Best practice in the treatment of patients with mRCC

Prof Jens Bedke - Tübingen University Hospital, Tübingen, Germany

Prof Thomas Powles - Barts Cancer Centre, London, UK

Prof Michael Staehler - Ludwig-Maximilians-University of Munich, Munich, Germany

Dr Wenxin (Vincent) Xu - Dana-Farber Cancer Institute, Boston, USA

JB:    Dear colleagues, a warm welcome here from this ecancer educational round from the ASCO GU in San Francisco. Today’s topic is the changing landscape in the treatment of renal cell carcinoma. My name is Jens Bedke from the Klinikum in Stuttgart and Eva Mayr-Stihl Cancer Centre in Germany. I’m happy today to introduce my colleagues here for discussion: Professor Tom Powles from the Barts Cancer Institute, to my left, Professor Wenxin Xu from the Dana-Farber Cancer Institute and Professor Michael Staehler from the University of Munich. So welcome today.

TP:    Thank you.

WX:   Glad to be here, thank you.

JB:    So let’s start. We got a lot of abstracts which were presented as poster and oral presentations at this year’s ASCO GU and we got an update or updates for the TKI/IO combinations and the IO/IO combinations from CheckMate 214 but also from the CLEAR trial and from the CheckMate 9ER. Tom, are you happy to take the first question? So, if we refer to the TKI/IO combination, was there anything striking for you that will change practice or will give you new ideas in the treatment or treatment selection of patients?

TP:    Thank you for inviting me. Firstly, I think it’s fair to say that these trials, these VEGF TKI/IO studies, are all PD-1 based and there’s cabo/nivo, len/pem, axi/pembro. Those three combinations, like the Voyager space probe, it goes further and further out and we get updates coming back to us. But many of those updates are very similar to what we’ve seen before – the response rate and the progression rate are very stable actually. The key question is around the overall survival signals and the key question is is that survival signal being maintained, is the survival advantage more powerful at the start and is subsequent therapy rescuing some of these patients. There’s a debate about that and whether or not ipi/nivo has better longer-term survival and whether the curves stay apart. My opinion on this is well documented is that actually there are more similarities than differences between these datasets. The landmark analyses look very similar and all four combinations are really attractive and we’re lucky to have those and this cross-trial comparison is pretty unhelpful. One of the data that is being presented here is the CLEAR data which Viktor Grünwald is presenting from Germany. He is looking at different sites of disease and whether or not there are different responses in different sites of disease and whether the benefit from lenvatinib and pembrolizumab is across the board or just in some subgroups of patients. It’s exploratory; I think it’s an okay analysis, personally I don’t think it’s practice changing. Essentially it shows that lenvatinib and pembrolizumab, we know it’s a correspondence rate of 70% and it remains very active across the board, it doesn’t seem to be particularly more active in one group than another. Lymph node disease, it’s obviously easier to get responses in that population than bone metastasis. From my perspective it just reinforces that VEGF TKI/IO is slightly better at getting initial control of disease and that is one of the reasons why many doctors use it.

JB:    These abstracts of the different baseline RECIST diameters and the efficacy and the quartiles, first quartile, second, third and fourth quartile, whether it’s active irrespective of the tumour load. But, on the other hand, we saw a little bit that the higher the tumour mass and the higher the tumour burden is, that efficacy is less pronounced if compared to lower tumour burden. Maybe, Michael if I ask you, what does that mean for cytoreductive nephrectomy? There were also abstracts on that timing of cytoreductive nephrectomy. How is the role, how big is the role while decreasing the tumour load, the tumour mass, what is the timing?

MS:   So we have seen some interesting data but what we have got to admit here is that it’s all retrospective post-hoc analyses, it’s not really something where we learn from a prospective, nicely set-up trial what to do. One thing that turns out is that cytoreductive nephrectomy is an option in patients but we still don’t know whose patients are going to benefit from that. Years ago we were all believers in cytoreductive nephrectomy, no matter what. What we have learned now is that we should be a little bit more cautious in selecting patients towards those big surgical procedures in the metastatic setting of patients. We still haven’t understood who is the one who is going to benefit from it but what we do know is there is no downside in waiting for that decision and not rushing into the OR with each and every patient who is metastatic at the initial diagnosis.

JB:    I think you are a urologist so that’s a urologist’s perspective. Wenxin, what do you think, as a medical oncologist, of the role of reductive nephrectomy, also basing it on the new data which you’ve got? It’s retrospective, we’ve got other data for the IO/TKI combination, despite the fact of the CARMENA trial.

WX:   The takeaway in the immunotherapy era is that absolutely we have to be selective about which patients we take to nephrectomy. I think there is a role for nephrectomy still in highly selected patients. As you alluded to, years ago the CARMENA trial showed that in the Sutent era, whether you did a reductive nephrectomy up front did not improve outcomes for those patients for overall survival. Nonetheless, now with more data we’re learning that, at least in the retrospective literature, there do seem to be subpopulations of patients carefully selected who might benefit from tumour bulk reduction. We learned from the CLEAR update that patients who have these large, bulky primary tumours are unlikely to get a complete response from lenvatinib and pembrolizumab which is not surprising, given how much tumour is there. Perhaps some of those patients may benefit from a consolidative nephrectomy. We also have multiple ongoing prospective trials that are exploring this question. So trials, for example, like the PROBE trial being run through the cooperative groups, may end up giving us some prospective data in the immunotherapy era for the question that was previously asked by CARMENA.

JB:    I’ve been going a little bit back to the old question – we have four TKI/IO combinations and we have the ipi/nivo combination. We also saw data for triplets, not at this ASCO GU, from the COSMIC trial. And there’s the old question which regimen, which doublet, do we choose? We had three abstracts here at this ASCO GU comparing a matched indirect comparison of lenvatinib/pembrolizumab but also a network analysis comparing these four TKI/IO combinations with the ipi/nivo combination. Wenxin, for you, was there any new data from this, anything which said that this was favouring one or the other direction, or is it just more confirming of the efficacy results which we already had? I know it’s an indirect comparison but these abstracts tried by statistical methods to overcome this bias. So what do you think? What is your opinion based on these abstracts?

WX:   It’s a really challenging question. These trials, when we’re thinking about these immunotherapy doublets, they all had excellent outcomes overall. That’s really the key point. They all clearly show superiority for progression free survival and overall survival in the intention to treat population compared to sunitinib. It is important to do these post-hoc analyses but they must be taken with a grain of salt. What we see, though, is that this confirms the observation that IO/TKIs have very high upfront response rates, excellent tumour control rates. When you compare IO/TKIs against each other you have to be very, very careful because it’s not the same underlying trial population, despite the best statistical methods. Nonetheless, lenvatinib and pembrolizumab clearly continues to have a very high overall response rate and disease control rate. Not to be underestimated is cabozantinib and nivolumab and axi/pembro still, for their respective trials, show excellent outcomes. Ipi/nivo, it’s clear, has a lower upfront response rate and also has the longest overall survival follow-up and there’s something to be said about that.

JB:    We have the data from each trial as its own and we’ve also got an update from the CheckMate 9ER with a longer follow-up at this ASCO GU meeting. The data is what we expected, showing the benefit of cabo/nivo over sunitinib in terms of efficacy, PFS, response rate but also overall survival. But there was a small ‘but’ and still in the IMDC favourable risk group there is no overall survival benefit for the TKI/IO combination, what we also learned from ASCO last year and previous data releases from CLEAR but also from KEYNOTE-426. So what is in the favourable risk group, especially if we have a look at the CheckMate 214 data which presented the longest follow-up? They showed that with a longer follow-up that the immune-based combination seems to be more beneficial, also with an overall survival benefit. Maybe Tom I can ask you – what do you think about the CheckMate 214 data, the longer follow-up and with regard to the favourable risk group? Has that any impact on the TKI/IO combinations?

TP:    The reality is, with this eight-year follow-up data, the hazard ratio for ipi/nivo is less than 1.0 versus sunitinib and the VEGF TKI/Ios with their most recent hazard ratio were all above 1.0. Now, don’t get me wrong, they’re all the same as far as I’m concerned, they’re overlapping and it’s all the same number. But we haven’t clearly beaten sunitinib. I did a satellite symposium thing yesterday where people got really upset with me because I said sunitinib is actually a standard of care in good risk disease. It has not been beaten for overall survival and it’s clear that if you sequence immune checkpoint inhibition afterwards you’re going to rescue a lot of those patients. We had high responses, yes, you’ve got a higher PFS, but if you’re not translating to better overall survival it suggests to me that there's something going on that’s not quite right in that population. So we have to ask that question and ipi/nivo, I accept at the beginning of the journey the data looks inferior to sunitinib and that’s why it wasn’t approved. But now in our good risk population, with very few events, by the way, because the Kaplan-Meier curves are good risk, there may be a tail on that curve and it might be that up-front immunotherapy is actually really important in good risk patients. So I think it’s confusing; I think it’s wrong to say, ‘I know the best treatment for good risk disease,’ and I think that I would be happy to take almost any side in this debate as it currently stands. My position on that has changed. So if you go back to videos last year and the year before, my position has changed because the data has changed and therefore my position has changed too.

JB:    No, but I think it’s coming back to the individual patient selection. To summarise that, maybe we’ve got a new or more options to choose from.

TP:    Can I interrupt? So the one thing I would say is I don’t love the IMDC classification. I think what that highlights is that that classification is not helping us that much. I love it for prognostic effect but I don’t love it for picking patients for therapy. And that’s quite important. And this is highlighting to me that we may be going in the wrong direction by using this prognostic indicator that was designed accurately by Danny and friends to define patients who would do poorly – very important for patients and families to know you’re going to do poorly – it was never designed to pick patients for ipi/nivo. And as it currently stands I don’t think it does that very well.

JB:    Okay, but before we go too much into detail of prognostic factors of the IMDC and maybe make the switch to the monitor heterogeneity and the different profiles which are underlying behind that. Let’s go to a new classification. There was one abstract, also if I address that to you, Tom, but maybe also to Michael, of new questions for the quality of life which was developed by an expert panel in alignment with patient advocates. What is new, what is the importance? There were two or three new items which were proposed for the quality of life assessment.

TP:    It’s Chris’s work, it’s fabulous work, she’s doing an amazing job. A lot of these quality of life questionnaires were 30 years old. They’re validated but they weren’t validated for VEGF TKI therapy or immune therapy or the combination. What she has done is she has asked patients on therapy what they think of the questions they’re being asked. As it transpires, patients are saying they’re being asked too many questions too often, that’s the first thing. But also it transpires that, for example, haematuria is not relevant to someone who has had a nephrectomy. If you look, the patients say, ‘Yes, that’s not relevant, not relevant,’ but actually when it comes out of the large number of questions, only about 20% of the questions patients feel are relevant. So her point is let’s ask patients more detailed questions that are relevant to them because, number one, it’s easier for them, number two, we’re going to get better answers. The point that she’s making is that if you ask a whole series of irrelevant questions it will always go back to the null hypothesis, so there’s no difference between the two. So if you give patients really toxic chemotherapy and ask is haematuria relevant in quality of life, the answer is going to be no, so the stand-up is then quality of life is the same but it’s not the same because we asked the wrong questions.

JB:    We all know about this ridiculous question of haematuria in patients… of haematuria, of haematuria, of haematuria… Michael, what is your point on the quality of life and the improvement we need for the questionnaires and for the assessment and patients with metastatic disease?

MS:   I’m on Tom’s side here, I think reducing the number of questions that we ask within a clinical trial is helpful because we’re really overwhelming patients with 46 different questionnaires, they fill them out for hours before they even see a doctor – they’re not interested in that. It’s helpful for reducing administrative load in a clinical trial. Does it tell us about the patient? No, it doesn’t. We’re not asking the questions that are relevant to the patient, we’re just looking do we actually check the box on quality of life settings within a clinical trial. It doesn’t really inform us about the situation the patient is in; it doesn’t inform us about have they lost their job , are they struggling to take their drugs, what is their daily impact that they have from all these side effects and stuff? What are they really going through? But, on the other hand, it streamlines what we’re doing and we get a faster, easier, informed consent to approve drugs, not to actually manage therapy in an individual.

JB:    We’ve discussed a lot about the first-line treatment of the IO-based combination trials, of the quality of life. There was another abstract of the LITESPARK-005 which introduced a HIF-2α inhibitor, the belzutifan. We knew the data from last year’s ESMO congress, that was the primary data release, and we’ve now got the quality of life data. Wenxin, belzutifan is approved by the FDA so you have more experience than us in Europe for that drug, what is the importance? What is new from the data? What will change for you in the practice and the use of belzutifan?

WX:   Absolutely. What LITESPARK-005 showed us is that belzutifan is superior to everolimus for progression free survival. Not a surprising result – everolimus is a very weak comparator arm. But the quality of life is, in a way, just as important because what we saw from that trial, and this bears out in clinical practice, is that belzutifan for many patients is a much easier drug on quality of life than the third or fourth TKI. Oftentimes what we see is patients who have had multiple TKIs can really be worn down by the mucositis, fatigue, diarrhoea, weight loss. Although it’s not known, based on the data, whether belzutifan is going to be superior in the refractory setting to other TKIs like tivozanib, for example, what is clear is that many patients feel better after the switch to belzutifan. This is really, really important to patients because it lets them do things that they haven’t been able to do for a long time on their TKI. So with the FDA approval this is a good option for refractory patients and we are using it.

JB:    There was one interesting aspect in the abstract on the quality of life, the duration over the time that after… I think it was week 17 that the quality of life remained stable on the belzutifan while there was still a decrease of the everolimus. Is that related maybe to the mode of action of the drug, that if you have been on the drug for a longer time that you have no deterioration, that it seems to be stable, no decrease in quality of life?

WX:   I think so. I think that is a significant component because what we see with belzutifan, and this is different from what we saw with the TKIs, is that in someone who is on belzutifan and has anaemia or has mild anaemia, let’s say, and has no hypoxia, whatever their side effects are they’re not likely to get much, much worse in month four or five. Whereas for the TKIs, oftentimes the side effects are more cumulative over time. So while not everyone responds to belzutifan, the overall response rate is in the low 20s, patients who do respond and get lucky may have good disease control with no deterioration of quality of life for a long time.

JB:    Thanks. Now, having discussed first and second and late line settings, going a little bit back to the adjuvant space. We all know that we have pembrolizumab which is approved based on the KEYNOTE-564 data and we here got the OS data at this year’s ASCO GU which is significantly improved by pembrolizumab based on the KEYNOTE-564 data. Michael, you have a long experience in adjuvant treatment and trial participation dating back to the sunitinib/TKI era, now to the immune checkpoint era. What has changed with this overall survival improvement, the significant overall survival improvement? Is there anything that changes for the clinical practice for the IO adjuvant therapy?

MS:   I do think it has a huge impact because we always wanted overall survival for adjuvant therapy and now that we have it we’ve fulfilled our criteria that we wanted to see to use adjuvant therapy in patients who are at high risk of recurrence. That so, I just want to put a caveat on that because we still haven’t figured out who are the patients who will benefit from that therapy. We’re still struggling with that a lot. None of the trials are really comparable in terms of selecting patients, in terms of further management after progression, so it is a little bit hard to understand. The majority of the patients are not going to benefit from the therapy if we go by the criteria used in the trials because they don’t recur. So we have now a job to do and that is to identify those patients at need for adjuvant therapy. Keep in mind, a patient with a 1cm mass who just had a diagnosis of cancer is like, ‘This is high risk. I’m going to die from cancer.’ So the perception of the patient is always, ‘I am at high risk,’ and we might say, ‘No, you’re not,’ and to even that out is going to be a problem in the future that we have to face. We’ve got to address that.

JB:    Thomas, what is your impression from that data? We know that KEYNOTE-564 had different risk groups – the intermediate, high risk groups which was the majority of the patients, 86% of the patients were in this group. We had the high risk group and we had a new class, the M1NED group, after metastasectomy, patients who already had metastatic disease who underwent metastasectomy who had no evidence of disease. Are these three groups of importance with regard to the overall survival improvement? Does that help to make a patient selection? Does that answer the question of early treatment versus deferred treatment, treatment when metastatic disease is present? With these new data from the overall survival improvement.

TP:    So, significant overall survival benefit in the adjuvant pembrolizumab trial, hazard ratio of 0.62, the first OS significant result we’ve had in kidney cancer. When actually you look across the board in the adjuvant setting there aren’t positive adjuvant trials for immune checkpoint inhibitors in other cancers like bladder cancer, for example. So this is really important, for me it’s the most important data at this meeting. It reinforces Michael’s point, it underpins the reason we’re doing it. Why are you doing it? To make people live longer or feel better, that’s what we’re trying to do, everything else is kind of periphery from the patient’s perspective and this is making people live longer and that’s important. For me, DFS in adjuvant trials is always a surrogate for OS. I’m not a great believer in saying it’s a DFS therefore we should be giving everyone adjuvant therapy because Michael’s point is right – we’re overtreating half the patients, they don’t need therapy, they’re not going to relapse. Yes, of course we should do work to try and identify who those patients are and find that at risk population, but if you are treating unselected patients I think you need OS and that’s what they have here. Now trending towards OS, if it’s trending towards that way then that’s great and we hope we’re going to get there and that’s what’s happened in this particular trial. In terms of the subgroups, the M1NED population is only 6% of patients and when you look at the subset Forest plot you can see the OS benefits across all the other subgroups. So I don’t think it’s being driven by one of those particular subgroups. I think it’s intriguing that some of the other trials are negative, particularly the nivolumab study in this space. You can’t really pool all these trials together unless you know they’re all the same and therefore from a patient’s perspective this makes adjuvant pembrolizumab more attractive for this subgroup of patients.

JB:    Thanks a lot, and I think you pointed out it’s one of the major results from this ASCO GU congress, seeing the data for the overall survival from KEYNOTE-564 which really points toward what you said, we had the DFS as a surrogate and now we have the overall survival data which is a significant improvement across all these subgroups. Well, it was my pleasure to have this discussion with you today on renal cell carcinoma and I thank you very much for your attention.