Targeted and Immunotherapies for Advanced Renal Cell Carcinoma

Clinical implementation of targeted and immunotherapies for advanced RCC

Dr. Schlürmann
So hello and welcome to this podcast on clinical implementation of targeted and immunotherapies for advanced renal cell carcinoma. I am Dr. Friederike Schlürmann, a GU medical oncologist from the University Hospital of Brest and Quimper in France and a member of GU CONNECT. And I'm so delighted to be joined today by Professor Thomas Powles, Genitourinary medical oncologist at Bart’s Cancer Centre Institute, UK.
So Thomas, we've seen the treatment landscape for metastatic RCC changing a lot over the past decade. So current guidelines recommend for first-line advanced RCC include various combinations of targeted and immunotherapies based on the data from a number of key trials. Maybe you could start off by discussing a little bit about what these trials showed us.

Prof. Powles
Okay. I mean, that's a good place to start. So I think it's fair to say that in chronological order - and the reason it's relevant is these trials got the longest follow up - the ipilimumab and nivolumab study, CheckMate 214, was compared to sunitinib and this trial was positive for overall survival, which was one of the three primary endpoints. It was also turned out, in the end, to be positive for progression-free survival and response as well. But the reality is it's the overall survival data that's really impressive and that's largely limited to the intermediate and poor-risk population. So IPI NIVO (ipilimumab nivolumab), you know, something like a 30% reduction in the risk of death compared to sunitinib with five years follow up, with 50% of patients getting to about five years. There's a tail on the progression-free curve, so patients go into durable remission, and you know, particularly after the IPI NIVO phase, so the maintenance nivolumab phase, the ongoing quality of life is really good.

So that set a standard. And then there were a series of VEGF TKI-PD-1 trials, KEYNOTE-426, that is the AXI PEMBRO (axitinib pembrolizumab) trial, (CheckMate) 9ER that looked at CABO NIVO (cabozantinib nivolumab), and then the final trial is the CLEAR trial of lenvatinib and pembrolizumab, all of which were also positive for OS. And in fact, the OS hazard ratios are very similar across these different trials and indeed they're very similar to the IPI NIVO trial. And you've got lenvatinib and pembrolizumab, axitinib and pembrolizumab, and cabozantinib and nivolumab. These VEGF TKI-IO trials, they've got higher response rates. So,
their response rate tends to be between 60 and 70%, whereas IPI NIVO more like sort of 45%. So higher response rate and these VEGF TKI-IO combinations have longer PFS. And indeed, they seem to work, particularly in the initial cuts, well in good, intermediate and poor risk disease rather than just intermediate and poor risk disease.

From a tolerability perspective, I think they're a bit easier to give at the start. You know, I think IPI NIVO has got some challenges with immune combinations, but they're more challenging because you have to give chronic VEGF TKI therapy. So, I think it's fair to say that it’s swings and roundabouts from a toxicity perspective and because the follow-up isn't quite as long, it's also fair to say we haven't got as many durable remissions in these trials as we have in the IPI NIVO trial, which is also a fair point. So, I think in summary, IPI NIVO in intermediate and poor risk disease and then VEGF TKI-PD1 therapy in good, intermediate and poor. The three combinations we use, more similarities than differences from a VEGF TKI-IO perspective.

And then two quick caveats at the end, if I may. Number one is the most recent data for the VEGF TKI-PD-1 in the good risk population hasn't yet shown that survival advantage and I don't think it will in the future. I'm not sure. I don't know. But there's a debate about the good risk patients, which I think is an interesting one. And then the last point is the PD-L1 combinations have not been successful. So avelumab and atezolizumab have not been successful.

Dr. Schlürmann
So you talked about a lot of data that we have today, and I think it's pretty difficult for physicians today to choose between those combinations. So how do you choose what is the basis for you to maybe prefer a treatment to another? How do you choose?

Prof. Powles
I think this is genuinely difficult. The first question is, do you want to use IPI NIVO? Let's talk about the intermediate and poor risk, you've got four regimes to use. Are you going to use IPI NIVO or are you going to use a VEGF-PD-1? I think because the response rate for VEGF-PD-1 is higher, and the primary progression rate is lower, for those patients where you really feel you need to get control of disease - bone metastasis, aggressive liver metastasis - if you're really worried, you probably are better off with the VEGF TKI-IO combinations.

Dr. Schlürmann
I agree.

Prof. Powles
And I think that's a fair thing to say. And I think most people agree with that. There is some recent data from the COMIC 313 study, which I’m beginning to question the VEGF TKI in the poor risk population, but I think most people agree with that. I think you can't go far wrong by giving VEGF TKI-IO to everyone, in my opinion, although there are people, David McDermott, Hans Hammers, other people who say they want to give IPI NIVO to everyone, so that doesn't mean I'm right about this.

So, there's genuine choice, there are some intermediate-risk patients who maybe don't look like they've got rapidly progressive disease, who you can get away with giving IPI NIVO without that risk of primary progression and things, there may be subsets of patients, but it's probably easier to pick one regime or the other one.

Dr. Schlürmann
I think it's still a really difficult decision and it's for me, it's almost impossible to do that without seeing the patient and without discussing with the patient the different options that we have. And I can imagine for physicians that are listening to us today, it's kind of difficult too, because I think there are a lot of physicians who are afraid of the toxicity that comes with those doublets. So what could a physician expect as the toxicity from those doublets, IO-IO and IO-TKI? What do you see the most frequently with those doublets?

Prof. Powles
So Friederike, what I am saying at the moment. I'm saying pick one and use it well. And that's a phrase I'm using quite a lot. I was involved in the pazopanib sunitinib debate back in the day, and I probably got too involved in that. And actually, those drugs have more similarities than differences. And actually what it turns out was that many people were stopping the drugs early. And so actually education and training around how to give the drugs are much more important, and that includes patient training obviously. This is much more important than which regime you pick, in my opinion.

I think that the toxicity that you really do need to watch out for is particularly during the first 12 weeks for IPI NIVO, and that has to be immune-related toxicity, and almost anything can happen. And so, if a patient's coming in with a problem, you need to be on top of that and introduce steroids quickly, if in doubt, it's probably immune-related toxicity to give steroids under those circumstances. Wait at least two weeks until things have settled down after the steroids before reintroducing; otherwise, the problem's likely to recur. Make sure the patients are aware of the problems that may occur and also make sure that the nursing team and you have 24-hour support because the patient shouldn't be sitting at home for days with grade 3 colitis because they've got a hospital appointment in a few days’ time.

So that's what I'm saying for VEGF TKI-IO. Of course, the same rules apply for PD1 and VEGF targeted therapy because you can get, you know, grade 3, grade 4, dare I say it, grade 5, immune toxicity with a PD-1 and VEGF TKI combination as well. What I have noticed, with the exception perhaps of the LEN PEM (lenvatinib pembrolizumab) combination is we're seeing quite a lot of transaminitis with the VEGF TKI-PD1 combinations, and that requires attention.

It's possible, if you think it’s VEGF TKI related, it's possible actually, particularly with AXI PEMBRO, you know, grade 2 diarrhoea, not really sure, stop the AXI for a couple of days and see how you go. I wouldn't do that for, you know, if you got diarrhoea that's progressing over day three, I would then say, right, we need steroids, but it's okay with the AXI, particularly because AXI has a short half-life. It's okay to stop that and just see how you get on. Not in grade 3 toxicity, but in grade 1 and grade 2 toxicity because getting the dose right in the VEGF TKI is really important.

My opinion of lenvatinib at 20 milligrams, it’s quite high and most patients in the study about 75% had to dose reduce. But then lenvatinib does have the highest response rate. Axitinib is probably the easiest drug to give, you know, it's the shortest half-life, you can almost dose escalate, and you can reduce. And of course it's worthwhile mentioning the cabozantinib started at 40 milligrams, not the standard 60 milligrams and still got great results. And the quality-of-life data for the CABO NIVO trial, experts like David Cella tell me it's the best quality of life data of those.

So I think each of those three regimes, I've come up with a reason why you might want to give it. And again, you just I guess you need to pick as a clinician one of those and go with it.

Dr. Schlürmann
I don't know how you do it in your centre. I'm pretty blessed that in my centre we have a lot of resources to manage those patients. We have specialised pharmacists to see my patients to see if there's no interaction between the drugs that they already have. And we have a lot of nurses who can call the patient. We have applications. We are really lucky. We can do a lot to be there for a patient with all the staff that we have. I don't know, I would be interested to know how do you do it in your centre in the UK?

Do you have all those people around you to help you to guide the patient like nurses and pharmacists, things like that?

Prof. Powles
Don't give up your job and come to the UK anytime soon! Yeah, I think that there's lots of reasons not to do that, but it sounds to me like you're really well-resourced. You know, I think actually we're quite well-resourced at our centre, all joking aside. We've got some terrific specialist nurses. We don't have pharmacists in clinic, but I think we should, other teams at the hospital do. But I think we're quite well-resourced. We've got quite a big trial team. So we've got quite a lot of doctors and clinical fellows and a lot of our patients on trials, and they have clinical trials practitioners who they can phone as well. So, you know, we'd like each patient to have one or two telephone numbers. We'd like a big multi-disciplinary team to be seeing the patients and being involved in their care. And I think that's really important, you know.

I also think we've got to a position now where the emergency departments are no longer thinking immune therapies, chemotherapy. You know, there was a time about four or five years ago where you pitched up on pembrolizumab or nivolumab or atezolizumab and you got I.V. antibiotics if you weren't feeling well and had diarrhoea. I think we've moved away from that now, which is great. So there's some primary care education which is super important, and patient education is important, too.

Dr. Schlürmann
Yeah, I think it's a big challenge to teach all the staff of a hospital for those kinds of drugs. And it's a big challenge to teach your patients, and that's really a big part of it. For me, it's like one of the biggest because it's the patient who is going to alert somebody, the patient who's going to come into the emergency room and the one who can give the information of what treatment he's on. That's really important. But I think we're lucky. You're lucky, and I'm lucky that we have all of this. So, I always try to think about what we could do to help practitioners who don't have all those resources to still be able to give the doublet therapy, which is now for me, the standard for intermediate and high-risk patients.

So I don't know if you have any idea, but I think it's really difficult to help those practitioners because they don't have as much time and as much staff to still be able to prescribe a doublet therapy and do this in a secure way. What are your thoughts on that?

Prof. Powles
I think is difficult as well. I mean, what I say to my patients, particularly during the first 4 to 6 weeks of therapy when there's an oral targeted therapy, not the IPI NIVO regime, I say, listen, the first four or six weeks is a bit of an experiment, and you won't be taking the tablet every day.

Dr. Schlürmann
That’s funny because I say the same thing to my patients. I always say it's going to be like a little bit rocky and rough two months, round about. And after that, normally it should be easier.

Prof. Powles

It's probably the case that if you're not seeing large numbers of patients, it's probably a bit easier to give the VEGF TKI-IO, IO-IO combinations. But I think from a patient perspective, it's nice to be on single agent nivolumab after 16 weeks. I think it's a nice thing. It is swings and roundabouts. We need to be very careful about that issue. I think that if you've going to give IPI NIVO, you need to be working somewhere which is
comfortable with that immune combination. It's obviously given a lot in melanoma. I don't think it's given that much outside of renal and melanoma. I think there were some studies where it's statistically positive, of course, but I think chemotherapy plus immune therapy in lung cancer is the standard. It's not the standard in bladder cancer. I don't think it's a standard in the GI cancers, although I think DURVA TREME (durvalumab and tremelimumab) just got a license somewhere.

As a rule, if you're not treating large numbers of patients and you're hospital’s not giving a lot of immune combination therapy, PD-1-IO might be an easier thing to reach for, but I also feel that and I know many colleagues of mine would say there is a really important role to play with immune combination therapy, but you don't have to give it in kidney cancer, right now. So, I probably would say you might be better off, and I think clinicians who are happy giving VEGF TKI therapy may find it easier to switch from VEGF TKI to VEGF TKI-IO than IPI NIVO. That doesn't mean that's the thing I think you have to do. I'm just saying in practical
terms, if you're seeing one or two patients a year and your site's not set up to give IPI NIVO, that might be an easier approach.

Dr. Schlürmann
Yeah, you're so right. I think one of the most important things about all of that is that you have a learning curve. And we are all able as an oncologist to learn and to get used to those drugs. It just takes some time. And maybe you should not be afraid of asking help from other colleagues who do it a little bit more often and try to get used to these drugs and not to not prescribe them, because we still have patients, and I still see patients sometimes who are on monotherapy, which is kind of sad for the patient because I think they should get a doublet. But I think it's manageable, like you said, but you have to maybe stick with one combination and just do it good and well and know what you're doing. I think that's the right thing to do and to say.

So thank you so much for that discussion. So could you just summarise maybe all of that, what we said today about like first line treatment of renal cell cancer and maybe just like a quick word on what you think is going to happen maybe in the next months and years? How all of this is going to develop? What do you think about all of that?

Prof. Powles
Well, I'm very happy to have a quick stab at that. And then perhaps I'd be really interested to hear what you think as well. I think in summary, I think what you said is correct is that the
PD-1 combinations have superseded single agent VEGF TKI therapy, particularly for intermediate and poor risk disease. And I think that there are four options ipilimumab and nivolimab, IPI NIVO of course, and then three VEGF TKI, PD-1 combinations. The first was actually AXI PEMBRO, the second CABO NIVO, and the third lenvatinib and pembrolizumab.

I can make an argument for giving all four and I'm currently saying pick one and use it well. I think we've discussed how important it is to have allied healthcare professionals involved in the management and how important is that the patient to what well informed to maximise efficacy and minimise toxicity.

I think in terms of looking to the future, we've had the recent COSMIC 313 data. I think we're going to need to see an overall survival signal before triplet therapy changes practice, that's the first thing I'd like to talk about. The second thing is we've also seen some phase 2 belzutifan data but we really need to see some phase 3 data before that becomes standard of care.
I think the future of that drug is in combinations. And then the last thing I think I'd like to say is we haven't seen enough of the biomarker data in advanced disease yet, and I'd like to see some attempt to select patients, particularly for that question around immune-immune versus immune-VEGF therapies. And that's going to be really important. We haven't done as well as I'd like in biomarkers in kidney cancer and we should I think have done a bit better.

We didn't do a great biomarker with sunitinib and pazopanib. But at the moment we're not doing great biomarker work yet, although there is some really nice exploratory data, particularly actually with the PD-L1 inhibitors. There was a Nature Medicine publication and a Nature publication for atezolizumab and for avelumab, which are PD-L1 inhibitors. So let's have a look and see some more PD-1 data for the future. What are your thoughts? What do you think's going to happen next?

Dr. Schlürmann
Yeah, I think it's so true what you said. I think right now the challenge for me and for most of the physicians is really to get the doublet into clinical practice everywhere so that we don't lose our patients like with a monotherapy. This is kind of a thing still today if you look at the data. And for me, the biggest question will be then what we do after that. And you talked about the belzutifan. So we're really waiting for those trials with that drug that it seems to be amazing and it could be for us really a solution after the doublet therapy, because this is for me right now the biggest problem. What do we do after the doublet therapy, so I’m eagerly waiting for those phase 3 trials to help us to know what to do after the doublet therapy. I think that's really the biggest question for me right now.

Prof. Powles
I think that sounds pretty sensible to me.

Dr. Schlürmann
So thank you again. That was really nice talking to you, having this overview about RCC, and thank you to our listeners, and we hope you have found the discussion useful and that you like to listen to us today and maybe we'll see each other again another time. Thank you so much, Thomas.

Prof. Powles
Thank you very much.