Episode 144: Pembrolizumab for bladder cancer

Dr. Arjun Balar discusses bladder cancer and his recent move to industry.

 

Tom:
We’re joined by Arjun Balar. Arjun, do you want to introduce yourself really quickly?

Arjun Balar:
Sure. Tom and Brian, my name is Arjun Balar, a medical oncologist and still an associate Professor of Medicine at NYU Langone Health’s Perlmutter Cancer Center. But as of today, formerly, the GU director there and also formerly the CTO medical director there. And I’m in transition now awaiting a new job, which I’ll start-

Brain:
You’re unemployed currently, is that accurate?

Arjun Balar:
I am currently without a paycheck. That is correct.

Tom:
Arjun, this is exciting. I see why, because we’ve got three or four things we’re going to talk about. It’ll become apparent how it will unfold for those who are listening. So firstly, I wanted to talk about non-muscle invasive urothelial cancer. The first podcast we did together was with you and Seth Lerner and pembro had just been approved in non-muscle invasive urothelial cancer and BCG refractory disease in the CIS population. What’s happened to that program? What updates have we had? Has the data matured well, like fine wine? Or has it been more like one of my trials, which seems to get worse and worse and has ratio drops?

Arjun Balar:
That’s true. Our very first podcast was about that data and, the maturity that we published earlier this year in Lancet Oncology is kind of what’s in the public domain. And essentially demonstrates that about one in five patients will have durable CRs in the bladder with the systemic immunotherapy in patients who have BCG-unresponsive CIS. And that durable CR… and I think we have to remember that durability in metastatic disease is very different and should be looked at through a different lens than durability in localized disease, which is highly curable with a surgical procedure like radical cystectomy. Albeit it is a morbid procedure and associated with non-trivial mortality rate. But that durability is measured at a year to 18 months or longer. That’s probably the longest kind of median duration of follow up that we have in those patients.

Arjun Balar:
Now we’re going to follow those patients for longer period of time. Now, obviously those are going to be other investigators, not myself, who are going to present that data. But I’d say about one in five have something beyond a year or more.

Brain:
And Arjun, how many, I don’t remember the publication, how many avoided cystectomy? Because it’s more than one in five, correct?

Arjun Balar:
Absolutely. Now I think that, so the target enrollment of the study was 120. The data that was submitted to the FDA were just over a hundred. Now the efficacy of valuable population was 96. Now it’s important to understand that avoiding cystectomy is not a meaningful endpoint by the FDA. And that’s because the majority of the patients who enrolled in this study were not nonsurgical candidates. Majority were patients who said, listen, I understand cystectomy is an option. It’s curative. I know I’m a surgical candidate, but close to 80, 90% of the patients enrolled were patients who just did not want to cystectomy.

Arjun Balar:
So if they continue to “avoid a cystectomy,” that’s not meaningful. Now we did have 38 patients who did eventually undergo a cystectomy, three out of those 38 had upstaging to muscle invasive disease or higher, which translates to roughly about 8% of patients having muscle invasive disease or higher. A lot of those patients were 100, 200, 300 days later, well beyond after they had discontinued study therapy.

Arjun Balar:
Again, telling you that, patients will do anything they can to avoid surgery. And it reminds us that… But even then, despite that, right, so the upstaging rate, if you look at contemporary series of patients who have BCG-unresponsive CIS, upwards of 15, maybe 20% will be upstage. So it tells us that systemic therapy is doing something perhaps that while it may not lead to durable CRs in a majority of patients in the bladder, it is not unsafely delaying a cystectomy. And so if patients opt for this option, they can safely do it. If they don’t achieve a CR, they should be counseled about their other options, but not worry that they’re unsafely delaying a cystectomy if they choose to do so.

Tom:
Arjun, is it fair to say that the proportion of patients who have a durable CR if you take the hundred to start with, it ends up, at a year and 18 months, about one in eight or one in 10 patients, is that right?

Arjun Balar:
Say that again, Tom?

Tom:
So of the hundred patients who start with pembro, how many, 12 months later are in durable CR?

Arjun Balar:
So the exact number I think was something like 18? 17, or 18 out of that 96 efficacy of valuable patients that had… So the median duration of response of the patients who achieved a CR was 16.2 months. And out of the total patients treated, the patients who crossed that kind of 15 months DOR… Remember, so you have to add three to that number because to achieve a CR you have to be at three months. And then you measure that CR at that point, it was roughly about 17 or 18 patients who made it past that point. [crosstalk 00:05:45]

Brain:
I was going to say, it’s not terribly dissimilar if you think about the metastatic setting, right? The tail of the curve.

Arjun Balar:
It’s almost identical.

Brain:
The response rate is pretty similar. Very different setting, but the numbers are pretty similar.

Tom:
And Arjun what attempts have been made to pick the winners? And what does the biomarker data look like and how much biomarker data have we seen? Because the stakes are quite high for this population in that, it’s cystectomy, no cystectomy, it’s a curable setting. What does the biomarker data look like?

Arjun Balar:
I would, to be quite honest with you, it’s quite weak. And that is because, PD-L1 expression, much like in metastatic disease, is woefully inadequate. And I think we’ll find out that that’s the same in non-muscle invasive disease including CIS where it may be a much more difficult biomarker to even evaluate, much less validate from a predictive standpoint. And if we looked at the 96 patients actually, PD-L1 low patients somehow trended better than the PD-L1 high patients, which doesn’t make a lot of sense. And so we don’t put a lot of weight into it.

Arjun Balar:
And so we have studies like KEYNOTE-676, we have other trials. Pfizer’s leading a study, AZ has a durvalumab study in the first line setting. And so we have a lot of other randomized trials that’ll hopefully have better quality biomarker work as well as larger ends treated in the randomized setting. But so far it is weak to say the least, but I will echo what you just said is that the stakes are much, much higher. And so for a patient who is destined not to benefit at all from a systemic immunotherapy who has a highly curable disease, I think wasting our time with systemic treatment in that patient is something we need to know up front.

Brain:
And Arjun, are there attempts to build on it? So I mean, I know there’s some trials going on, pembro plus drug X, Y, or Z in this setting. I mean, those numbers seem reasonable, not overwhelming, but reasonable again, given the stakes. So what’s going on in that space, if you’re aware?

Arjun Balar:
Yeah. So there are, certainly, and systemic immunotherapy plus an immune adjuvant in the localized disease setting makes a lot of sense, right? So things to enhance antigen release in the tumor microenvironment, whether that’s an oncolytic virus, there’s a drug called CG0070. There’s some promising phase one data showing that it’s safe and some early data suggests that it might actually lead to some localized immune responses that may be further enhanced with the systemic checkpoint antibody. Certainly in combination with BCG, so both Pfizer and AZ are leading randomized trials in the upfront BCG naive setting, where patients are randomized to BCG alone, BCG induction alone, without maintenance, plus a systemic PD-1 antibody versus, BCG induction plus maintenance plus a PD-1 antibody. And those trials really do address a chronic issue that is not going to be solved at any time soon, which is the BCG shortage. And then-

Tom:
Arjun, before you go any further. On those trials, so Potomac and those other studies, what are the chances of those trials being positive in your opinion?

Arjun Balar:
I think very high.

Tom:
Okay. That sounds good. I like confidence. That sounds good. Arjun, I’m going to switch to instiladrin, if I may. Over this side of the Atlantic, we hear that there are problems with the FDA approval of this drug. Do you know what’s going on there?

Arjun Balar:
So I know as much as you do, and certainly I follow the press releases and reassuring emails that tell us that really it’s not the quality of the data, it’s not quality of the safety and efficacy has been reviewed. It’s really about manufacturing a quality product that can be reproducible in a commercial sense. And I think that just reminds us that, that transition from an investigational product that is shipped to sites in a controlled fashion. And then, operationalizing a commercial product that must be readily available at community sites, not only regionally, nationally, around the world, that to scale, it is a much larger feat. And so I think that’s what’s awaiting the final FDA approval. That’s what we’re waiting for.

Tom:
Is this problem solvable?

Arjun Balar:
Absolutely. I mean, I think it just takes time. It takes money and resources and expertise in manufacturing.

Tom:
We’re going to switch gears, if we may. You were also leading the frontline pembrolizumab approval in KEYNOTE-52, that label has recently changed. Why has that label changed? It’s changed twice actually, but why has it most recently changed and what impact has that had on your practice?

Arjun Balar:
So, this is… I’ll use a little bit of romantic language here in saying this has been a labor of love for me, in terms of something that was very important early in my career was to… And the patients that we treated- [crosstalk 00:10:30]

Tom:
I remember we sat down in a bar in Chicago and talked about it after ASCO. Then we had, I remember really clearly, and you were saying, “Tom, I think this is going to work.” And I’m saying, “I’m not sure, I’m not sure.” And you were very… And guess what? So I thought it was terrific and congratulations.

Arjun Balar:
Yeah. So, I mean, I think in 2017, you and I both agreed that single arm studies to make a broad label in the first line setting was going to be problematic. And we knew that because the outcomes with immunotherapy are quite binary, either patients respond or they don’t, and you don’t have a chance to choose twice, right? And so if you guess wrong, you’re in real trouble. And what randomized trials don’t allow you to do is to use clinical judgment in determining which patient receives chemotherapy and which patient doesn’t. And not all CIS ineligible patients are going to succeed with immunotherapy and, nor can be the same with chemotherapy. And so this flipping of the curves phenomenon is not just something that we only see in bladder cancer, but we also see in head neck and in lung cancer, basically, it’s a phenomenon we see in all, essentially, chemotherapy responsive cancers that are also treatable with immunotherapy.

Arjun Balar:
And so this evolution from 2017 through 2018, and then culminating in 2021, where we just became smarter about the use of frontline immunotherapy, was naturally going to happen. And it just tempered our enthusiasm. And this was a necessary thing to happen. [crosstalk 00:11:53]

Tom:
Do you think the FDA’s got it right?

Arjun Balar:
I think right now, I think they did. And I was very reassured and I definitely put a lot of work into helping prepare for the FDA ODAC in April this year, in terms of at least preserving access to first line immunotherapy for the patients who want it and those for whom chemotherapy is not a safe option. And you and I both have treated patients well into their eighties and nineties. And for whom, platinum is not a safe option.

Brain:
Arjun, do you think we could design, maybe not in this setting, but just general question, sort of risk adapted strategies for which you’re alluding to? I mean, it’s been done in testis cancer and the Spanish Group’s done it well. Is that something that we can even pull off?

Arjun Balar:
Well, you know what I would like to see, Brian, is… So one thing that I think that, and this is my feeling about immunotherapies, is that when you have a drug and a mechanism of action, that really, it doesn’t address the tumor, it actually addresses the host. And when you’re addressing the host and you’re trying to compare it to treatments that address the tumor, randomized trials fundamentally are not designed to make binary comparisons. Is A better than B? And what is required is in the incorporation of clinical judgment. And so, modern trials are not really designed to really assess the true value of immunotherapy. That’s my opinion, others may or may not share that with me. What I would love to see, and I’ve kind of spit balled this with folks at Merck, I said, “Would you guys support a prospective observational study of chemotherapy versus immunotherapy incorporating physician discretion?”

Arjun Balar:
Have some key eligibility criteria, allow for some entry criteria that allow for CIS ineligible patients to be enrolled, but also incorporate some degree of physician discretion and then observe, what is it that we’re missing in that piece, right? Because CIS ineligibility from a regulatory standpoint, are these codified criteria that the FDA use, but the three of us know that… We don’t pull up a table to determine how we treat patients in, in the clinic, right? And that’s the piece that’s really missing. [crosstalk 00:14:05]

Brain:
Eyeball test.

Arjun Balar:
Yeah.

Tom:
Arjun, the FDA went in a different direction for atezolizumab, for pembrolizumab. They said that the results could only support the use of pembrolizumab in platinum ineligible patients, but they continued the label with atezolizumab in cisplatin ineligible PD-L1 positive. Why did the FDA go in different directions of the two drugs?

Arjun Balar:
To be completely blunt and honest, I think that, with the IMvigor130, I think they got a little bit lucky. The biomarker worked in that trial and perhaps SP142 and IC measurement is a bit more consistent than let’s say, CPS, maybe that’s what it is. And also it’s an immature trial where survival is still pending. And so they’ve got a combination of a biomarker that works in a monotherapy arm to some degree, in a randomized study with some enrichment of upwards of 38%. Whereas it didn’t look as much in the single arm study, albeit with 119 patients only, and in an immature trial. And so they got lucky.

Tom:
And so it’s fair to say that, I mean, the 142 Roche biomarker for atezolizumab has been inconsistent as well. It didn’t work in 211, it obviously didn’t work in 010. It seems to be working in 130. And then the pembrolizumab biomarker it’s also got… There’s just a lot of inconsistency. Does this whole program, this whole area, trouble you? Is this something where there’s so much uncertainty that makes you nervous?

Arjun Balar:
Yeah, absolutely. I’ve kind of had conversations with a lot of my colleagues in the field and some will say, “Well, look, this biomarker works and therefore I’ll use atezo in PD-L1 positives, but I won’t use pembro because of this trend in this trial.” And I think that you have to look at the totality of all of the immunotherapy trials in bladder cancer where you are assessing PD-L1 expression to make decisions. And what you see is a great deal of inconsistency. And so this trial cannot stand alone as, okay, well, look, this is the one study I’ll pay attention to. You have to look at everything, this is the same reason why we don’t use adjuvant sunitinib in RCC. We don’t just pay attention to that trial, we look at the totality of adjuvant TKI trials, right? So it does trouble me and to be quite honest, I’ve never used PD-L1 expression to help me make decisions, because I’ve always thought that something about it just didn’t feel right. And I think this is proving a point, we need better biomarkers. Maybe TMB is it, maybe it’s something [inaudible 00:16:49] and will be reproducible.

Brain:
I was going to ask if you were, sort of, king of the world and controlled all resources, would you put any more resource into studying PD-L1 as a biomarker in advanced bladder cancer?

Arjun Balar:
No, I wouldn’t. Frankly, I wouldn’t.

Tom:
We’re getting lots of black and white answers, Arjun, which is terrific. When I ask Brian these questions, he tends to skit around and then we’ll get all sorts of funny answers, so I’m very impressed. Arjun, perhaps the reason you’re giving such blunt is one of the reasons why you’ve been attracted to industry. Do you want to talk a little bit about this move in your career? You’re obviously at a crossroads, for whatever reason. You’ve been a very successful investigator, you’ve been in a very prominent institution in a big city, in the most successful country in the world and, you’ve got all these things going in your direction. What made you make that switch away… From the outside, it looked like, Brian and myself, look at it and say, well, everything’s going in the right direction. What’s going on in you and, what are you switching to?

Arjun Balar:
Yeah, it’s an interesting, I guess, the perspective from how I made the decision and I guess how, perhaps my peers, colleagues and friends might see it, might be a bit different. It was not an easy decision. I thought about it for months and months. And I talked to probably 40, 50 people, close friends, my family, mentors that I’ve had over the years and people who really know me as a person, not just from my professional standpoint, but as an individual. And I think that some people may say that, well, look, if things are going so well, why change? Frankly, I think that many times that’s often the reason to do it, because if you feel that you’re successful, if other people feel that you’re successful, maybe there are more things that you can also still achieve.

Arjun Balar:
The question that, kind of, floated in my mind was that, I’ve had the opportunity to participate as a clinical investigator in some extremely important practice changing studies and I’ve had the privilege of doing so over the last nine plus years. But that’s been largely because of transformational drugs that come out once a generation, right? Whether it’s the immunotherapy wave, whether it’s new technologies that are developed that allow us to safely deliver cyto toxics in the form of antibody drug conjugates, or better understanding of molecular biology and next generation sequencing and developing better molecularly targeted drugs or combinations. But, what I early on realized is that, as clinical investigators, if we have a painting and we have a pallet and a canvas, we’re only as good as the paint brushes and the colors that we’re given.

Arjun Balar:
I realized that after nine years of doing this, I wanted to be on the other side of the protocol, is kind of how I would put it.

Tom:
And Arjun, what job are you doing?

Arjun Balar:
So I’m joining Loxo Oncology at Eli Lilly, a close friend of mine, Dave Hyman, who was my co-intern and co-fellow in fellowship, kind of picked his brain back in May. And he gave me a flavor of kind of what life is like on the other side and my opportunity to make an impact, my eyes widened immediately. And I think there’s much more work that I hope I can do and provide to patients. And I think the scale with which I can do it, I think could be much larger, much larger than at any single institution. I’ll be a vice president for Global Clinical Development there, I’ll work with him and some key people to develop new cancer drugs.

Brain:
So Arjun, it was really about making an impact in a different way. I mean, we’re all pulling in the same direction, I hope, right? To help patients. But there’re different ways to help them, and certainly when I transitioned to Vanderbilt, part of it was, how can I make a bigger impact? And it sounds like to me, that was a prime mover for you. Is that correct?

Arjun Balar:
1000%.

Brain:
The other rumor going around is that since you were on our very first podcast, and that was really such a bad experience for you, that you decided to abandon academic medicine. Is there any truth to that rumor?

Arjun Balar:
There is some partial truth to that.

Tom:
Well, I’m not surprised.

Arjun Balar:
I’ve been seeking therapy and counseling ever since [inaudible 00:21:24]

Brain:
We’ve been driving people out of academics.

Tom:
You’ve made great progress with that therapy, it’s almost impossible to tell there’s something wrong. Arjun, last question. Two last question, one, last question. What are you looking forward to most about this switch and what do you think you are going to miss most about clinical practice?

Arjun Balar:
What I’m going to look forward to the most is, frankly, a bit more time with my family, a better work life balance, and a very clear kind of delineation of what my roles and responsibilities are. I’ll have a clear idea of, my client is the FDA, my competitors are these other pharmaceutical companies and institutions, but frankly, we’re all in the same business. The enemy is still and always will be cancer, right? And in academia, as collaborators and competitors, those are exclusively just collaborators and it’s just much more clear, those relationships. And I’m really looking forward to that, is just that we’re just in it together. And that I think I’m really [inaudible 00:22:54]

Tom:
Arjun, before you get to what you’re going to miss most, just to build on that, why can’t you do this with investigator initiated trials through cooperative groups? Why is there this necessary switch?

Arjun Balar:
So, investigator… I can’t say that I have extensive experience putting through studies through the cooperative groups. So I will tell you my experiences in N-of-2, where I put two concepts through about eight years ago. And I thought they were good studies, niche studies that addressed unmet medical needs that other companies and larger pharma were not interested in. And only to find out two years later after I had drug commitment, investigator commitment from other folks that, that did not meet higher level needs within the NCI and CTEP. And so it is a slog and it’s where not only concepts die, but careers can waste. And I say that with the deal of disappointment, because when I counsel fellows and early career investigators, I say, “You got to have a lot of irons in the fire,” because, the [inaudible 00:24:05] process, while it can be very rewarding, it just takes way too long.

Tom:
I agree with that.

Brain:
Last question for me, and I know we haven’t finished Tom’s question, but did COVID play a part in this? Because I know at Vanderbilt we’ve had a couple very senior people leave for industry in the last 18 months. I don’t know if that was necessarily COVID induced, but it just seems to me, we’re hearing that more now where we didn’t hear as much about it in years past.

Arjun Balar:
I mean, to be transparent, I think it did in the sense that, it allowed me to be a bit more introspective about what was important to me and what I wanted to do with my life. I think pre COVID we were just constantly running around and many times, because we’re constantly running around, we don’t even have time to think about what we might be doing otherwise. And so it gave me a moment to really think what else I might want to do. So, I mean, it just gave me a second to pause. So yeah, absolutely.

Tom:
Brian, that was one of the most professional interruptions I’ve seen during [crosstalk 00:25:16] during the course of these podcasts, it was a seamless interruption. Arjun, this has been really interesting, I’m really excited for you. I think it’s a terrific transition. I kind of agree with a lot of what you said about the need to look at things in a slightly different way. And certainly if you want to make a huge influence in the way we treat cancer patients, developing successful approved studies and drugs is a really effective way of doing that. And I think it’s easier doing it within company sponsored studies and investigator initiated trials as things stand. So good luck to you and I wish you the best. Will you come back in a year’s time and let us know what the thing you miss the most is?

Arjun Balar:
I will. And actually, I will share though that already it’s a week later and I know already what I miss and it was very, very bittersweet. I thought that making the decision was the hardest part. And I thought that three, four months ago when I made it and I resigned and I thought that was the hardest part. And then everything else was going to be easy. But I remember the day that I cleaned out my office, pulling out some old manuscripts, the first prints I’d saved from early on in my career. And thinking to myself, I’m leaving behind a program that, when I started at NYU there wasn’t much there, right?

Arjun Balar:
And over the years we built something that is regionally recognized. It’s a place where patients can be referred to and expect high quality in multidisciplinary care. So the referring providers and the patients expect that, and I feel that what I’m going to miss the most and I already miss the most is that, there’s a feeling of leaving work that is undone. I’m sorry, unfinished. And that part is really tough.

Brain:
Well, congratulations, let’s celebrate over a good glass of bourbon sometime. Appreciate you joining us.

Arjun Balar:
Absolutely.

Tom:
Thanks a lot, Arjun. We’ll see you soon, okay?

Arjun Balar:
You got it. Bye. Bye.

Tom:
Bye.

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