ESMO 2024: Latest updates in mRCC

Dr Javier Puente – Hospital Clinico San Carlos, Madrid, Spain

Dr Guillermo De Velasco – Comunidad de Madrid, Madrid, Spain

Dr Cristina Suárez – Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain

Prof Stéphane Oudard – Georges Pompidou Hospital, Paris, France

JP:         Hello, welcome and thank you for joining us in this expert panel discussion as a part of the ecancer educational meetings entitled The Latest in the Treatment of Metastatic Renal Cell Carcinoma. I’m Javier Puente, a medical oncologist and I’m currently the head of the GU Cancer Unit at Hospital Clinico San Carlos in Madrid in Spain and it is my privilege to welcome you to this roundtable discussion meeting focussing on the management, diagnosis and the treatment of renal cell carcinomas held just after attending ESMO 2024 here in Barcelona in Spain where important therapeutic advances have been taking place. For this discussion we have three key opinion leaders, three well-recognised medical oncologists, all of them with a high expertise in the field of kidney cancer. So let me introduce all of them before the discussion. First Dr Cristina Suárez, medical oncologist from Hospital Vall d'Hebron in Barcelona

CS:        Thank you, hello.

JP:         Thank you for joining us. Secondly my friend, Dr Guillermo De Velasco, medical oncologist from Hospital 12 de Octubre in Madrid in Spain. Thank you for joining us Guillermo.

GDV:     Hello everyone, it’s a pleasure.

JP:         And finally my friend Stéphane Oudard, medical oncologist from Hospital Georges Pompidou in Paris, France. Thank you for joining us.

SO:        Hello.

JP:         The key objectives with this meeting is first to gain feedback about the recent data that has been presented during this ESMO meeting and secondly, and I think more important, how can it affect your daily clinical practice, how are you going to modify your treatment decision making when you return to your hospital, your country, whatever. So we have selected several abstracts for this discussion and I think that we can initiate the discussion with the first-line setting that we have changed a lot in the last ten years. Finally we have different alternatives of treatment, like lenvatinib/pembrolizumab or another TKI plus IO or a combination of IO/IO. Recently we have a new combo coming from China with the combination of a new generation of drugs. Stéphane, how do you see the data that has been presented?

SO:        Well, it’s interesting. A study coming from China with a new drug which are not available in Europe, I would say, with a difference in terms of looking at the immune checkpoint inhibitor because it’s anti-PD-L1 as compared to PD-1. So maybe this is a difference at the end, we don’t know yet, but combined with a TKI. The study is a huge study, a phase III trial like the other phase III trials, and the outcome seems to be okay in terms of PFS and objective response rate for the patients as well as the tolerability so far. I wanted in this trial maybe to add another arm in this study, maybe to compare this new combination compared to sunitinib and compared to ipilimumab/nivolumab to see if it’s going well in terms of efficacy regarding a combination of checkpoint inhibitors. So I would have loved to have had a three-arm study because it’s come from China and we don’t know yet how to handle these results so far. But it seemed to be interesting and I think that the TKI seems to be quite well tolerated, as tivozanib, for instance.

JP:         Guillermo, you’re part of the panel of the guidelines from ESMO and in the past they have included another combo coming from China. How do you see this new combo? Could it be included in the guidelines?

GDV:     So the idea of having different or even in the guidelines something from China, for example, is we acknowledge from the guidelines that sometimes… We are aiming to basically cover the world in terms of indications and sometimes people from different places come to the guidelines and they want to get the guidelines from their own countries and all this is different. So that’s why when a trial like this one is bringing the information from a phase III clinical trial we have to somehow acknowledge that information. So we have another IO plus tyrosine kinase inhibitor, as Stéphane was saying, improving PFS, response rate. So it’s something that is obviously valuable. Maybe not for us, from Spain, because we won’t have that combination but we need to acknowledge that, again, an IO plus tyrosine kinase inhibitor is working. The point is how it’s really affecting our daily clinical practice. It’s not. So we have already well-established combinations: cabozantinib/nivolumab, lenvatinib/pembrolizumab, that we are using for our patients, for most of our patients with IO plus tyrosine kinase inhibitor, so I don’t think we really need another IO/tyrosine kinase inhibitor. Stéphane was saying we need to go for what’s the next step for our patients? Which really need IO/IO, IO/tyrosine kinase inhibitor, or which patients really need a triplet, for example? So that’s where we should focus.

JP:         I fully agree with you. The other study that has been presented from the Italian group and they are using a faecal microbiome transplantation, Cristina, how did you see this data this morning?

CS:        I think it’s quite preliminary data but it’s a phase II trial anyway. The data is really promising so I think microbiota is going to be, at some point, I don’t know when, included in the future treatment. So this data had a very good overall response; with faecal transplantation they improved the overall response rate in a good way. So we had also the other drug with microbiota, the CBM588 that is being combined with nivolumab/ipilimumab and nivolumab/cabozantinib and also looks great in other tumours like lung cancer, they are also developing a lot in combination with immunotherapy. We are in a good way but we still need to establish and know how to combine and who to combine with or what to combine with. It’s good data, phase II, but…

JP:         And Stéphane and Guillermo, it’s time to move forward for phase III study with this kind of approach so this will…

SO:        Maybe, I think it’s a little too early, I would say. Because maybe we need to know what is in this microbiota of this donor patient. The donor patient was a patient having immunotherapy, a long-lasting response for five years, I think, so this is the donor. Maybe it’s more useful or less complicated to see what kind of bacteria are useful in order to give FMT. Maybe if we can look more precisely. We know so far that we have some bacteria which are associated with a good outcome and can reverse resistance of immunotherapy so maybe if we want to speak about a lot of patients we won’t be able to afford to give these [??] and to make a colonoscopy and so on. So it’s time-consuming, it may be difficult. So I think it’s not yet time.

GDV:     Yes, absolutely, I was just thinking the same. So we are not yet to think about a randomised phase III clinical trial with one thousand patients, especially because one of the issues when you are thinking about microbiome is the variability. This may affect, as we were saying before with the treatments, that’s also affected by new microbiomes. So how the same microbiome may really change from one country to another country, so there’s a lot of factors there that it’s going to be really, really difficult to think about a phase III clinical trial, especially when you are thinking about those transplants you need to do. That would be different if you had some pills or some specific microbiome that you could have, but in terms of having… So the proof of concept has been really good, so you’re proving that in the same kinds of patients you are doubling response, that’s amazing, but it’s a really well study for proof of concept, as I say. You need to continue working on that to see what really you need to do for a phase III.

JP:         Yes, absolutely. So from a practical point of view there is no change in the way that we are thinking in the first-line setting in clear cell carcinoma. But we have a new phase III study, for the first time, randomised study, in non-clear cell carcinomas. Guillermo, how do you see the data with the SUNNIFORECAST trial?

GDV:     SUNNIFORECAST has been a very exciting study. First of all I think we need to congratulate the authors because it’s really difficult to do such a study with response rates study for multiple non-clear cell histologies, which I think is pretty good. We have seen data with ipilimumab/nivolumab. I guess the main message is that we were waiting more for the combinations with ipilimumab/nivolumab. We’ve seen decent data, some positive data, but I guess it’s not enough. It’s not enough, why? Because we are thinking those non-randomised data from the KEYNOTE-B61 with lenvatinib/pembrolizumab, we really may see data in more than a hundred patients. Also nice data with cabozantinib/nivolumab. So somehow you’re expecting to see something better. I know that those trials were not randomised but looking at SUNNIFORECAST, data, as I was saying, are okay but I don’t think are going to change the practice in most cases with non-clear cell histologies.

JP:         Stéphane, do you think that some of the weakness of these studies, the mix of histologies maybe, or maybe while the poor PFS, for example?

SO:        Yes, we were speaking about heterogeneity regarding all the tumour types except, of course, clear cell carcinoma. I think this is not now the right way to do that. With Cristina we tried to separate histologies from one type to another to propose either according to the disease, cancer disease pathway, to propose a specific treatment to have the greatest effect. So for chromophobe we would like maybe to add a checkpoint inhibitor because there is no reason to add checkpoint inhibitor in the chromophobe subtype of kidney cancer, as well for biliary tumours. I found out that they included also biliary tumours which maybe you should go more for chemotherapy, for instance. In this study one of the weaknesses is that around 40% of the patients in the standard of care treatment did not receive the so-called standard of care, cabozantinib, which seems to be the greatest drug to give, at least in papillary tumours.

JP:         Cristina, do you think that we have to incorporate this combo in the guidelines?

CS:        That’s a difficult question.

JP:         Because it’s a phase II study, it’s a positive study.

CS:        Yes, yes, that’s the strength of the study, it’s a phase II trial randomised with IO. So, as Guillermo mentioned, this is the strength of the study. The primary objective was met but the primary objective was… we could discuss if it was the right primary objective that was the percentage of patients OS at 12 months but this benefit was not maintained and there was not benefit in PFS. As Guillermo said, I would feel much more comfortable using lenvatinib/pembrolizumab and/or nivolumab/cabozantinib in those patients because I think the results, the data for the monotherapy arm, phase II trial are better. But we could include it in the guidelines as an option, why not, but I would not say a preferred option.

JP:         Okay, so at the end we have one possibility to change a little our way of thinking, is the inclusion of this combo in first line non-clear cell carcinoma, at least in a subgroup of patients. Let’s move to the second line and I think that we have at least three main studies, or even four, that’s the TiNivo study, the LITESPARK-005 with belzutifan, the overall survival results, the nivolumab subcutaneous administration and finally the CaboPoint study and the final results. So I think that we can start with the nivolumab study in subcutaneous – how did you see this data, Stéphane?

SO:        I think that those data have been already presented so we have the update regarding follow-up so far. So it seems to be okay regarding IV versus subcutaneous treatment. One thing is we don’t have so many antibodies regarding nivolumab so far, so it’s reassuring for us and for the patient. [??] response rate and PFS and so on are equal so there is no issue regarding that. So maybe it’s easier for the patient not to come to hospital daily and maybe it’s cheaper as well, so it’s good news. Maybe it’s going to be practice changing and inducing less costs for our patients tomorrow at the hospital.

JP:         I think so, yes. What about TiNivo?

GDV:     Well, TiNivo is a second-line study that has shown that it doesn’t make any sense to continue with immunotherapy once you have progressed in the metastatic setting. So the idea is that we had the contact showing that the maintenance with an immunotherapy after progression on first line did not make an impact on PFS or OS; we’ve seen the same with tivozanib. You can give a second tyrosine kinase inhibitor, in this case tivozanib, but the maintenance with another anti-PD-1 therapy in this case, because the previous time was anti-PD-L1, does not affect PFS or OS. So basically we have now two studies proving that the rechallenge is not really working in kidney. It makes sense – you are using for first line an anti-PD-1 therapy and if it’s not working it’s not the same when you are sequencing a tyrosine kinase inhibitor. The good thing about tyrosine kinase inhibitors is that they are multi-tyrosine kinase so they can target different things. But when you are using PD-1 or PD-L1 you are basically targeting the same thing. So we were expecting that maybe the microenvironment could change and that was nice on paper but the reality is with two well-conducted phase III clinical trials we have proven that we should not pursue the maintenance with a rechallenge with anti-PD-1 therapy in kidney cancer.

JP:         I think that the question is clear, what about the patients that are receiving immunotherapy in the adjuvant setting and you have to move to the first line? You have lenvatinib/pembrolizumab, you have nivolumab plus ipilimumab, you have axitinib/pembrolizumab, how do you see this data in your practice when you are selecting those treatments?

CS:        That’s the million dollar question.

JP:         Yes, absolutely.

CS:        So with the arrival of adjuvant therapy we have a new situation with the patients and what to do with those patients. So obviously I think that we all agree with that it’s not the same as patients that progress on treatment with pembrolizumab and patients that progress after six months and patients that progress after twelve months. So I don’t know if you agree with that, for me, a patient that progresses on treatment for sure I would go for a TKI. I think that these data from TiNivo and the CONTACT trial tell me that it’s not worth it to do a combo with IO/TKI because I’m not going to reprogramme them [??], that was what we were expecting to do. Patients, that’s my opinion, that progress after twelve months of stopping adjuvant pembrolizumab, for me, could be like a third-line patient. For me, the most difficult question or situation is patients that progress between 6-12 months.

JP:         We need more data.

CS:        We need more data and we need to generate data around these patients because they are patients that we are going to see more often every day.

JP:         Yes. The final abstract that I want to comment briefly is the LITESPARK-005. These are the final results of this study. Stéphane, how did you see this data? You are going to modify your way of thinking about the drug, about belzutifan?

SO:        It’s a nice study with an update from Brian Rini comparing belzutifan versus everolimus in later stage of the disease. With a longer follow-up the PFS is maybe better; at the end there is no difference in terms of OS which was a little surprising and a pity for the patients. But it tells me that maybe belzutifan needs to be given earlier because in this study you could go to a fourth line of therapy and so on, so a heavily pretreated patient population. So the toxicity is not a problem because there is no new signal. So I think that belzutifan is going to be proposed maybe in the near future with cabozantinib to give a high response rate, with lenvatinib for instance, in combination, even though the toxicity is maybe of concern so far. But I think that belzutifan is going to play a role in earlier disease.

JP:         Guillermo, tivozanib before or after cabozantinib in your treatment decision?

GDV:     Tivo?

JP:         Tivozanib versus belzutifan after cabozantinib, what do you expect? Do you think that belzutifan will be used before tivozanib?

GDV:     Yes, I mean in most cases like… So belzutifan works in around 20%, maybe less, but when it’s working it’s working pretty well and the patients will have an amazing quality of life. There is no question about that. If you compare any tyrosine kinase inhibitor with belzutifan, the tolerance, the quality of life, is going to be much better. So now you know that only it’s going to work for a few patients, that’s why we don’t see the overall survival. But still there’s a global benefit for PFS against everolimus. So for me it’s a go, definitely, for the drug. Now, obviously there are some situations when you can go for tyrosine kinase inhibitor in more aggressive disease but in those cases with more indolent disease and when you really want to think about quality of life belzutifan is going to have the place.

JP:         I think that we have covered the majority of the abstracts that have been presented during this ESMO 2024 here in Barcelona. I would like to say thank you, all of you, for your valued contribution. Thank you to the audience and thank you to ecancer for the organisation of this debate. Thank you.