JP: Hello, welcome and thank you for joining us in this expert panel discussion as a part of the ecancer educational programme entitled ‘The latest in the treatment of metastatic kidney cancer.’ I’m Javier Puente, a medical oncologist here in Madrid in Spain and it is my privilege to welcome you to this round table meeting discussion panel held just after attending ESMO 2023 here in Madrid in Spain where important therapeutic advance has been taking place, especially in the field of GU cancers. So for this discussion we have three outstanding medical oncologists, all of them with a high expertise in the treatment of patients with kidney cancer. So let me introduce all them before the discussion. First, Dr Laurence Albiges from Gustave Roussy, Paris, France. Thank you for coming.
LA: Thank you Javier, it’s a pleasure to be here.
JP: Thank you. Dr Stéphane Oudard from Georges Pompidou Centre in Paris, France. Thank you for coming Stéphane.
SO: Thank you as well.
JP: And finally my friend Viktor Grünwald from Essen, Germany. Thank you for coming.
VG: My pleasure.
JP: So the key objective with this meeting is to try to make a brief overview about what is the most important abstract that has been presented during this ESMO 2023. How can we integrate this information into daily clinical practice? And, finally, how can we modify our treatment decision making? So we have selected some abstracts that we considered that were for interest and we can initiate it with the first line. Unfortunately we don’t have another phase III study changing practice but we have some subgroup analyses coming from different trials. Viktor, you have presented during this ESMO meeting your sub-analysis from the CLEAR study. Can you comment something about that?
VG: Yes, absolutely. Javier, as you said, I think it’s important to really investigate where are the merits, strengths and weaknesses of a given combination. For the CLEAR study where we investigated lenvatinib pembrolizumab versus sunitinib we wanted to really understand what is the ability to shrink tumours in different organ sites. Because we always have the objective response rate reported across all sites. So we looked into the dataset and, as you may understand, it’s difficult because you need to have the readout by organ site. So we looked into organ sites and we identified the target lesions by organ site and we used them as a surrogate, or it’s not a surrogate but we measured tumour shrinkage for these target lesions. As good as it gets, to the point where to make assumptions on how good is a given therapy in metastasis to the liver, metastasis to the lung or the lymph nodes or the bone, and that’s what we investigated really. So the question is what did we see? We have seen very similar efficacy compared to the overall group. So more benefit in the combination arm for lenalidomide pembrolizumab and it also did shrink the tumours in the bone. That’s also something that we were not so sure of in the past.
JP: So, Laurence, how can we use this information from your practical point of view where you are in front of patients with metastatic RCC and they have, for example, bone mets or liver metastasis? How can you choose this information?
LA: So I think you’re touching on an important point. We now have access in many countries, both on the doublet IO strategy and the IO TKI and we have several regimens available. The piece that Viktor commented on and he reported is that there are patients that have symptomatic disease and can have large tumour burden, including lesions at risk. We’re thinking about the bone but also the liver and it’s important to know that VEGF TKI IO regimens in this setting are able to reach not only an important tumour shrinkage rate, in the range of 70%, seven out of ten patients will have significant downsizing of their metastatic spread, but also very few primary refractory tumours. It is important in a symptomatic patient that we go for this objective so that the patient will be less symptomatic or to prevent further disease progression.
JP: Stéphane, do you use this kind of combination, the TKI plus IO, in your daily clinical practice?
JP: According to the site of metastasis do you use one or another or are you going for metastasis.
SO: So I would say a few years ago, based on the nivolumab cabozantinib combination and maybe the fact that cabozantinib is really working well on bone metastasis, I do prefer to use nivolumab cabozantinib. But now, based on the new data regarding pembrolizumab lenvatinib, I think that we also can use this combination and the objective rate is quite high as well. So now we have two options, I would say, so I think it’s more comfortable for the clinician.
JP: So another abstract that has been presented in the first line has been presented by the Italian group, by Roberto Iacovelli. This is very interesting data coming from this trial because for the first time they interrupted treatment with a TKI and with an IO. Can you comment on this trial, Stéphane?
SO: Yes, I think it’s an interesting trial because, as you know, in combination with IO TKI we usually have to decrease or to stop the drug for a while based on the toxicity due to the TKI. So it’s a nice study looking at avelumab plus intermittent axitinib after nine months of exposure. For those patients who had either a partial response or complete response, they stopped axitinib and then it could be restarted after progression with avelumab. So the primary endpoint was to look at the proportion of patients free of progression at eight weeks after stopping axitinib and around, I would say, 40% could achieve to stop axitinib, or to have intermittent treatment with the TKI. Around 70% of the patients had a good objective response rate and you can decrease the rate of toxicity, have a better quality of life. If you look at the median PFS, the median PFS is very good. So I need just to say that for those patients in the phase II trial they have selected patients with no tumour burden, no visceral metastases, no symptoms and previous nephrectomy, just to avoid having patients who could progress rapidly in case of stopping axitinib. But the rationale is good for our patients, based on the fact that we had the survey, the big survey, regarding patients, what they want to have in fact in daily practice and they said that they want to have a better overall survival and also to stop the treatment at what time. So I think it’s a good idea.
JP: Viktor, we know that TKI for a long time we can suffer hypertension, we can suffer proteinuria and sometimes you have to interrupt the treatment and finally discontinue the therapy. These data coming from this trial could be used right now in your daily practice when you are prescribing, for example, axitinib pembrolizumab or lenvatinib pembrolizumab?
VG: Yes, it’s a very good source of data and it’s not the only one. I think it builds up to the whole story that we investigated for TKIs. So single agent use where you had a lot of discontinuation therapies, interruptions. So we learnt, really, from those data in the old days that it is safe to interrupt without compromising the outcome. That data adds to this body of evidence, actually, but now it’s combination therapies and it’s informative for the clinical practice, yes.
JP: Laurence, you are more comfortable interrupting immunotherapy or interrupting the TKI?
LA: I think what I care about is my patient quality of life and therefore I’m pleased to be able to offer drug holidays, speaking of the TKI. I consider that coming to the infusion room every six weeks or every three weeks or four weeks, based on the regimen you have, is okay. What I want is my patient to have drug holiday without the daily side effect.
JP: And do you it is feasible to reintroduce the same drug after progression when you are making these break holidays?
LA: Yes, I think it is, I think it makes sense. In a patient that is responding well you can offer some treatment break. We’ve been doing that, as Viktor mentioned, for many years with VEGF TKI and I’m glad that we’re starting to have TKI IO data supporting that as well.
JP: Absolutely. So let’s move to the second line. Obviously belzutifan is one of the most interesting drugs that has been presented during this ESMO 2023. It’s the first drug in this class of family that has been a phase III study. So, Laurence, can you make a brief summary about the phase III study compared with everolimus?
LA: Sure. Thank you for highlighting this. This ESMO 2023 was important because we are reporting for the first time the LITESPARK-005 study. This study is indeed evaluating a new drug, we will say, belzutifan. What we do know is that in kidney cancer, clear cell RCC, there is a key role of the HIF pathway and there is an innate activation of this pathway leading to VEGF activation, basically. What we do know is that belzutifan is a drug that is already approved in the US for VHL-associated, a certain form of VHL-associated, disease and we had until now some phase II data supporting the activity in sporadic RCC. For the first time we have a randomised phase III that tested this agent in patients with clear cell RCC who had previously failed at least one VEGF TKI, up to three, and one immune checkpoint inhibitor. Patients were randomised between belzutifan that is an oral administered drug, 120mg/day, or everolimus as one of our standards of care in late-line therapy. What are the key things to know about this trial? Overall 740 patients randomised, 370 per arm. These patients were heavily pretreated meaning that 85% of patients were treated in the third or fourth line setting. So this is not a pure second line trial, it is rather third and fourth line setting. But the great news is that the study is positive, met its coprimary endpoint for progression free survival assessed by BICR and what is it? An increase in progression free survival with a hazard ratio of 0.75, that is true at interim analysis one and two. What we have is although the median are the same one we have a very nice curve suggesting that belzutifan is able to have this long-term control even in a heavily pretreated patient population. The response rate is also increased with 22% of objective response versus 3.5% with everolimus, including patients achieving complete response in more than 3%. So that’s very interesting. Safety-wise this agent is extremely well tolerated. It has a different safety profile from TKIs because it is a different mechanism of action. For instance, anaemia is anticipated because HIF-2 plays a role in the synthesis of erythropoietin as well as inducing some hypoxia because of the sensoring of hypoxia in the lung being related to HIF-2. So a specific safety profile but amazing patient reported outcome data as well. Because in terms of time to clinical deterioration this agent is extremely well tolerated and favoured upon everolimus which is an agent that is usually considered to be quite manageable.
LA: One of the coprimary endpoints is overall survival. There is a trend favouring belzutifan with more than three months delta, the hazard ratio is less than 1.0. We need more follow-up; it’s not yet statistically significant with overall survival. So here what we have is a positive study in pretreated patients, opening the way of a new mechanism of action drug. I can’t wait for our authorities to take a close look and hopefully get access for our patients.
JP: Absolutely. I think this is a practice changing trial. But first question for all of you – what is the most frequent drug prescribed after immunotherapy and after cabozantinib in your hospital right now in third line? What is the most frequent drug that you prescribe?
LA: So a patient that would have failed IO/IO or IO/TKI and then cabozantinib second line?
LA: In France we would be using axitinib if it hasn’t been used before or outside France, when available, lenvatinib plus everolimus.
JP: Yes. Viktor in Germany?
VG: It could be anything, to be honest. I would go with the patient profile, so if there is a lot of tumour load or symptoms I would go for lenvatinib everolimus, to be honest, that would be my preferred choice. If that’s not the case, after cabozantinib I would go for everolimus as a single agent but we’ve seen the data – it does not shrink a lot the tumour so it’s mainly stable disease. But median PFS 5.6 months, this is not so bad. So I think it’s also a reasonable choice.
JP: And Stéphane, do you think that everolimus is also a good comparator? Or do you think that you need more data compared with another TKI, for example tivozanib?
SO: Yes, why not tivozanib? But the study is positive, we’ll still use everolimus in further lines so why not? So, of course, maybe we could have chosen to compare TKI versus TKI and we know that now everolimus is useful but for very few patients, in fact, for those who do have [inaudible] mutation. But anyway it’s a positive trial and the duration of response is impressive so far and the toxicity profile is very good as well. I was part of the VHL study so I have experience with this drug and so far, except anaemia, and you can take easy care of this side effect, hypoxia is maybe different but the toxicity profile is really good. So that’s why this drug is going to be used in combination and to move to earlier stage of the disease.
JP: Yes, in this sense we have another trial. We have the trial in combinations with cabozantinib. Can you make something, can you say something about this trial, Laurence?
LA: Sure. As Stéphane highlighted, because it’s a well-tolerated agent that has a different mechanism of action it is currently being investigated in second line with lenvatinib, a randomised study, lenvatinib plus belzutifan versus cabozantinib, in first line in triplet strategy as well as in the adjuvant setting. All of them are randomised phase III. What has been presented at this ESMO 2023 is combination data of belzutifan plus cabozantinib first line but also later lines. To put a long story short, first it seems to be doable in terms of safety and, second, the adjunction of belzutifan on top of a potent VEGF TKI seems to increase the response rate. For instance, in the frontline setting we have a 70% objective response rate, cabozantinib plus belzutifan. But this is not the only study. For instance, last ASCO meeting we had the umbrella arm that was lenvatinib plus belzutifan which was assessed in later lines. Here again about a 50% response rate which is actually extremely high when compared to what we would anticipate in late lines: single agent of cabozantinib maybe in the range of 30%. So what we have until now is response rate and PFS rate but very intriguing findings. That speaks to the fact that maybe by inhibiting both the VEGF plus receptor plus a HIF-2α, meaning within the tumour, could be additive, I won’t say synergistic, but clearly the response rate is appealing.
JP : According with all these data that Laurence has mentioned, where do you think that belzutifan will play a major role in the future? In the adjuvant setting, in the first line, in favourable risk?
VG: That’s a good question. Maybe I’ll start off. What’s the strength of belzutifan? Its great tolerability and also efficacy-wise it does shrink the tumours in almost one quarter of the patients. So that’s a very good asset. Does it add something in the adjuvant setting? I think we’re exploring this and it is a principle that we should explore because it could have impact on disease free survival, I think that would be reasonable. This is where it plays out its strengths at the best, so tolerability and efficacy. In combinations, it’s a good combination partner because of that as well. So it becomes more toxic but more efficacious.
JP: Something relevant is that in all these studies we can see durable responses. In this subgroup of patients it could be interesting to have more information about them. Finally, just in time, we have data, preliminary data, from the new drugs like the MEDI5752, very interesting in the future, Stéphane, in combinations, for example, with axitinib or lenvatinib right now. How do you see this data that has been presented during this ESMO with this drug?
SO: First of all about the cabozantinib belzutifan in combination, I was very impressed about the fact that almost no patients had progressive disease. So it’s amazing if you look at the data, it’s very impressive so far. I would say that the goal for me for this combination would be to go for favourable group risk because I think that mostly is driven by, for 50% or 60% of the patients, [inaudible] and VHL. So that’s a point.
JP: Laurence, MEDI?
LA: MEDI5752 that got baptised volrustomig is an agent that is a bispecific antibody targeting both PD-1 and CTLA-4. So basically it’s one drug that is able to have a dual approach as we would have, for instance, with nivolumab plus ipilimumab but with more specificity in terms of biology. So the thing is how does this agent compare to nivolumab/ipilimumab? What we have until now is phase I and phase II data with different doses that have been tested: 1500mg, 750mg and 500mg. We saw at ASCO last year, back in 2022, the first results. What has been presented by Martin Voss this ESMO 2023 is about 32 patients treated with 750mg and 32 as well with 500mg. The key findings are great response rate, in the range of 45-50%, but looking at IMDC intermediate you are actually higher, almost reaching 60%. Bear in mind there is no TKI here, it’s just your bispecific antibody. The second thing is duration of response. It seems that this agent is clearly associated with a long-term duration of response. Because this is phase II data we don’t have randomisation yet so we don’t know how that would compare with our agents but, as you stated, this drug is currently being investigated in combination with lenvatinib. So there is a lot of enthusiasm to see a new PD-1 CTLA-4 mechanism of action because bispecific antibody coming, this agent will be developed further. It is indeed, for now, the very first results but we’re getting to a large number of patients with great activity. The safety profiles need to be carefully monitored. Bear in mind that those patients are being treated with a CTLA-4 in the long run, so this is very interesting.
JP: We will see, the toxicity.
LA: But nevertheless, the waterfall are extremely interesting and we wait to see more with this agent of interest.
JP: Yes, hopefully in the future we have another phase III study positive. So I think that’s all. We have covered the majority of the most important abstracts that have been presented during this ESMO in Madrid. Thank you all of you for your valuable insight and contributions. Thanks to the audience and thank you to the ecancer team for the organisation of this debate. Thank you.