The Uromigos Episode 147: Toni Choueiri Renal Cancer Christmas Special

Tom and Brian take a look back at the year in kidney cancer with Dr. Toni Choueiri.

Episode Transcript

Tom:
I’m joined here with Toni Choueiri and Brian, of course. This is the final Christmas podcast, the Kidney Cancer Podcast. Both previous ones have been relatively good.

Toni Choueiri:
Relatively.

Tom:
Well, I say that. I mean the first one we’d had some issues and so did the second. In previous years I fell down the stairs in a pub with Matt [inaudible 00:00:43] so it was better than those. So, we’re expecting great things from you Toni, of course. But the 1 thing I do also want to do today is give you an award for, this will be the highlight of your career so far, the most popular podcast of last year.

Toni Choueiri:
Are you kidding me?

Tom:
We normally get a handful of listeners predominantly from friends and family but your Clear trial, the Clear one that we did with you last year got 2000 listeners, about 2000. And I’ve assumed there’s some sort of Ponzi scheme where you’ve got someone on complete redial. So, I just wanted to check with you there was no foul play. It’s only to make sure there no foul play there.

Toni Choueiri:
No, I think what happened, which we have to say it’s in the holiday spirit, we have to start clean. Brian and I sent it to our fellows and made them listen to it 24/7.

Brian:
A thousand times.

Toni Choueiri:
I’m sorry to tell you that but I’ll get the award.

Tom:
Well Tony, I’m not surprised because I went back to listen to the podcast a few minutes ago and I did perhaps the rudest introduction I’ve ever done.

Toni Choueiri:
Exactly.

Tom:
And then Brian …

Brian:
That’s saying a lot.

Tom:
I’m very critical about the pronunciation of how you pronounce your surname.

Toni Choueiri:
I lived in France for 15 years.

Tom:
Very rude about that. And then this was followed by a comedy of errors. I got confused between OS and PFS. You misquoted Churchill at one point. And then when I said, we didn’t know the right dose of Lenvatinib, you came back and said, I didn’t know the right dose of Sunitinib, which I thought was extremely rude.

Toni Choueiri:
And then people were listening it’s like, “If these are the experts, oh wow. Let’s move somewhere else.”

Brian:
It’s more entertainment than information, Tom, if you haven’t figured it out by now.

Tom:
Well, Toni, I have to say congratulations. It was by far the most popular one we had.

Brian:
Was this the Clear trial, Tom? The Clear one?

Tom:
Yes, it was.

Brian:
I’m looking at it right now. 1,680 listens.

Tom:
Yes, how many was it?

Brian:
1680.

Tom:
Wow. That is amazing. So that’s fantastic. Look, Toni, so let’s talk about kidney cancer this year. Number one is, what do you think is the biggest advance in kidney cancer this year?

Toni Choueiri:
I mean, I think I would divide this into 2 categories, the clinical trials and then what happened in the lab. Clinical trials, we’ve seen trials that started actually in 2020 and publish in 2021, the combination. So, we talked about Clear, we talked about 9-ER. I mean, these are 2020, 2021, if you want, but published in full format and these are the most recent combination. And I would say the next generation combination although, in this regard 9ER OXC and PEMBRO.

And on the other hand, is the adjuvant studies. Certainly, the adjuvant study with PEMBRO is the first to read and certainly met its primary endpoint and it’s going to be more important in the next couple of years when overall survival is going to read. So that’s one, the clinical. And second …

Brian:
Toni.

Toni Choueiri:
Go ahead.

Brian:
So, let’s stop on adjuvant for a minute. So how are you applying this in your clinic now? Are you giving it to everyone? Are you giving it just the higher end of what was enrolled in the trial? How are you selecting patients, I guess is the question?

Toni Choueiri:
Yeah, no good. It just got approved, I believe. Not a long time ago in November. First of all, what I noticed in uptake in referral because many of our urologists or our patient reading the news, look there could be something in addition. So, our practice even starting since ASCO picked up and this is the honest discussion with the patient based on … I show them, I have my laptop usually in the room and I show them the curve and I go through explaining the forest plot and who could benefit and not benefit. I am not giving it in patient that don’t meet the eligibility criteria of KEYNOTE 564 but you know guys very well that the approval came in a more general way.

Tom:
Can I ask a question?

Toni Choueiri:
Yeah.

Tom:
Are you, how so … I agree with what you said. I think with the data we have, it’s effective across broad subgroups of patients. So, there are 2 questions. The first is, are you picking patients? And the second piece, which is really important is how strongly are you recommending it to them? Because clearly you can sit down with patients and in the end, you said, “You should definitely have this.” And on the other hand, the other extreme. You can say, “This is an option available to you.” It’s got lots of side effects and it may or may not have OS.

And clearly if you pursue the first approach, “I’m an expert in the field. You should definitely have this.” 90% of patients will likely go with it, with your view, maybe not with me. But in the other extreme, when you said, “Listen, take it or leave it.” You’re probably more like 50/50. So, I’m actually not interested in the population because I think the population in the forest plot doesn’t really put out groups, particularly, I’m more interested in how strongly you’re selling it to your patients.

Toni Choueiri:
Well, luckily, I’m an expert in the field that doesn’t know how to dose Sunitinib so take that with a grain of salt. But I think I am my own thing, how I’m not an extreme in anything in my life. So, I’m always somewhere discussing it with them. So, the other day I’ve seen a 40-year-old man with stage 3 B who came to me, and I think here it’s devastating for this man if they progress in the next couple of years. So, this discussion will be different than another consultation my colleague had on an 83-year-old man that came to them, a lot of comorbidities who had the same actually profile even with a bit of sarcomatoid features.

So, it’s a bit of a different discussion here and I think we are going to refine that in the future because the approval came irrespective of the histology. So, imagine seeing a person in your clinic that has a chromophobe kidney cancer, which we know at least in stage 4, doesn’t respond much to immune checkpoint inhibitor and who come with an M1 and N3, 3 years after, 4 years after initial diagnosis. The 1 -year cutoff we used in 564, there is nowhere to be seen in the FDA approval and this is going to be a bit more challenging.

Brian:
So Toni, how would you handle non-clear cell then? I mean, it’s an interesting point and as you say, chromophobe not as responsive, papillary more so. So functionally in the clinic, you see a high-risk patient with papillary, are you giving them adjuvant PEMBRO?

Toni Choueiri:
Yeah, well we had a discussion in our group growing a lot of experts. We are now at 25 oncologists, and we don’t agree, and many may not agree with my approach but in someone who’s really young, willing, no co-morbidities, based on Keynote 427 with Dave McDermit and the front-line activity that we’ve seen mostly in papillary and unclassified. If you have to pick 2 histologies it’s these 2. And if you want to pick a histology that doesn’t respond, it’s chromophobe.

Anything in the middle like translocation is in the middle. So, I have someone who had papillary high grade lymph node positive, resected, mid-forties and I offered it. I said, “Look, this is the situation. I am going to offer it to you, and I had someone even in my group said, “Well, you said you want to go through KEYNOTE 564, why don’t you wait until this patient has metastatic disease?” The issue with these high-grade papillary tumors, when they have metastatic disease, I’m not sure how I’m going to salvage them and with what. So, I offered this patient with a grain of salt and the insurance covered it.

Tom:
It seems to me that that’s living somewhere near Alpha Centauri compared to where we are in Europe at the moment. We are having a pretty active debate about whether actually we’ve bought into the primary data in the clear cell and the reason why that’s the case is, we are not yet sold by the overall survival signal because it’s not yet statistically significant, although it has gone apart.

Brian, you and I have had this terrific meeting in the Canary Islands recently where you said that some of the things that I was saying around the survival signal was inconsistent. What’s your current opinion on the survival signal, these early signs pointing us in the right direction, giving patients hope that it’s the right thing to do. So, my current position is, you need to have something from a survival showing it might be going in the right direction. My nervousness is when there’s no survival at all or none presented, you can’t say to patients, “Look we’ve hit PFS. We think it’s a marker for OS and everything points us, at the moment suggests that’s the case from the data.” That is the case from 564 and that’s why I supported it. You disagree with me a little bit about that position.

Brian:
You’re asking me? I think we just don’t know. I agree the curves are starting to go apart, but it’s so few events we just don’t know. Tony, the question I was going to ask you is, let’s say survival doesn’t come back positive. I mean, I hope it will. Of course, I think it will and then I think that’s sort of the end of the discussion but what if it doesn’t for some reason? What if the early signal was all those sorts of nasty sarcomatoid patients who benefited from PEMBRO and obviously not from placebo but it’s going to level out over time and not be significant. Will that significantly change your use, or no?

Toni Choueiri:
It may, yes. Of course, they will be a group like the sarcomatoid M-positive. If you look at some of the data, we presented at the plenary at AUA, grade 4 benefited more than grade 3, N-plus benefited more than N-negative so I will be selecting more patient. However, I agree with Tom. I am quite optimistic that the survival benefit will be reached. Why is that? If you look at S-TRAC and Assure, those adjuvant Sunitinib and Axitinib trial and you put the 2 -year OS and you just glance at the Kaplan Meier curve, there was really no separation.

And here after 1 year, you see the clear separation and the hope here is that we will not wait a lot. Tom and I who are very much involved in the study, we can tell you we are pushing as much as possible the statistician, as you know it’s a landmark, event driven analysis. And we say, “What about giving a year of follow up just in case?” And of course, we know that’s not the most crucial way to do it, but we really want a bit more follow-up just to see how things go. Because you know very well that even with 6 months or 12 months more follow up than the 24 months we had, you can still look at events very well. That’s where all the events, most of the events will come. So, let’s hope so.

Tom:
Toni, last question for me, how much of this is being driven by the M1 NED population? How much will benefit?

Toni Choueiri:
I think some but definitely not a lot because it’s only 5%. If you take out the M1 NED, the confidence interval is still less than one.

Tom:
What percent of patients do you think will get life changing toxicity from a year of adjuvant PEMBRO?

Toni Choueiri:
A minority, 7%. I would say these are the patients that were steroid, so 7% and some of them were reversible. I’m worried about the patients we are going to give them diabetes knowing that there is a treatment for that if the price is curing their disease. We don’t know today, but if we believe the data in other malignancy and in metastatic disease, immune related adverse events tend to be associated with better disease control. I had a patient who had actually a hypophysitis cancer didn’t come back and is on replacement steroid. And this patient has a somewhat normal life, except when they have to have a surgical procedure or when they’re sick, have the flu or anything else, they have to increase their steroid intake.

Brian:
Tony, last question for me. What do you think of the ESMO guidelines around the M1 disease for adjuvant PEMBRO? They basically recommended against it because they don’t think these patients should be getting resected if I have it right, Tom.

Tom:
No, we’ve given it actually, a 2B recommendation, which is less strong than the 1A recommendation and we’ve recommended against doing surgery within the first year. But we have recommended for giving PEMBRO if you did give surgery. So, if you find yourself in the unusual position where you’ve done it …

Brian:
So, follow half of our guideline, but not the other half.

Tom:
That’s exactly right. In 5 years, you’ve here, which you shouldn’t have done then this is what you should do, which has caused a bit confusion. I agree but I’m still supportive of it.

Toni Choueiri:
Yeah, no I disagree with them, especially because Tom is on the guidelines. I think the problem was not recommending. I think at the ESMO guidelines this time, you’re trying to outsmart the system. Let me explain why. Because you are thinking that within a year, if someone with the disease came back within a year, et cetera, they’re very aggressive, they should not go surgery. I totally disagree because simply that metastatic lesion most likely has been missed.

That is the pulmonary nodule that nobody looked at has been missed. You may be right but actually in my experience, it’s the other way around and I will certainly recommend that. My problem is patient coming 4 years after with 1 pulmonary nodule or 2 in the same lobe, resected, the surgeon or the expert saying, “I want to give PEMBRO but go check with Brian and Tom in case they will give you the PEMBRO and they come here and then you have to change the conversations.”

Tom:
We could be wrong; we could be right. Toni, there was a boxing match, Wilder versus Tyson. I don’t watch boxing myself because I struggle with someone getting hurt but I do read about it in the newspapers. I think that’s probably a contradiction because you probably do one or the … Anyway, I find myself reading about it and the most recent fight that they had was apparently extraordinary in that it started, and Wilder was winning and then Tyson was winning and then Wilder and then Tyson. It changed and changed. Is that what’s going on with Ipi-Nivo and VEGF-TKI IO combinations?

Does it appear that the tide is changing and the data is now supporting more Ipi-Nivo because of that long term data and the curve staying apart and maybe the OS curves for the VEGF-TKIs being less strong, or do you still think that initial response that we’re getting with the VEGF-TKI, IO combinations trumps everything else and we’ll just have to wait for the fullness of time before we make any comments on the OS signal for VEGF-TKIs, IOs?

Toni Choueiri:
I think it’s easier to give VEGF-TKIs, IO. And when you have an overall survival, a busy clinician in the community, not us that have all the time in the world to decide is going to go by VEGF-TKIs IO. What I can tell is, community physician, very good doc, amazing, they’re getting more and more familiar with Nivo-Ipi and more comfortable giving it, especially with Ipi-1.

I still think if you don’t have a trial and the disease is not progressing very fast, Nivo-Ipe is my treatment of choice because then they’re on Nivo maintenance, it’s way easier. It avoids the VEGF toxicity. How many patients can do that? That’s the call, the hard call when you see a patient.

Brian:
Tony, what else in terms of highlights for last year, I would throw out sort of Belzutifan and VHL?

Toni Choueiri:
Absolutely. So Belzutifan VHL and the fact that I don’t know in your, I have patients coming for the HIF-2 inhibitor and I’m trying to get it approved since it’s available on the market but not for clear cell. My experience so far has been mixed. So, the HIF-2 inhibitor and hopefully other HIF-2 inhibitors that are going to come, I think the 1 thing I’m going to mention is also the plethora of the data all between 2020 and 2021, and you Brian have been involved in some is the single cell sequencing. I can name 5, maybe 4 or 5 paper from Columbia, Vanderbilt, Dana Farber from the Crick.

It’s all point to the fact that this is a very powerful technology and with more advanced staging from stage 1 to stage 4, there is more immune circuit dysfunction, which is not surprising. And there is a crosstalk between the myeloid cell and the T-cell. So that’s the whole thing suggesting more source, some maybe rationale combination but it’s the single cell era in renal cell cancer, 2021.

Brian:
Based on that biology in those data, do you think in our lifetimes we’ll get to a day where we actually have a clinically useful biomarker be it RNA gene expression, or single cell data or whatever because there’s clearly an antigenic phenotype. There’s a T-cell phenotype. There’s a myeloid phenotype, as you alluded to. Do you think we’ll get there where we’re actually assigning treatment or is this just understanding biology?

Toni Choueiri:
That’s the question being asked for 15 years for [inaudible 00:18:58] who’s like smiling at me. I mean but yelling as well. He smiles at me but yells as well.

Tom:
He does yell, absolutely.

Toni Choueiri:
But it’s deserved I mean with you. I think it is possible. You’re working on that; we’re all working on that. My only thing is the RNA based signature are so tough because you put 2 gene in, you take 2 gene out, suddenly things change. And that’s illustrated with the Axitinib. We try to validate the emotion data and we just over fitted, and we show our data. It’s better simply because we’re doing the experiment.

So same thing with your cancer cell letter, you and Bob and Tom, Brian, we’re going to try to see how this signature can validate and the test become commercially available. I think though, honestly, if the combination, the triplets, and maybe in the future, the quadruple are showing some safety and a CR rate that is reaching 30, 40%, it is going to be even harder to tease out a responder when really your CR is very high. The only difference I would think, MET alteration in papillary driven disease. Tom and I are involved in a couple of trials like that. That may be the only genomically precision medicine in renal cell cancer.

Tom:
Toni, just looking into the future, the 3 wise men, I get the impression they turned up a couple of days late. Is that correct?

Toni Choueiri:
The 3 wise men, you mean in the Bible?

Tom:
Yeah, I think Jesus was born when they turned up. So strictly speaking, they were a little bit late. So even wise people don’t get everything right. However, Toni, what I would like you to predict is a little bit about the future and I’d like you to start with obviously nothing, no one knows any of the answers to the questions. Cosmic 313 is Ipi-Nivo versus Cabo Ipi-Nivo. If that trial was positive for PFS and for response and by all rights, it should be because even Cabo Nivo should beat Ipi-Nivo for PFS and response, is that going to be practice changing for the triplet or does it need OS?

Toni Choueiri:
I think in the short term, it will even without OS. People are going to look at OS, remember these are intermediate and poor, so you’re going to have a signal. This is not a good risk. You’re going to have death. It’s not 1%, 5% like we had in Keynote 564, where in the adjuvant setting, there is no death. So, I think if there’s a signal of OS, PFS and response rate, people yes will change but they need to know how to handle. The referral will come for us first to give it, how to handle toxicity. It’s going to be more challenging, even with 40 of Cabo and 1 mg/kg Ipi. They need to know how to manage toxicity, but I think, yes. If I’m one of the, let me see Tasbar, Melsur, and Baltazar.

I’m going to be Baltazar because it sounds … [inaudible 00:22:28]

Brian:
I got a question. What does the response rate in PFS of the triplet have to be? Because as Tom said, it’ll beat Ipi-Nivo. I think to me it’s a given, but it kind of has to beat Cabo-Nivo I would think.

Toni Choueiri:
It has to beat Cabo-Nivo.

Brian:
So, what are those numbers do you think need to be? Cause Cabo-Nivo was 55% and 18 months. Is that right? Something in that range.

Toni Choueiri:
16, 17, so yeah. I think it has to be probably 20. The PR was 55%. You probably have to be over 65% response rate and the CR rate has to be over 10% with a clear signal going toward OS. Now … go ahead. Go ahead.

Brian:
Does it need to beat LEN PEMBRO then because you can get those numbers with LEN PEMBRO?

Toni Choueiri:
Yeah, you can except LEN PEMBRO 25% of patient have good risk. So, this is pure intermediate and so that’s the difference. But Brian, you are right. If the hazard ratio for OS, let’s say after, I’m going to predict 20% death. I don’t expect more, 20% OS event because it’s going to be an early cut. If your OS has a ratio after 20% and I do hope the sponsor shows it, not like we are in an adjuvant study like other where they don’t show at all the OS. If it’s one, I’m not sure. People may not get excited about it but if it’s suddenly 0.75, yes, you didn’t meet the stringent criteria. People going to start making a lip of it.

Tom:
Toni, next question. I’m going to go back to Belzutifan if I may. It’s a drug which is being tested third and fourth line versus Everolimus. That’s the registration path in metastatic disease. Is that the right setting for this drug or where does Belzutifan end up?

Toni Choueiri:
Yeah. I mean it followed the regular path of approval that we all fought to bring them earlier, but it ends up being late. I think the study is fully accrued or accruing very fast and I think it’s okay because remember we only had data on 55 patients. So, it’s okay to go in a refractory setting. Hopefully, it will beat Everolimus, which should be a very easy beat. I hope so. And then it’s moving to the front line as you know, in the triplet study. At some point, this is a tolerated drug, so it can be combined. I see good future for it but what I’m more excited about is now it’ll attract other companies to have a HIF-2 inhibitor.

Brian:
Toni, if that refractory trial is negative for some reason because I agree Everolimus isn’t a great standard, but the activity of Belzutifan is modest in the refractory setting. It’s not necessarily overwhelming. I don’t think it would’ve beaten a VEGF-TKI. If that registration study is negative, does it dampen your enthusiasm or not really?

Toni Choueiri:
It does. It does dampen an enthusiasm. We have to then see why it’s negative. One of the worries, unlike Everolimus, Sunitinib or any PD-1, anything, the median time to response is 7 months. It’s double or triple than we see with other therapies. So, I want to make sure the data, hopefully this is event driven and hopefully we going to see a PFS benefit because it’s going to be hard. I mean PFS for Everolimus is 4 months. So, if it’s negative, that’s a problem. If the response rate is delayed, that I can understand but it will be a big problem. We have to dig into the data, new formulation, what happened, who are patients that were enrolled but it will be a big surprise.

Tom:
Toni, talking about negative trials and this is my last question. CANTATA was negative. Nazia came on. Brian and I chatted to him, and he talked a lot, and he said a component to that trial were positive and it was exciting in subsets. My conclusion was actually that targeting these metabolic pathways are probably a lot less exciting than maybe targeting the microbiome. I thought that CBM 588 data, that Montegra’s group presented was super cool. What’s your take on these new targets? Is there anything out there at the moment that you’re queuing up to, to get your hands on?

Toni Choueiri:
Well, the problem with these metabolic pathways, everything is a metabolic pathway and renal cell is a “metabolic” tumor and this is 1 small part of it. I mean the glutaminase pathway and all that is very complicated. We do have a couple of experts here. I talk to them, and it becomes, the Krebs cycle was the worst thing in medical school, and it was taught to us by a priest, by the way, who was an MD. So, you can see the level of compounding of misery.

Tom:
That is a very pure education you’ve had, a very clean …

Toni Choueiri:
Yeah, too clean but this is how I end up so tells you how clean it is.

Tom:
The irony there, Toni, the irony.

Toni Choueiri:
It is complex. I think this was 1 shot on goal. It’s almost like starting by the weakest VEGF TKI. I still think it’s promising, and we have to continue through other ways. The CBM compound, very exciting. This is a very small study, 20 versus 10 but this is cheap. This is easy. Virtually no side effects. It merits a couple of randomized trials.

Brian:
Agreed, Toni. My last question, looking ahead I think we should start to get some other adjuvant trial data next year, Atezo in the adjuvant setting and maybe some others. What’s your prediction for those trials? Will they be uniformly positive like KEYNOTE or is this going to be an S-TRAC circumstance where one’s positive and the rest are negative?

Toni Choueiri:
Well, it may well be that. I am surprised at Atezo study, and I don’t have any insights here. I’m not involved in the Atezo adjuvant study but it’s a study that finish accrual. It’s a study that eligibility criteria are the same as KEYNOTE 564, very similar. It had an M1 NED population, so I do not know why it’s not read yet. I’m quite surprised. The endpoint is central review. So maybe there is a delay in the scans but if it’s negative, I think that’s a problem knowing that’s a different drug. With S-TRAC and Sunitinib, Atezo will tell you from the bladder experience failed in multiple situations.

Tom:
And succeeded in others of course, Toni.

Toni Choueiri:
And succeeded in others, but we’re talking about bladder.

Tom:
No, in the ones I wasn’t involved with. So successful in 130, unsuccessful in 211.

Toni Choueiri:
No, when other people are involved, it’s successful.

Tom:
That’s true.

Toni Choueiri:
In the trial, you lag. The adjuvant Atezo in bladder and the second line. If you mirror them versus another PD-1 inhibitor, they were negative. Is it the PDL-1 inhibition versus PD-1?

Tom:
Yes.

Toni Choueiri:
Okay. What is a politically correct way to end this podcast?

Tom:
Sorry, Tony someone just walked in. I missed that last bit. When I said yes to you, I was actually saying yes to someone who was asking something else. So, I’m not sure what I agreed to there but anyway, we’ll have to go back and find that out. You’re now asking about how we end this podcast. I don’t think there’s any formal way of ending it. I’m hoping it’s going to be less chaotic than up to now. I think we should start by congratulating you on the award for the most popular podcast of last year, despite its poor quality.

Toni Choueiri:
Very poor. I mean, Brian did the best, but you and I didn’t do well.

Tom:
And I’d like to wish you a really, really Happy Christmas. Brian, you as well and I really hope we see each other very, very soon indeed.

Toni Choueiri:
Yeah, before we run out of Greek alphabet letter for COVID please.

Tom:
I hope so, Tony. I hope so.