look at the hazard ratio, the hazard ratio is 0.67 so in favour of pembro-axi. So really good data; clinicians can rely on those data to give this combination to the patient. So that’s fine. So we will have different opportunities for the patient to use one of these combinations.

JP: Absolutely. I think that one of the questions with this long follow-up is if it is comparable, the results, with the nivo-ipi combination in terms of durable responses, in terms of the tail of the curve, in terms of curing patients. What is your thinking about that, what are your thoughts? Is this comparable or not? What do you think about that?

CS: First of all, we do all the time what we shouldn’t do: comparisons across trials but we do all the time. That’s fair enough. So nivo-ipi has a good thing, as we all know that overall response rate is higher with TKI combination regimens but then the median duration of response we know that the only trial that has not reached the median duration of response is nivolumab-ipilimumab, the CheckMate-214 trial, despite being the trial with the longest follow-up. So this means something, I don’t know exactly what it means in terms of what I’m going to do when I have my patient in the clinic, how I’m going to decide the treatment, but for sure it means something. It means maybe the responses you achieve with nivo-ipi are of better quality, I don’t know, but yes.

JP: We don’t know that. Viktor, do you think that this data supports the use, for example, with axi-pembro or len-pem in the favourable risk group because there is a lot of debate in this subgroup of patients?

VG: Yes, I think that’s a good question and there is not a clear answer. The only thing that I would really summarise is that there is more efficacy if you combine, there is more objective response, there is a deeper response and there is better progression free survival. Data is not mature so you cannot really comment on the overall survival. That’s the point that I would make. With CLEAR data, with the subset of the favourable risk group of patients, you see the first time it’s moving towards… it’s 0.89 so it’s moving below this 1.0 threshold which has been crossed many times in that group of patients for the combination trials. So the discussion is not really over, we really have to wait for a couple of years, actually, to make that conclusion.

JP: And Stéphane, what about the toxicity in this long period of time of follow-up? You have mentioned that the five years’ follow-up of the KEYNOTE 426 has no new signals in terms of toxicity. Do you think that this long period of time treated with a TKI is safe for those patients? Because obviously we are treating patients with this combination with a long period of time, maybe four years, five years, using axi-pembro, for example, or len-pem, and we don’t know what happens with the patients that are a longer survival. So do you have any concerns about that? Do you think that they are safe for a long period of time?

SO: I think that’s completely true, that for patients having a TKI for a long period of time they are bothered by side effects every day – GI toxicity and so on. So if you use ipi-nivo, and we know that nivo in maintenance therapy does not too much induce side effects as compared to a TKI, so in terms of quality of life I would prefer to go on nivo as compared to having a TKI such as axitinib or lenvatinib for sure. But maybe, as we said, for symptomatic patients in the first-line setting I would prefer to go for IO/TKI just to get rid of the symptoms due to the disease and to have a great effect very quickly. But I completely agree, TKI for a long period of time could bother the patient in his life, yes.

JP: Fortunately we have all these combinations available in the first line, based on the guidelines, so we have different alternatives of treatment. But let’s move to the second line…

VG: Maybe one topic, just a final comment on the first line. When you discuss what is really the impact of the TKI/IO business versus IO/IO, I think TKI/IO in all those trials what we delivered strongly is really the reduction of early deaths.

JP: Absolutely.

VG: That’s a major asset.

CS: That’s for sure.

VG: Because you said, Stéphane, it’s in the symptomatic patients where you need this rapid response and I think that’s exactly what it does.

JP: And it explains the hazard ratio initially in these studies compared with at the end of these studies. OK, let’s move to the second line. Cristina, what about your thoughts in the awaited results of these trials in the second line comparing cabozantinib plus atezolizumab? What are your thoughts?

CS: So the CONTACT-03 trial is, for me, the most important trial that has been presented at this ASCO, the most expected one.

JP: Absolutely.

CS: So in the past with TKI monotherapy it was very easy to do a sequence – you have two drugs that improve overall survival, nivolumab, cabozantinib, and whatever you did it was OK. But now with the arrival of IO combinations we don’t know what to do after patients progress to this combination. So that’s the big question, what to do in the sequence and the CONTACT-03 trial tries to answer this question and especially tries to answer if we should maintain immunotherapy after immunotherapy progression. So, as you know, it’s a phase III trial that randomised patients with clear and non-clear cell components, so non-clear cell were also included, and randomised patients 1:1 to receive cabozantinib versus cabozantinib plus atezolizumab, patients that have received a previous IO. So the co-primary endpoints were progression free survival and overall survival. Unfortunately, that was a negative trial, there was no difference in PFS and OS between the two groups and with a higher toxicity in the atezolizumab cabozantinib arm. So we don’t have the answer what to do, what we should do after IO combination, we are still working on it. I don’t know, we need to wait for the TiNivo-2 trial that compares tivozanib versus tivozanib plus nivolumab in the same population. It’s the PD-1 version of the CONTACT-03 trial. I don’t know if this is going to make a difference or not but we’ll see what happens with the TiNivo-2 trial.

JP: I think that these trials, or the results of these trials, have more questions than answers today because obviously, as you mentioned, atezolizumab is one drug that, in some cases, has failed in the results.

CS: Especially in RCC.

JP: Especially in RCC compared with nivolumab or pembrolizumab. But the second question is this is the final answer about the use sequentially of immunotherapy because these are questions that we have today with the use of pembrolizumab in the adjuvant setting – what happens for those patients that progress after receiving immunotherapy even in the adjuvant setting? So what are your thoughts? Do you think that there is no role for rechallenge with immunotherapy or using, continue using, immunotherapy? Do you think that there is some subgroup of patients where that could be an option? What do you think, Viktor?

VG: First of all, I think that trial is negative and it did not show…

JP: Any signal.

VG: Any signal, yeah, so I think that’s very obvious. So is there a role for subsequent immunotherapy? I think it depends. I would say in the sequence using up-front combination, using next line additional immune component there is no rationale to support that. With every rule there is some exception, so we have those escalating trials where you start off with nivo and then in case of progression you switch into more intense immunotherapy, adding ipi. It did work in some of the patients so having alternative immuno components that you kick in into the therapy, I do see the principle that could work here, to be honest. But for the TKI/IO combination it does not make sense to maintain in the second line, at least from the data whatever we have.

JP: Do you think there is a difference from patients that are being treated in the adjuvant setting?

VG: I think it does not really apply because what we have tested is in the metastatic setting and whether the setting in adjuvant and metastatic is really the same is one of the questions. The second one is also because you expose and you have progression, depending on the time schedule I think it can be interpreted differently than in palliative treatment where you just wait for progression and then switch. 

JP: We will see, we will see with the next trial, with the TiNivo, if these results confirm or not the value of continuing immunotherapy. Let’s move to the third scenario now, the non-clear cell scenario. We have at least three important abstracts on the combination of len-pem by Dr Li, the use of cabozantinib plus nivolumab, and finally the IMDC meta-analysis in patients with sarcomatoid or rhabdoid with non-clear cell carcinomas. Stéphane can you make some summary about, for example, the data coming from this meta-analysis? 

SO: First of all, in non-clear cell carcinoma there is no recommendation so far. A very small study, a mix of patients in first and second line, heterogeneity within variant histology, for example for papillary tumours for instance. So TKI monotherapy in the past, now more combinations. So we had this combination of lenvatinib plus pembrolizumab from Dr Li which seems to be really interesting so far. A huge number of patients, it was a big phase II with more than 150 patients, and the objective response rate was almost around 50% and the PFS was quite long, around more than one year. So really in second line, in first line, it’s great for those patients having aggressive disease, especially for translocation variant disease as well. And if you get rid of the chromophobe subtype you even increase the rate of objective response rate and PFS because we know that for chromophobe those tumours do express CD8, not exhausted phenotype, so you don’t need to have immunotherapy. So maybe you should only treat those patients with TKI or a combination of TKI, for instance, I don’t know, belzutifan plus lenvatinib, for instance. But I was impressed by these results with a good toxicity profile. So I think it’s good news. 

JP: Yes, absolutely. Do you have any preference, based on the histology? For example, in patients with papillary tumours based on the results of the cabo-nivo or len-pem? Do you have any treatment algorithms about that? For example in papillary?

VG: First of all, I think it’s great that we discuss sub-entities because usually it has been all mixed up in non-clear cell and it’s like the lung story many years ago. So now we start recognising individual diseases.

JP: Different subtypes.

VG: And it makes a lot of sense.

CS: Stop saying non-clear. 

VG: Yes, we should not use it.

CS: We should stop at some point saying non-clear.

VG: Yes, so in papillary there’s good rationale to use cabo-nivo. It has very good data. I know that some people prefer to stay with single agent TKI, for instance cabozantinib, because it has randomised data suggesting it’s the better TKI compared to sunitinib, for instance. It’s part of the discussion. In Germany we use combinations in these patients and the preferred option is cabo-nivo, I would say, at least from my perspective. But it’s a moving target so it becomes more and more interesting with other combinations. So there’s a preference in papillary.

JP: And what about in unclassified or patients with a very aggressive disease? 

CS: I think the results of the B61 trial in this small population classified as patients with [inaudible] are amazing. So the results in all of B61, it’s very good. As you mentioned, it was 49% overall response rate and a disease control rate of 83% in the overall population. But, for example, in patients with translocated tumours that we didn’t know what to do with these patients, there were only six patients included in the trial but the overall response rate was 67%. So it’s amazing the results and very, very, very far away from what we had before. So I would go for a combination for sure in these patients, especially len-pem with this data.

JP: Finally, obviously, one mention to this meta-analysis, Stéphane, because obviously I think that this is practice changing. Because obviously we are not thinking about the possibility to use immunotherapy in patients with non-clear cell. Obviously now with the cabo-nivo or len-pem in this subgroup is interesting but when we are looking for patients with sarcomatoid we are always thinking of the nivo-ipi. But now we have some data with these combinations, what are your thoughts about that?

SO: I think it was a very interesting study looking at the international metastatic RCC database consortium with a huge number of patients. Only 100 patients having sarcomatoid or rhabdoid differentiation who were treated with either an IO combination or TKI immunotherapy, sunitinib or pazopanib. Really, in terms of objective response rate, time to treatment failure and OS is in favour of IO combinations, so either IO/IO or IO/TKI. So maybe the recommendation now is, of course, to look at whether or not you have sarcomatoid differentiation or rhabdoid differentiation, and maybe to go for this combination. But it’s retrospective data so maybe we need to move to a prospective study. For those patients having no sarcomatoid or no rhabdoid differentiation there is no difference at all between IO or TKI.

JP: And now the next step is to try to do trials focussing on these kinds of subtypes of tumour, for example in papillary we need new trials with a control arm based on cabo-nivo, for example, or we have to continue doing phase II studies, exploring new combinations. What are your thoughts about that? It’s so difficult because you need a huge number of patients.

CS: Ideally, I think we should go for randomised trials. In fact, we are going to start the XL092 304 trial that combines XL092 plus nivolumab versus sunitinib in non-clear cell trials. But again it’s non-clear but I think we are still not prepared for that. We should go for biomarkers and subpopulations and treatments specific for every population but, honestly I think we are not still prepared for that, I would love it. The other thing is, as you mentioned, if you, at least in many countries, like in our country, if you have data from a phase II trial they are not going to give approval for the drug. And it is very important, this is very important, because in other countries this is not an issue. But we need randomised trials to get the drugs approved.

JP: Or at least do you think that we have to modify the ESMO guidelines, for example, in this subgroup of patients with non-clear cell?

VG: I would say yes but I think it’s a lot of discussion because of the question of availability, reimbursement in different countries and then it’s also the lack of a randomisation in these trials. So the cabo-nivo trial is informative because it’s already labelled so it really informs physicians on how to pick the best choice. I think it delivers nicely on efficacy and that’s why I do use it as a preferred option, honestly, although I don’t have a formal randomised comparison. So we have to accept some level of uncertainty in these rarer subtypes. 

CS: I agree with you that the data are amazing and I would use it if I was able to do it but the thing is that we are not. 

JP: Do you think that there is any subgroup of patients in this context of non-clear cell that have to be treated with a TKI alone at this moment? Any of them? Or at least with another drug, chromophobe for example?

SO: Maybe for chromophobe, yes.

JP: What is your standard of care today in this setting? A TKI or an mTOR inhibitor?

SO: As Viktor said, we need to have prospective studies, and maybe a randomised study, but for chromophobe I think that immunotherapy does not add anything to the TKI except toxicity maybe. But we need really to push at the European level and the international level to study because it’s a rare tumour. If we don’t act all together we won’t have any guidelines to give to the clinicians and to the patients.

JP: I think that we don’t have more time to continue. We had a lot of abstracts during this ASCO meeting but time is ending. Thank you for all your insight in these abstracts, we appreciate it. Thank all of you for following us and we will see you in the next congress. Thank you.