Alicia Morgans: Hi, I'm delighted to have here with me today, Dr. Arjun Balar who is the Director of GU Medical Oncology at NYU Langone Health where he's a medical oncologist. So nice to have you here today, Arjun.

Arjun Balar: Thanks for having me.

Alicia Morgans: Thank you. I wanted to talk with you today about non-muscle invasive bladder cancer and I think some may say, why is it important for a medical oncologist to really be engaged in that conversation. I think that the time may be here where we do need to engage and that's because of systemic checkpoint inhibitor therapy and some of the recent developments in that arena for men and women with non-muscle invasive disease. Can you tell me a little bit more about that story?

Arjun Balar: Absolutely. You point to an important issue. Non-muscle invasive bladder cancer has historically been in the domain of urologic oncologists and for good reason. They do the cystoscopies, TURBTs. They instill intravesical therapy. They monitor these patients for disease response and progression and then counsel them about radical cystectomy when that time is appropriate. What is different now and maybe changed forever for the future, is that we are now demonstrating activity for systemic I-O agents, specifically PD-1 antibodies in non-muscle invasive bladder cancer based off of a very important study, Keynote-057 which was conducted specifically in high-risk BCG unresponsive and NMIBC.

Alicia Morgans: Great. Where does this stand though, in the process of ultimately getting to patients? Can you review the data, response rates, those kinds of things in Keynote-057?

Arjun Balar: Absolutely. Let's firstly give a little bit of context to the evolution of this particular trial. It actually first begins in 2013 when the FDA convened with the AUA and other leaders in bladder cancer and held a workshop. At that time what was recognized was that there was a clear lack of new therapies in non-muscle invasive bladder cancer. For decades we had been using intravesical BCG, which we know is highly effective. It leads to responses in about 70 to 80% of people with carcinoma in situ. However, about half of these patients will ultimately either recur or be persistent despite BCG. Historically, what's been a common urologic oncology practice is that some patients just kept getting BCG despite having a persistent disease. But many of these patients were counseled about an older drug called valrubicin, which was FDA approved in 1998 but had very few, if any, long-term responses and then off-label therapies such as intravesical chemotherapy, intravesical mitomycin with also gemcitabine and docetaxel.

What that reflected was that patients who were BCG refractory or unresponsive, while they were counseled about cystectomy, most patients opted for nonsurgical therapies because they were desperate to keep their bladders. There's a substantial issue with this. Most patients are terrified of having their bladder removed because of the long-term consequences in terms of impact on the quality of life. Also, the short-term issues related to the morbidity of the surgery and sometimes mortality as well. At this 2013 workshop, investigators got together and defined that number one, a single-arm trial design was appropriate for conducting studies for future drug development in non-muscle invasive bladder cancer. They set some benchmarks in terms of what they thought were important efficacy endpoints in terms of complete response rates as well as the durability of responses.

Now it was in that context that Merck, who is developing an anti-PD-1 antibody pembrolizumab, met with the FDA and set some of the framework for a potential study in what was called high-risk non-muscle invasive bladder cancer. Then as time went on, another major important advancement came, which was to define, well actually what was BCG unresponsive bladder cancer? What that reflected was that historically we didn't define it well. Some patients were treated with very short courses of BCG, some had exposure to BCG but sometimes recurred many, many months later, sometimes a year later and these patients were included. And given that practice, it was important for the FDA along with urologic oncology specialists to define, well what is truly BCG unresponsive bladder cancer? What they first defined was what was defined as adequate BCG and then subsequently what were the criteria for having cancer that has recurred or persisted despite adequate BCG?

That was the framework and then that led to ultimately this trial called Keynote-057. Keynote-057 was a two-arm parallel study focusing on two cohorts. Cohort A, which was the focus of the FDA ODAC, which I'll mention in a moment, focused on patients who had BCG unresponsive carcinoma in situ with or without papillary tumors. In essence, patients with carcinoma in situ have a patchy diffuse disease that can be present throughout the bladder. These are patients who are at high risk for progression to muscle-invasive bladder cancer. Patients had disease going into the trial because you can't fully resect carcinoma in situ given its diffuse nature. Patients received pembrolizumab once every three weeks at the standard dose and had every three-month cystoscopic evaluations and urine cytologies.

An important issue that the FDA mandated in the conduct of this trial was that at any point during efficacy assessments if there was ever any persistent or recurrent disease, patients had to be discontinued from therapy. Primarily because this was kind of an unknown space primarily, because we didn't know what the efficacy and safety would look like. And so patients must be taken off study if they had persistent or recurrent disease and counseled about cystectomy. The data that I'm about to share with you had an early efficacy assessment at three months. So a three-month cysto and cytology determined whether patients would continue on treatment or not. What we found was that after three months of the ultimately 96 patients that were used in the efficacy analysis, the complete response rate was 41%, demonstrating that systemic immunotherapy could eradicate CIS in about 41% of patients after just three months of therapy. And of those patients, they continued on treatment and at roughly 12 months ... and at this point we have about a 28-months median follow-up for the patients who enrolled in this trial ... and that at the 12 months, the estimated, kind of complete response rate that is maintained, is about half of those CRs. So out of those 41%, half of those are actually maintained 12 months and beyond.

That roughly reflects about 20% of the intent to treat analysis. And then the median duration of response right now is about 16 months. Some of the patients which I treated on this trial from its very inception have actually had complete responses that are lasting two years or longer. Now those are small numbers right now because of the follow-up. But what we're seeing is that systemic I-O can actually lead to not only complete responses, but they can be durable in the bladder and these are patients who don't need to have their bladder taken out. I think it's a very important advancement in terms of developing novel therapies and specifically for patients who are terrified about having a radical cystectomy which we know has its own complications.

Alicia Morgans: I think just to emphasize again, this is a BCG, a truly BCG nonresponsive population that has been defined really rigorously based on that 2013 meeting with the FDA that said you guys have to be standardized. You have to be ...

Arjun Balar: Absolutely.

Alicia Morgans: ... clearly identifying this high-risk population. I think that demonstrating a response of that duration in this very high-risk population is really a critically important piece as well.

Arjun Balar: Yeah, and I think you raised an important issue which is that since it's stringently defined as a rigorously conducted study with central assessments of imaging, biopsies, urine cytologies, clear efficacy endpoints and landmarks, this sets the bar for future conduct of trials in non-muscle invasive bladder cancer. The urology literature has a number of retrospective cohort studies. It's difficult to make sense of what real at-risk populations are and ultimately what the efficacy of novel agents could be. This sets the bar against which future trials will always be compared.

Alicia Morgans: Absolutely. As you think about this moving into the clinic, which I imagine it will probably do within the next few months maybe, how do you see that working in practice? Because this is a systemic checkpoint inhibitor that would need to be given to patients. Is this a partnership between medical oncology and urology or how do we do this well, but also safely knowing the risks of these drugs as well?

Arjun Balar: That is absolutely critical. The patient's safety is probably more paramount obviously than the efficacy of any agent. I think we can say that across any disease type, right?

Arjun Balar: Importantly at the FDA ODAC which meant yesterday, there was a nine to four vote in favor of approving the drug. There was some controversy and one of the issues raised by the panel members was, well how is this going to roll out into the clinic and ultimately who is going to take real responsibility? You know, in my practice and what I have experienced in a multidisciplinary group is that the medical oncologists, we are experts at giving immunotherapy because we've been doing it in bladder cancer for at least several years now and also in treating other cancer types. Obviously none of us are ever going to pick up a cystoscope and evaluate the bladder. This really needs to be co-management between medical oncology and urology for it to be effective and safe. Where we administer the systemic I-O agent and then the urologists do the most important aspect, which is on treatment disease efficacy and monitoring. And then counseling the patients when they develop recurrent disease about their other options, which may still include a radical cystectomy.

But that model works ideally in academic, multidisciplinary centers. What do you do in a community? Urologists in most community settings will still be the best people to take care of a patient with bladder cancer, whether it's non-muscle invasive or even muscle-invasive disease. I think there it becomes a bit more challenging. What will need to happen is hope that they have a lifeline of medical oncologists in the community that they can work with. If ultimately they are in a situation where they're the ones overseeing the systemic I-O agent, they need to have kind of a Rolodex of specialists within GI, pulmonary, endocrine, perhaps even neurology ...

Alicia Morgans: Cardiology.

Arjun Balar: Cardiology, disease-specific, these kinds of specialties so that if they encounter a toxicity that they don't fully understand, that they're quick to call their specialists to help them out because ultimately the last thing you want is high-grade toxicities in a patient receiving systemic I-O. We know it doesn't happen often, but when it does it can be life-threatening.

Alicia Morgans: Absolutely. And also to counsel patients who had not really received to this point at least, systemic therapy, that this is a treatment that could, even though it's "immunotherapy", could put you in the hospital, could have life-threatening complications. Keeping both the patient and the physician community informed is going to be really critically important.

Arjun Balar: Absolutely.

Alicia Morgans: So, wonderful. If we had to wrap all of this up in one message to the audience, what is your real overarching theme, take-home point for Keynote-057 and the use of pembrolizumab in non-muscle invasive BCG-refractory patients?

Arjun Balar: I think many of us will recognize that this was a watershed moment in the management of bladder cancer. Systemic I-O, a systemic therapy is active in a localized luminal process in bladder cancer. This point forward is going to basically open a new era in systemic therapies and potentially other combinations in non-muscle invasive bladder cancer. I'm very hopeful that fewer and fewer patients need a radical cystectomy for the treatment of their bladder cancer.

Alicia Morgans: I completely agree. A message of hope for patients to keep their bladders and to do it safely. And a message for clinicians that we need to work together, but we can do it and we can get this therapy to patients in a way that's safe and helps them ultimately. It's a wonderful message. Thank you so much for your time.

Arjun Balar: My pleasure.