The Uromigos Episode 109: Adjuvant Pembrolizumab in Renal Cancer

Episode Transcript

Rob:
I guess it’s our second to last podcast, although I don’t know which order they’re being shown in, so it’s a ridiculous comment and I apologize. So, I sort of feel I’ll start again, but I’m not going to. I’m joined by Toni Choueiri. Toni is a great friend of both Brian and myself. Congratulations.

It’s a plenary session at ASCO, which is a highlight of anyone’s career and Brian, and I would like to reach out to you and say it’s a huge achievement and so congratulations on that. We’d like you to introduce yourself for a little bit, and then maybe just give a quick overview of the study and why you think it was chosen as a plenary session at ASCO this year.

Toni Choueiri:
Yeah, no, thank you guys for having me on. I don’t think it was my first time, but this study involved in renal cell cancer and to patient and their families, and I’m happy that it was featured in the planetary session because it’s the first study to show a benefit from immunotherapy in renal cell cancer.

The first study was in 1992 at ASCO, actually from a German group, followed by an intergroup American study couple of years later, using cytokine for a year that were completely negative. And we all know we went through vaccine strategies. We went through TKIs, and all these were largely negative and proceeded by trials of hormonal therapy, radiation therapy and cytotoxic chemotherapy. Kidney cancer kills 180,000 people globally and it’s one of the top ten cancers. [crosstalk 00:02:14]

Rob:
The way I look at it, I’ve been thinking about this. It’s a bit like the lottery paradox, where the chance to win the lottery was not altered by the chance of buying a lottery ticket and that’s a fact or statistically, and the same is true here.

It was almost a state, where no matter how many trials we did in the adjuvant setting in kidney cancer, even with promising drugs, we really struggled to get positive trials, and there was kind of a bit of a dogma at one point about going into this setting because it was difficult to achieve. Would You agree with that?

Toni Choueiri:
Yeah, I agree with that. I agree with that when you have something like that and I like the lottery analogy, although I would be the first to admit that I have never won anything in lottery, but there will be always a first-

Rob:
[crosstalk 00:03:02] you know, I once won something lottery without buying a ticket, knowingly buying a ticket, [inaudible 00:03:05]

Brian:
You’re getting off topic. Hey, Toni, talk to us about the study design, specifically the inclusion of the resected M1 patients, which other studies have done, but not always.

Toni Choueiri:
Yeah, no thank you, Brian. So, this is an unmet medical need, as you know. Any population that was quite hard to enroll. So let me start by the trial design. Patients with resective renal cell carcinoma at reasonable risk for recurrence. So how do we define that? We define it in three categories, intermediate high, high M1 and ED, so patient needed to have [inaudible 00:03:43] renal cell cancer and undergo radical, or a partial nephrectomy with a certification based on the geographic region and on M1 and ED, no M1 and ED.

Then we have one certification based on the no M1 and ED. So how did we define that? And just to let you know, going back to the literature. There isn’t a perfect model clinical more than me to define recurrences and this was really captured very well by a subgroup analysis from The ASSURED trial, by Rob Uzu and his team at Fox Chase, showing that all the prognostic models when he used ASSURED are imperfect.

We suggested a patient with stage two tumor if they have a grade four or sarcomatoid, N.E.T three, N.E.N Plus, and N.E.M.1 and ED. Now, the M1NED was quite controversial. Because as you know, Brian, when we were together in Cleveland, we had a model that we looked at and the two years from the diagnosis to recurrence we could push it up to two years.

After two years, I think, the chance of curing a single metastatic disease becomes higher and higher, but then we elected at the end after discussion with authorities and with other expert to limit it to a year. This was a hard-to-treat population, and we have two studies in the TKI setting that were negative and didn’t really enroll well with [inaudible 00:05:20].

Patient were randomized equally to pembrolizumab or placebo for a year and the primary endpoint was DFS by investigator assessment. So, this is overall [crosstalk 00:05:32] yeah?

Brian:
The, the M one N E D, there weren’t that many patients, I think less than 6%. Was it because of that year timeframe or were there organ restrictions? Some of the other studies that had organ restrictions…

Toni Choueiri:
So, brain rightly so, brain and bone was organ restriction. As we know, it’s impossible to have a clear margin and they’re treated mostly with radiation. I think that’s part. And the other part I would say is cultural because adjuvant studies for people that do RCC have not typically included. So, it’s not on folks radar as much. We expected more, but we end up, like you said, with 6%.

Brian:
And talk about that …

Rob:
The primary endpoint to the trail and what you show.

Toni Choueiri:
The primary endpoint was investigator assess DFs after immediate follow up of 24 months only. The hazard ratio favored for the DFS, favored pembrolizumab with the hazard ratio of .68. So, 32% decrease in the risk of recurrence or deaths.

Rob:
There was also a forest plot analysis and there was a subset associated with that. Was there anything on the forest plot that stood out for you coming back to Brian’s point, was the M1 population of particular interest?

Toni Choueiri:
The M one population, the hazard ratio was .29. So, it was quite encouraging to see that. Am I surprised? I would say these are the highest of the highest risk, but I was happy and comforted to see that the non-M one and ED the 95 confidence in terms vault did not cross one, beside that every analysis show there has a ratio less than one and I would stop there rather than over-interpret their results.

Rob:
Toni, what about the PDL one subset, some folks have come up to me and asked me about that subset that has a ratio looked a bit better and the PDL one positives, also a lot of patients were PDL one positive. If you look back at historical controls, what do you think about that?

Toni Choueiri:
Yeah, when you look at CPS, every company, every trial has its own way to look at it. But when you look at many of the studies with pembro that have mostly one way to look at the PDL one with a combined positive score that involves not just tumor cell, but immune cells, you see over 50% of patient are defined, including study that just today, great job, Brian on the update of four to six, I gleaned at the PDL one positive patient on the study and I think it was 50 to 60%. So, depending how you define it was a bit even higher than that. Why is that? I only have hypothesis.

I think one of the hypotheses is that all the specimen, no exceptions, are recent because these patients who had surgery, you are enriching for result that could be barely positive to really clearly positive and that makes it high. If you do the [inaudible 00:08:51] one with BMS PDL one, which is tumor cell, I think we all agree here looking at 2, 1, 4 90 R and other that the positivity is less than 50%. If my memory serves me well, it’s around 25 to 30%.

Rob:
Yeah. The assay is really important. The other piece that goes with that is in urothelial and in other cancers, we’ve also shown that trend towards higher PDL, one positivity, irrespective of the method associated with earlier disease. And some people feel that the adjuvant area or that perioperative space, those patients are more kind of immune primed. And some of those patients are cured by surgery, which is why we never see them at the metastatic space.

Toni Choueiri:
It is possible. It’s very possible and at the end of the day, what matters? Something that Brian taught me a long time ago when we were in Cleveland, both of us branched is just look at the data. There are way more preclinical studies than clinical result. When you have very larger studies, and I would say this study could have been done with smaller number, but it’s almost a thousand patient. I think you feel comforted that at least the primary and the secondary endpoint are real and were statistically powered, at least for these endpoints,

Brian:
Toni, I have two questions about overall survival results, one specific in one jet [inaudible 00:10:21]. Looking at the curves now and they look pretty overlapping up to about 16 months, which is right where a lot of sensor data starts and then they seem to split a little bit. But the hazard ratio is 0.54, which seems awfully low, just looking at the amount of distance between the curve. That’s one question, and then the money question is, do we need to see OS for this to be widely adopted? I’m sure there’s been a lot of discussion about that.

Toni Choueiri:
Absolutely. This is a very, very, very fair question. I will start by the first one and it’s always debatable and you’ve seen many adjuvant studies now, not bothering to show OS there is no power. On one hand, I could say the number of events that happens on the placebo arm are double. On the other hand, look after a year, almost no events happen for OS.

I think for folks that really want to have a quick look at OS to adopt, they’re on the fence, there’ll be three type of folks I would say here. Folks that are very fine with DFS folks that will never change their practice under the COS and the folks on the fence and for the folks on the fence, seeing an early result that an OS, especially at several time point, 12 months, 24 months, not associated with a hazard of 1.5, et cetera, makes them feel more comfortable to adopt the FS and that’s why we had to put everything out after. I agree with you. It’s too unstable.

Now your other question. An eternal question for solid tumor. I want to bring you back to breast versus lung. In breast cancer, the adoption of disease-free survival, invasive disease it’s universal. People look at OS, but I believe not, speaking for the breast community, this is adopted. Now you go back to lung, and I think this was a plenary at ESMO, the ADU trial with E G F R inhibitor, in high-risk patient.

I believe the hazard ratio, if my memory served me well with DFS, was kind of like point two or point three, and even with that, you see debate back and forth, if folks should wait for OS, even though this study presented metastasis free survival, which we know, this is something serious. If, you have metastasis lung cancer in the brain. Renal cell is no different.

However, I would say that if you look at the FDA document from 2018 and Dr. McKay, I believe mentioned that in her discussion, disease free survival is accepted, if you run a well randomized control trial that has a reasonable control arm where patient have other options and we see that way more in colorectal, in breast, and even in renal cell with the abstract.

So, we are working on the intermediate folks that are on the fence more than anything else, and soon as OS we have enough event, not 24%, we will push for an OS analysis for sure.

Rob:
Tony let’s move on to safety and tolerability. The safety profile showed about 20% of patients having grade three or four related out those events. About 20% discontinuing for adverse events, 7% steroid use and there were no treatment related grade five events. The way I interpret the data. When you look at that, is that typical? Is that acceptable? Is that something that you think is tolerable?

Toni Choueiri:
I had this discussion with Brian at some point, how the whole CTACE criteria needed an overhaul with new therapies, which was developed in the chemotherapy era, but it needs a complete overhaul because, I remember the time where we could say that treatment possibly, likely, probably, and now it’s yes or no. So, unless it’s in all grades, but there is a lot of times where I’m not sure. This is subjective and I don’t think this is related, but then you have a small chance and you put a treatment related.

This is why we have been adopting the discontinuation rate, the rate of steroid alternative ways to look at it. I don’t think when you go against placebo, you’re going to have a higher side effects profile. I don’t think, I’ll be honest with you, that there are new signals.

The hypothyroidism for immune related AE is the same as we’ve seen on the metastatic pembro XY. I think it is overall tolerated. Even people that had to be discontinued you on median, they receive seven cycles of treatment and maybe those borderline patients are the one where you have to discuss even more the side effect profile.

Rob:
Tony, we had a conversation with James Larkin. We had podcast with him. And what James said that the melanoma field had a learning is that there are some irreversible, potentially devastating side effects, and you’ll need to see those once or twice and it really focuses the mind. What worries you about most about that statement?

Toni Choueiri:
Yeah, I think James is, is right. I think James has more experience than anyone with these, but I would think that maybe James also mentioning when we add, because with his experience with melanoma, when we add panitumumab CTLA four inhibitor.

There is no doubt that the immune related AE is going to be worse and there is no doubt that if you look at numerical differences, there are some side of effects, pneumonitis, hypophysitis, numerically that happen higher on the pembro arm. I worry about intensifying the treatment with another IO, like a CTLA four inhibitor. The experiment needs to be done.

No doubt, especially that some of the trial is restricting the IO to six months, which is good. Maybe we don’t need a year. Maybe we need more. But I would like to see the toxicity here in the adjuvant setting of dual IO, and if it’s the same in the metastatic disease, and what’s the risk benefit profile.

Rob:
Let’s go to the crunch issue then, and maybe I’ll give you my perspective of this. We were in a position now where from, I guess from a global perspective, as you say, there’ll be three groups of people, there’ll be those that are brought into this on DFS alone, and most people I speak to are uncomfortable with that. Irrespective of, although I agree has ratios a two point, I saw the same lung cancer data with hazard ratio of 2.3 and 2.4, I think it was one of the other plenary sessions at ASCO or the slides with that.

And I thought, wow, that looks amazing. I also agree, I couldn’t believe they were debating. So clearly there are areas of DFS which gets over the line. Do you think the DFS signal in this study is enough to get over the line by itself without that OS?

Toni Choueiri:
Well, as of now, I would say, yes, we’ve seen approval, not based on OS for approval in the United States. If we’ve simply followed abstract rationale, yes. Europe, I can’t speak for European and including …

Rob:
My take on this is that your second point is important, is that with a very strong DFS signal, you then need to look at two other issues, the toxicity because what’s risk and also is there a trend towards OS? It’s my feeling that when Brian is correct and he says that the OS is not currently compelling, but it is giving us an indicator that it’s going in the right direction.

And I can see the conversations with the patients being, we can delay the time of the cancer coming back and they’ll say “well, but we don’t know if you live longer yet, but as a trend towards that happening.” And I can see if patients are given that information, they’ll probably say I would want to have the therapy, and my feeling is the EMA will come back. I think the EMA will approve this. I’m not involved, and I won’t be involved. That’s the question is …

Brian:
Is the OS data mature enough to even say that, again, I think the number that hazard the ratio is much more impressive than the curves, right?

Rob:
I think that people would agree with you at that, Brian, and I think this is a good place to have that debate. The reality is that when curves are pretty flat at the top, but they are going in the right ‘direction.’ I think that going in the right direction is enough to say to patients, is it just delaying the time for my cancer to come back?

Brian:
[crosstalk 00:19:45] Don’t to convince patients. I think patients will want it. It’s going to be the docs. So, the docs going to accept what I think is relatively minimal.

Rob:
No, no. Okay. Let me put that differently. It’s about broadcasting to one’s colleagues about where one is with this. I think with toxicity and with no indication of OS, as was the case with sunitinib and with a Metro analysis with other trials that were also negative for OS that didn’t hit PFS. It was relatively easy to say the initiative story, although it has FDA approval, doesn’t really hold water.

We’ve all had that discussion before, right? Because these curves are beginning to go apart and because the principle in the metastatic setting, unlike the [inaudible 00:20:33] targeted therapies, that the drugs are associated with long term durable remission, it’s reasonable to say, that it’s hit the PFS endpoint and there is a chance it will go on and hit that OSM point. And for that reason, giving the patient the benefit of the doubt while we wait, seems reasonable.

Brian:
Question for you Toni. Do you think this is the first trial reported and obviously positive sort of the opposite of the TKIs, where we had a bunch of negative trials and then abstract came in positive. What do you think is going to happen with the other ones? And do you think there’ll be a PD one PDL one difference like we see in the metastatic setting?

Toni Choueiri:
The straight answer first when I go back, just one minute to what Tom said, is the non-acceptance by some, by many of sunitinib as adjuvant is not just based on the overall survival, it’s based on the other TKIs, including sunitinib and in re-analysis of assured that it doesn’t have the DFS. If the other trials with Zanib [inaudible 00:21:43] had the Fs invent with OS has a ratio of one, who says that approval will not happen and control arm should have been a TKI. It’s having …

Brian:
And toxicity too.

Toni Choueiri:
And toxicity. [crosstalk 00:22:00] The prediction here, if pembro is active in this setting let’s go one by one. I think the [inaudible 00:22:11] has a good chance to be positive. Despite there are situations as you know, in bladder cancer or in renal cell cancer with combo, with Bev and other where [inaudible 00:22:21] fell short.

We don’t know if it’s [inaudible 00:22:24], is it the PDL one inhibitor? Or is it the study design? The study is smaller. I have to say, but this is a step in the right direction. The other study is extremely promising, important study to support. It’s just finishing accrual if it’s not just done and hopefully it is positive. It doesn’t have an adjuvant arm.

So having the neoadjuvant only, doesn’t exclusive benefit from adjuvant. There are the two studies, one we’re all involved in, in Rampart, in the UK and there is the other adjuvant study that asks the question of CTLA four plus PD one. One of the things, despite it’s a question that need to be answered because maybe we can cure more patients and have an OS earlier at two or three years.

The problem here I have is a melanoma study that is larger. That looked at the ITT and P DL one negative. I forgot the checkmate number by the way, where relapse free survival, not overall survival was not met. In a disease that is the poster child of IO therapy. Having said so, renal cell is different. The dose of IPI is different and six months makes it attractive.

That’s the checkmate study. So, a lot of questions. I think we are on the right track. I hope these studies finish accrual or about to finish accrual. If before pembro approved, if it is to be approved, because then it will be hard to accrue because there are patients that will give adjuvant pembro.

Rob:
Brian, from your perspective, you obviously saw the data. Brian, Tony and I were involved from trial. Obviously, Tony led the study. When you looked at it, how are you going to approach this with your patients? Cause assuming it gets FDA approved.

Brian:
I think that the DFS benefit is real. I don’t necessarily need an OS benefit. So, there’s two issues. One is, are we delaying recurrence in a subset of patients and by how much? We have that quantified by hazard ratio, but not by medians yet. I don’t necessarily think there needs to be a survival benefit.

Then a question that’s really hard to answer unless you have really long follow-up, is, are we preventing recurrence in a subset of patients? I mean that’s a different equation. If we’re just delaying without a survival benefit, it’s less palatable. But if we’re curing a proportion of patients who wouldn’t have otherwise been carried with surgery alone and I don’t know what that right number is, but even if it’s an extra five or 10% of patients, that’s a real benefit to me. So, I would anticipate using it.

Rob:
You both. What would you normally do in your last night of ASCO? I tend to go to that fantastic French party. That’s a discussion for a different day. Tony, if you are giving this regularly and let’s say a patient’s tumor relapses after adjuvant pembro, what goes through your mind about how you are going to treat them?

Toni Choueiri:
I think that duration from the last dose is going to be very, very important both for future studies and for current therapy. Whose tumor progressed after a year could be re-challenged. Although this is not the same as platinum based.

That’s what we do in bladder cancer and lung cancer based on low level of evidence, going to be lower with IO because there’s a memory response here. So that’s what’s going to happen. Luckily, there are two randomized studies that are open and enrolling, that allow prior IO as adjuvant, and maybe these studies will have enough patient treated with prior IO and I think they will be very important.

I can tell you in the metastatic setting there isn’t a clear, the best data is for IO V E G F post IO, which I would be the first to say, including from our place that it could be the veg GF effect, ref target therapy only. There are studies from Brian and others, about nivo IPI and certainly post PD one blockade and certainly there are responders that are durable, but it’s half, if not one third of what you see in IO and I E with Nevo.

Rob:
Brain, same question to you.

Brian:
As Tony says, I think it’s a matter of duration since last immune therapy. If it’s recent, then it’s either going to be V E G F alone, or maybe IO V E G F. If it’s more distant, I’m not sure it’s going to matter that much. I think if it’s five years ago or something, if they got their adjuvant pembro or whatever, five years ago, I’m not sure that it’s going to impact it that much. So, I think it’s sort of like platinum refractory and ovarian other diseases.

Rob:
I’m sorry. I had a last question about another one. Are you going to use more surgery? Are you going to do more metastasectomies because of this data? Cause someone came up to me and said, this supports doing cutting out lung metastasis, is that fair? I kind of disagreed with them a little bit, but luckily it was over the internet. So, I came across as very polite, very British.

Toni Choueiri:
You mean in renal?

Rob:
Yeah [crosstalk 00:27:56] renal cancer. Someone came up to me and said, well, this, this supports surgery for metastatic disease because you can do surgery and then give adjuvant pembro. Well, what’s your take on that?

Toni Choueiri:
Well, I do not agree. The question going to happen if the approval is within a year is that folks will give it, the problem is not this the problem, if it’s between one and two, two and a half years, what we’ll do, because if there a single, so side of metastatic disease or too close to each other, and you enter the patient M one N ed, after three, four years of follow up, I’m not going to give adjuvant here.

They could be cured but what if there is 15 months, 14 months, we know one year was arbitrary and I showed you data from Cleveland clinic with Brian, myself, that show a two year. So, what if it’s 18 months? And what would you do? And it’s in theory could be off-label. Brian?

Brian:
I think people will still give it in that circumstance. I think they’ll probably give it many years after metastasectomy but Tom, let me just address your question. Surgical resection of Mets has always been part of kidney cancer, right? It or local therapy SBRT that’s always been part of kidney cancer. I don’t think these data make you want to do it more, but certainly support.

Rob:
I think we also know that there are patients who are not suitable for surgery and there aren’t that prospective data supporting it.

Brian:
If somebody has 12 lung nos, you shouldn’t say, well, I’m going to cut out all 12, just so I can give Magine pembro, because there’s a benefit. That seems backwards to me.

Toni Choueiri:
Unless you really want to do surgery and justify it. Yes. The one thing though, I would say the adjuvant ACHI study, I think the design is to administer in the M one N ed group. It’s after one year.

So, we are going to look at subgroup analysis if they have 20, 30% there. And if there is no benefit at all, that could be actually something where there could be no benefit. Just because many of those patients are cured. So, I’m to look at that.

Brian:
That study also restricted site of Mets, as I remember. So, it is very different, but as you could say, we look at both subgroups and see how they do.

Rob:
Toni, Brian I’ve run out of terrific questions. Brian, have you got any? No. Have you got any questions, Brian?

Brian:
No. Tony. Congrats again. Great accomplishment. And thanks for joining us. We appreciate,

Toni Choueiri:
Thank you. Great new stunning patience.

Rob:
Stunning performance, Toni. Fantastic. Congratulations.

Toni Choueiri:
Thank you. Thank you.