Bladder Cancer Podcast

How Bladder Cancer Immunostimulant N-803 May Shake Things Up

Cheryl T. Lee, MD; Karim Chamie, MD, MSHS


April 20, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Cheryl T. Lee, MD: Welcome to Medscape InDiscussion, season 2 of our bladder cancer series. I'm Cheryl Lee.

More than 82,000 new cases of bladder cancer will be diagnosed in the United States in 2023, and the great majority of these cases will be non–muscle-invasive bladder cancer. Even just a decade ago, we had limited treatments beyond bacillus Calmette-Guérin (BCG) for many of these patients. Fortunately, the treatment of bladder cancer is expanding rapidly.

In the first episode of this season, we discussed an exciting gene therapy: nadofaragene firadenovec-vncg [Adstiladrin]. Today, we'll learn more about the immunostimulant nogapendekin alfa — that's a mouthful. So, we're going to call it N-803,its nickname. We're going to learn about what it has to offer as a treatment option for non–muscle-invasive bladder cancer. Who's a candidate for N-803? How effective is it for individuals with non–muscle-invasive disease, and what complications are associated with its use?

To answer these questions and more, we've invited Dr Karim Chamie, who's an associate professor in the Department of Urology at UCLA. He also serves as the Director of the Bladder Cancer Program, and he directs the Society of Urologic Oncology Accredited Fellowship Program. Welcome, Karim.

Karim Chamie, MD, MSHS: Hi there, Cheryl. How are you?

Lee: I'm fantastic. It's great to have you on the program today.

First, I thought our listeners might have some interest in your background. You have a unique research background. Your work spans health services research, translational research, and even clinical trials. I'm wondering if you could first start with an update on your journey to become a clinical trialist and how you integrated all these other areas of discovery into your academic practice. And as a follow-on to that, how do you hope to influence the treatment landscape for bladder cancer?

Chamie: Thank you, Cheryl; it's an absolute honor to be here with you. Obviously, as a thought and key opinion leader in this field, it's great talking to you about this.

Regarding my background prior to getting into medical school, during medical school, and during my residency, I did a fair amount of benchwork and basic science work. You know, during residency, we always thought that in academia, publishing is currency, right? It's almost like writing a paper is a $5 bill and getting a grant is a $100 bill. The more papers you wrote, the wealthier you were — from an academic standpoint, obviously. We were naive back then, thinking that a number of papers meant anything like that. But, as residents, we just wanted to keep busy and wanted to write papers. So, I delved into some large databases, observational databases, and taught myself some biostatistics and kind of liked it, in addition to some of the benchwork that I was doing.

After completing my residency, I went on to do a fellowship at UCLA. I met Mark Litwin, and obviously, he's my hero when it comes to academia in urologic oncology. As one of the godfathers of health services research in urology, I was completely in awe of some of the things that he did, some of the things he was working on, and all of the other fellows whom he's trained. So I said, "Well, I'm to start doing some health services research, but I want to do it in bladder cancer." I completed my fellowship, did the whole coursework training, wrote some papers and grants — some of which got funded — and then I got hired on staff at UCLA and started treating patients with bladder cancer. In doing so, I realized we didn't have any clinical trials for patients with bladder cancer; there weren't many basic science projects. So, I started working with large pharma as far as accruing some of these trials to preserve organs. I worked with TheraCoat (now UroGen) for upper tract cancer, to preserve kidneys. I worked with Altor, which then became Nant and now ImmunityBio, to preserve bladders for patients with BCG-unresponsive bladder cancer. I basically had no choice. We didn't have a clinical trialist in bladder cancer, and so I kind of filled that role.

Lee: You are clearly a star in the field, and we're all excited that you followed the journey that you have.

I wonder if we can reflect a bit on N-803. It's an agent that many of us don't have a lot of experience with unless you were part of the clinical trial that we're going to talk about in a little bit. Maybe you could start by telling us about its mechanism of action and whether it has been used to treat any other conditions or disorders.

Chamie: The exact mechanism of action is truly unknown, but we think it works as an immune modulator on both the innate and the acquired immune system. We think that it works primarily through the natural killer (NK) cells, but it also helps recruit cytotoxic CD8 T cells and without any additional accrual of regulatory T cells, so we think it's primarily NK mediated. We know that BCG does a lot of work through NK pathways. If you knock out mice that don't have the ability to make NK cells, giving them BCG does absolutely nothing to them, whereas if you give them checkpoint inhibitors, it works systemically but in the bladder it does nothing. We think that the NK pathway is important for local activity in bladder cancer, and we think that that's how N-803 works.

There are two trains of thought. One is, "Is the cancer because people become BCG-unresponsive?" And the other is, "Is it the host who is unable to mount an immune response?" We think it's probably the latter — mostly the latter; maybe it's a combination of the two. But we think that some of the efficacy that we see is probably related to the host being adequately stimulated, and therefore you get an immune response that results in a complete response and durable activity.

Lee: That's interesting — this thought of host exhaustion.

Chamie: It's being studied for several cancers. I know that for a while, it was worked on for melanoma. It's been worked on for breast cancer and pancreatic cancers in combination with other therapies, although in those settings, it's given systemically, not locally.

Lee: I know that you've played a key role in the QUILT 3.032 study, and I think our listeners would appreciate learning more about the data that you presented recently at the American Society of Clinical Oncology (ASCO) meeting. Can you share some of the details about the study design and the key findings?

Chamie: We used the framework that the US Food and Drug Administration (FDA) came up with as far as the definition of BCG-unresponsive bladder cancer. We used the framework that you'd find in a number of other trials — whether it's the KEYNOTE-057 study with pembrolizumab or the nadofaragene trial. We used very similar definitions as far as inclusion criteria: Patients must have been BCG-unresponsive, meaning that they must have received adequate doses of BCG — at least five of six induction courses and at least two of three maintenance doses. Some patients were deemed BCG-unresponsive if they progressed to high-grade T1 despite just an induction course, and they must have recurred or been refractory within a year. That's the definition with which we work. The sample size is derived primarily from what the FDA gave us as far as the 95% CI — that is, the lower end can't be lower than 20%. That's why most of these studies try to accrue 80 patients, because that's statistically how many you need to get to that number; we followed that.

We did deviate, though. This is a single-arm study, but we did deviate in the sense that in most studies if a patient had a recurrence of bladder cancer, despite an induction course of a study drug, they were deemed ineligible to receive any additional drug. They basically were eliminated from the trial or excluded from pursuing additional treatment in the study. What we felt was that we were truly looking at patients with BCG-unresponsive disease, and these were patients who absolutely refused a cystectomy. So, we thought, "What if we actually allow patients who maybe had a partial response and see if we can keep them on the study and reinduce them?" Or if they've got low-grade disease, just keep them on the study and continue treatment as though they didn't have a recurrence. There were some modifications in patients who had carcinoma in situ (CIS). Maybe the CIS got a little smaller visibly, even though that's an artificial definition that we were allowed to pursue in the study.

What we found was that most of the complete responses occurred after the induction course. About 55% of patients who received an induction course had a complete response. But that meant that 45% of the people didn't, so they failed the study. What we did was give some of those patients a second shot of an induction course. We found we were able to get an additional 16% of patients to have a complete response. That's how we came up with 71%. We were able to get 55% plus 16%, and that got us to 71% of patients as complete responders.

Lee: Was that almost reminiscent of what we historically have done with a second induction course of BCG or giving patients an option to get at least a first maintenance course, to see if you could restimulate their immune system or the pathway in some way, shape, or form?

Chamie: Absolutely. We're standing on the shoulders of giants, right? We know that some patients respond, even after failure of an induction course of BCG. We thought an additional course may benefit some of these patients and we might see a response there.

Lee: It is clear that you were able to use the FDA definitions in helping to design the study. What about toxicity? We see a lot of new agents. I think we all recognize that patients are concerned about side effects. Many patients are trying to avoid adverse events, and so they are leery to try a new agent. What did you see in terms of toxicity?

Chamie: Very rare or uncommon systemic side effects. If you look at treatment-related serious adverse events, there were less than 5%. But patients did have local toxicity. I saw several patients treated in the trial who did have urinary frequency. They go to the bathroom every half hour, every hour, or every 2 hours. I've had to give some of those patients steroids and antibiotics and hold off on treatment. I had to deviate a little bit to get these patients to maintain their bladder.

For the most part, it was well tolerated. The side-effect profile is not that much different than with BCG alone. But again, BCG alone isn't a walk in the park either; patients have toxicities associated with it.

One of the interesting things that I found was that in the patients who had a profound immune response locally in the bladder, it caused local toxicity. When I gave them steroids and antibiotics, and I had to hold off on any additional treatments, those patients still maintained their complete response. So, this was kind of cool, in the sense that I think we primed the immune system locally enough to the point that although it may have gotten overheated there, at least it's maintained that response for years later. I think there's something to be said about the immune response there.

Lee: Do you have any sense of the number of people who were unable to complete the treatment during the trial?

Chamie: The number of patients who didn't complete treatments was pretty small in number — in the single digits. Most patients were able to complete the study.

Lee: Fantastic. I know a lot amazing work was done in that trial, particularly with a population of heavily pretreated patients. So I think there's a lot to look forward to.

How do you see this treatment fitting in to the current management for non–muscle-invasive disease — maybe I should say the current landscape? We've got several new agents on the horizon. We've got some doublet chemotherapy agents now being tested in the BCG-naive setting. Where do you see this agent fitting in?

Chamie: I think nadofaragene is a convenient drug to start off with — particularly for patients who may have BCG-unresponsive disease, but maybe a small volume, or for patients who have significant lower urinary tract symptoms — because the treatment intensity is not there; I think patients do well. I think N-803 is probably the most effective right now as far as efficacy; I think you're going to get most patients pursuing that.

Obviously, patients could still receive gemcitabine-docetaxel, although in the community setting, it may be a little bit of a challenge, because they may not have access to chemotherapy. For patients who fail N-803 or fail nadofaragene, Jimmy McKiernan's study of the triple combination chemotherapy of cabazitaxel, cisplatin, and gemcitabine is going to be the end-all, be-all treatment. Probably the most important thing that I've learned from this study is that the data look really promising. We had a 71% complete response, and the median durability is about 2 years. You say, "Okay, 2 years later, 35% of the patients are still disease-free, but that means that 65% of the patients either failed initially or failed ultimately." The lesson that we've learned from this is that only about 15% of patients went on to get a cystectomy. I think what we're learning is that maybe these patients' cancers are not as aggressive as we originally thought. The classic teaching during residency and fellowship is that in someone who has BCG-unresponsive bladder cancer — at least based on Harry Herr's study data — you've got to do that cystectomy because their outcomes are significantly better. What we're seeing is that at least in the KEYNOTE-057 study and in this study, most patients didn't have a cystectomy, and they're still alive and doing well. We're becoming a lot more comfortable in our own skin managing patients who failed some of these advanced options. So, I think that's the biggest lesson I've learned from this study.

Lee: The encouraging piece to me also is that we have salvage options. When you have moderately effective salvage options, I think we're willing to keep persisting to preserve the bladder; and that's what most patients obviously want.

Let's talk a little bit about drug accessibility, because, of course, I might ask you, Do you ever envision testing this agent in the BCG-naive space? We must contend with the BCG shortage that will continue for several years. We know that even nadofaragene firadenovec, although effective, is not accessible because of several reasons related to production. First, I will ask you, What are your thoughts on the accessibility of N-803, should it make it through the FDA? I know it's in consideration. Then, would you ever think or plan to test this in the BCG-naive space?

Chamie: For the first question, that's above my pay grade. I can't speak to the commercialization and the manufacturing. I think the company is going to be able to be up and running as soon as it's available, so I don't think that's an issue.

Regarding your second question, there is an ongoing study called the QUILT-2.005 study for patients who are BCG-naive. That is a blinded study in which patients are randomized to either BCG alone or BCG plus N-803. That study has been going on for a few years. But the company put that study a little bit on hold because they had to supply the BCG, and it was becoming overwhelming during this era of BCG shortage to supply it for the BCG-unresponsive and the BCG-naive patients. I think the event rate was probably lower than they anticipated. The number of patients needed to accrue for the study went up and they were running out of BCG, so they put that study on hold. But when I looked at the data back several years ago, it was very, very promising for patients who had CIS, and I think it worked better when you combine N-803 plus BCG for CIS patients, compared with those with papillary disease or for patients with BCG only.

Lee: Well, this has really been exciting. I know we've covered a lot of ground. In the past 20 minutes, is there anything you'd like our listeners to take away from our discussion today? Any key points?

Chamie: We're going to be looking at a lot more combinations. Obviously, the Southwest Oncology Group (SWOG) is going to start looking into adding N-803 plus BCG with other drugs, such as checkpoint inhibitors or maybe potentially chemotherapy or other agents. I think we're going to have to start getting used to multiple pharmaceuticals — meaning we're going to have to add different drugs to improve the efficacy rate for this sometimes difficult-to-treat cohort. To get the efficacy and the response rates that you and I want for our patients, that our patients deserve, we're going to have to add multiple drugs. That's one takeaway.

I think the second takeaway is as these treatment options become more and more effective, we're becoming increasingly more comfortable in our own skin as far as keeping patients on these salvage options and avoiding and forgoing or delaying a cystectomy. I think those are the two key points.

Lee: Fantastic. Well, everyone, thanks for listening to our conversation with Dr Karim Chamie in this second season of our bladder cancer series. There's much more ahead in the coming episodes, so be sure to check out the Medscape app, and share, save, and subscribe if you enjoyed this episode. I'm Cheryl Lee, for Medscape InDiscussion.

Listen to additional seasons of this podcast.


Bacillus Calmette–Guerin (BCG) Immunotherapy for Bladder Cancer: Current Understanding and Perspectives on Engineered BCG Vaccine

ADSTILADRIN [prescribing information]

FDA D.I.S.C.O. Burst Edition: FDA Approval of Adstiladrin (Nadofaragene Firadenovec-Vncg) for Patients With High-Risk Bacillus Calmette-Guérin Unresponsive Non-Muscle Invasive Bladder Cancer With Carcinoma In Situ With or Without Papillary Tumors

IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer

BCG-Unresponsive High-Grade Non-Muscle-Invasive Bladder Cancer: What Does the Practicing Urologist Need to Know?

Functions of Natural Killer Cells

QUILT-3.032: A Multicenter Clinical Trial of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 (N-803) in Patients With BCG Unresponsive High Grade Non-Muscle Invasive Bladder Cancer

Pembrolizumab Monotherapy for the Treatment of High-Risk Non-Muscle-Invasive Bladder Cancer Unresponsive to BCG (KEYNOTE-057): An Open-label, Single-Arm, Multicentre, Phase 2 Study

Intravesical Nadofaragene Firadenovec Gene Therapy for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: A Single-Arm, Open-label, Repeat-Dose Clinical Trial

Final Clinical Results of Pivotal Trial of IL-15rαfc Superagonist N-803 With BCG in BCG-Unresponsive CIS and Papillary Nonmuscle-Invasive Bladder Cancer (NMIBC)

Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer

A Phase I Trial of Intravesical Cabazitaxel, Gemcitabine and Cisplatin for the Treatment of Nonmuscle Invasive Bacillus Calmette-Guérin Unresponsive or Recurrent/Relapsing Urothelial Carcinoma of the Bladder

Surgical Factors Influence Bladder Cancer Outcomes: A Cooperative Group Report

PK Sub-Study of QUILT-3.032 (CA ALT-803-01-16) and of QUILT-2.005 (CA ALT-803-01-14)

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