Christopher Wallis: Hello and thanks for joining us for this UroToday Journal Club. Today we're talking about current and emerging therapies for non-muscle-invasive bladder cancer following BCG therapy. I'm Chris Wallis. I'm one of the fellows in Urologic Oncology at Vanderbilt. Joining me is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.

Today we're focusing on a recently published collaborative view in European Urology Oncology led by Dr. Kamat titled "Evidence-Based Assessment of Current and Emerging Bladder-Sparing Therapies for Non-Muscle Invasive Bladder Cancer After BCG Therapy: A Systematic Review and Meta-Analysis". To supplement this we're going to include some emerging data that Dr. Boorjian presented at the GU ASCO meeting in February 2020 looking at the particular characteristics of Nadofaragene firadenovec (Adstiladrin®) based on a new Phase III trial that isn't yet published.

By way of background, we're going to rely on a number of collaborative reviews and systematic reviews to lay the groundwork for our discussion of the current article, but for context, bladder cancer is the ninth most common cancer worldwide. More common in industrialized nations, including most of the Western world. It is the 13th most common cause of cancer mortality and has a male predominance. As you can see in this very sophisticated pie chart approximately three-quarters of all newly diagnosed bladder cancers are non-muscle invasive while about one-quarter present with muscle-invasive disease. As most urologists and GU oncologists will know urothelial histology predominates, although it's not the only histology, but these papers will focus almost exclusively on urothelial histology.

Now, this is data from the US looking at SEER results. What we can see is that over time, dating back all the way to 1975, we've had essentially a steady state in terms of both bladder cancer diagnoses and bladder cancer deaths. This can be interpreted two ways, I suppose. One is that it's not rising but the other is that we haven't made significant increases in our management of patients with bladder cancer, such that we've driven down mortality in the way that other cancers have experienced.

This is corroborated by this figure looking at five-year relative survival. Again, from the 1970s through till present day we haven't noticed a dramatic change in five-year survival. It's important to note that this is taking into account all-comers. So again, relying on SEER data, we see the five-year relative survival for patients with bladder cancer is highly dependent upon the stage of disease at the time of presentation.

Now to focus a bit more on non-muscle invasive bladder cancer, which is the focus of the article we're reviewing today, we're talking about cancers that are superficial and in the lining of the bladder. So you can see the classic TNM classification looking at Ta, CIS or carcinoma in situ, and T1 bladder cancers. In terms of a distribution of presentation approximately 70% of non-muscle invasive bladder cancers are Ta, about 20% T1, and 10% CIS. Obviously these can coexist. Commonly high-grade Ta or T1 may coexist with CIS.

Now the risk of progression and recurrence drive our management of non-muscle invasive bladder cancers. As long as it stays non-muscle invasive this isn't typically a life-threatening condition, but rather risks of recurrence and progression predominate. So we look at a variety of tumor characteristics to determine risks of progression and recurrence. As you can see in this nomogram, and in both AUA and EAU guidelines, CIS, patients with T1 high-grade, and patients with Ta high-grade are at higher risk of recurrence and progression. There are obviously other factors in these nomograms, the number, and size of tumors, the rate of recurrence, but high-grade histology is one of the dominant factors in terms of predicting the risk of recurrence and progression.

To put it a different way this is a review from Dr. Kamat and the International Bladder Cancer Group. Based on risk stratification the risks of recurrence vary quite substantially over time, both at three, six, 12, and 24 months.

Now to put this in a slightly more usable fashion both the EAU, AUA, and SUO guidelines have come up with risk stratification approaches for non-muscle invasive bladder cancer. These differ somewhat but in general, for the purposes of this Journal Club, we're focusing on high-risk patients. That's high-grade T1, recurrent high-grade Ta or large CIS. Then the highest risk subgroup of these are the T1 high-grade with CIS, large high-grade T1, and recurrent high-grade T1.

Treatment, we know that TURBT is both diagnostic and therapeutic for patients with non-muscle invasive bladder cancer. Then further management beyond that depends on the underlying histology. This is out of the EAU guidelines and we used the risk stratification we just talked about. Those with low risk can receive a single post-operative dose of intravesical chemotherapy. Patients with intermediate-risk are recommended to receive one year of BCG therapy. Patients at high-risk are recommended for one to three years of BCG therapy.

Just by way of brief background, BCG is well established as the guideline-recommended approach for reducing the risk of recurrence and progression in patients with non-muscle invasive bladder cancer. The data for this dates back to 1976 when Dr. Morales from Queens University described the first case series of nine patients demonstrating both the immunologic effects of BCG intravesical, as well as evidence that it reduced the risk of recurrence.

Then perhaps the most well known and well-cited paper on maintenance BCG comes from Dr. Lamm and the SWOG Group looking at induction BCG followed by maintenance or without maintenance. As you can see recurrence-free survival on the far left, panel A, is significantly improved when patients received their maintenance regimes. However, BCG resistance and failure is relatively common. Patients with CIS may be particularly intrinsically resistant to BCG therapy. While a large proportion may have an initial complete response to BCG, a large proportion of those will fail to maintain their response, resulting in a large group of patients receiving BCG that either have no or a limited, duration of response to BCG. As a result, there's a need for ongoing treatments for patients with non-muscle-invasive disease who have failed BCG therapy.

Classification of BCG failure is somewhat of a moving target or an ongoing process, but this comes from the International Bladder Cancer Group and Dr. Kamat from 2016. They defined four categories: refractory, relapsing, intolerant, and unresponsive, based on the nature of a patient's response to BCG and timing of recurrence.

In 2018 the FDA came out with some specific definitions of how we should define BCG-unresponsive disease in order to guide trial design. In this setting, the FDA said that in order to be considered adequate BCG therapy, patients would have to receive at least five out of six doses of the induction course plus an additional two out of three doses of their first maintenance course, or five out of six doses of an initial induction course plus an additional two out of six doses of a second planned induction course. So patients had to receive at least seven total doses of BCG.

Then following that adequate BCG course BCG-unresponsive disease was defined as one of the following: persistent or recurrent CIS, either by itself or with Ta or T1 disease with some completion of BCG; recurrent high-grade Ta or T1 disease within six months of completion of BCG; or T1 high-grade at the first evaluation following induction of BCG, so that's at the three months cystoscopy.

With that for context, we move onto looking at this particular article and an assessment of the current and emerging options for non-muscle invasive bladder cancer after BCG with a focus on bladder-sparing therapy. But before we look at that we need to remember that bladder extra patient or with radical cystectomy remains a very reasonable option for these patients and non-muscle invasive bladder cancer is not a reason to withhold surgery. Acknowledging, of course, that many patients desire to keep their bladders for both functional reasons and due to the risk of surgery.

I'll hand it over now to Dr. Klaassen to talk about the nuances of this systematic review and meta-analysis.

Zachary Klaassen: Thanks, Chris. This study did a systematic literature search looking at articles from January 2007 until June 2019. You can see that they used the MEDLINE®, Embase®, and Cochrane Controlled Register of Trials to do their research. Then to supplement this, especially in the fast-moving academic world that we live in, they also looked at the abstracts from the SUO, AUA, ASCO, GU ASCO, EAU, and ESMO from January 2016 until June 2019.

The outcomes for this systematic review were evaluated at three, six, and 12 months. Most of these studies either looked at the complete response, recurrence-free survival or disease-free survival. For the purposes of the analysis for this systematic review, they generated a pooled estimate between these three entities. The discontinuation due to the treatment of adverse events. They looked at CIS and/or papillary-only disease.

This is the systematic literature review PRISMA diagram, which is commonly seen with large systematic reviews. You can see here at the top their identification strategy and all the way down to what their exclusion and reasons for exclusion were. You can see at the bottom of the slide that they included 30 studies, 18 were full-text publications and 12 were in abstract form only.

As I mentioned there were 30 studies. Data from 23 trials were included for the meta-analysis. Included in this, by way of description, were 17 single-arm studies, there were three Phase III trials, and there were four Phase II/III trails included.

By way of patient characteristics, in the population of bladder cancers in the elderly, so not surprisingly, the median patient age was 66-78.5 years. You can see on this list here the description of BCG trials, as Chris previously went through some of the terminology, there were nine trials for BCG-refractory, eight for BCG-unresponsive, six for BCG failure, three for recurrent non-muscle invasive bladder cancer, two BCG-refractory or relapsing disease, and one study looking at BCG-unresponsive or intolerant disease.

The way they grouped this was basically by the number of prior BCG courses, so the first set of slides we'll look at trials with greater than two prior BCG courses. You can see in this diagram that there are estimates provided on the right side. If you look down at the bottom, the overall, 46% of patients had a three month pooled estimate of complete response, recurrence-free survival or disease-free survival rate. Looking at some of the nuanced studies in 2017, looking at Nadofaragene firadenovec (Adstiladrin®), had a 68% three-month response rate. Looking down at the De Wit study and pembrolizumab had a 41%. The highest was actually in the paclitaxel hyaluronic acid at 73% at three months.

Similar and moving onto the six-month pooled estimate response rate decreasing down to 38% in the overall pooled estimate. Once again you can see that this was a consistent decrease at six months for these four studies.

Then finally, for the more than two prior BCG courses, there's the 12-month pooled estimate where it was 24% overall. Some of the higher ones, as we can see at the top, the Shore study looking at Nadofaragene firadenovec (Adstiladrin®), 37% 12-month complete response, recurrence-free survival or disease-free survival rate.

I'll take a minute just to highlight two studies here now. The first study, as mentioned by Dr. Shore and colleagues in 2017, was published in the Journal of Clinical Oncology. They looked at intravesical Nadofaragene firadenovec (Adstiladrin®) for high-grade BCG-refractory or relapse of non-muscle-invasive bladder cancer. This is a Phase II trial. Nadofaragene firadenovec (Adstiladrin®) is a replication-deficient recombinant adenovirus gene transfer vector.

This study, like I said, was a Phase II. There were 40 patients with high-grade BCG-refractory or relapsed non-muscle invasive bladder cancer received Nadofaragene firadenovec (Adstiladrin®) at two different doses. You can see the lower dose had 21 patients and the higher dose had 19 patients. They assessed patients responding at three, six, and nine months. If these patients had a response at this time period they were subsequently retreated at the respective four, seven, and 10 months with the primary endpoint in this Phase II study of 12-month high-grade recurrence-free survival.

This is sort of the take-home table from this study. You can see here this is the incidents of high-grade recurrence-free survival at three, six, nine, and 12 months. I'll direct your attention to the lower right of the screen, the overall 12-month recurrence-free survival was 35% corresponding to 14 patients. Among these 14 patients, there was durable response from most of these patients, up to 24 months actually.

The second study that we'll briefly highlight is the KEYNOTE-052. This was first presented at ASCO in 2019. It's yet to be published but this is the abstract form. This is pembrolizumab for patients with high-risk non-muscle-invasive bladder cancer unresponsive to BCG. This was updated results for KEYNOTE-052, the Phase II study assessing BCG-unresponsive patients with CIS plus or minus papillary tumors.

Looking at this paper they used pembrolizumab 200 milligrams every three weeks for 24 months or until the patient developed recurrence, progression or toxicity. The key endpoints for this study, by Dr. De Wit and colleagues, was complete response rate as well as duration of response.

You can see here in this table this is the complete response rate for 42 patients. It was a 41% complete response rate, which is actually quite good. You can see that 40% of patients had persistent disease and 6.9% had recurrent disease.

Looking at the duration of complete response, the median duration of complete response was 13.5 months. Importantly 80% of these patients complete response duration of more than six months and 57% had a complete response duration of more than 12 months.

Going back to the paper we're discussing by Dr. Kamat we then switch over to their second set of slides, in terms of trials with more than one prior BCG course. You can see that there are more studies included in this. In patients with greater than 50%, CIS you can see that at three months response rate was 49%. Whereas, patients with less than 50% CIS the response rate was 60%. Similar looking at six months in those with greater than 50% CIS the overall response rate was 38% and corresponding with those with less than 50% CIS component was 49% response rate at six months. Finally, looking at the 12-month response rates for patients with prior BCG course for patients with greater than 50% CIS there was a 23% response rate and 36% response rate for patients with less than 50% CIS at 12 months.

In terms of the safety analysis, this is looking at discontinuation rate to treatment-related adverse events for patients that had at least two prior BCG courses. Only 3% overall, you can see in the bottom right, discontinuation due to treatment-related adverse events. The Nadofaragene firadenovec (Adstiladrin®) study at the top, by Dr. Shore, had a 0% discontinuation rate. Whereas, the pembrolizumab KEYNOTE-057 study had a 9% discontinuation rate due to treatment-related adverse events.

Looking at the discontinuation rate in patients that had at least one prior BCG course for patients with greater than 50% CIS the discontinuation rate was 6%. For those with less than 50% CIS, it was 13%. For those with unknown CIS status, it was 3%. Taking everything together, all these studies, the overall discontinuation rate due to treatment adverse related events was 5%.

There's a number of ongoing clinical trials. This is part of the Kamat systematic review. You can see here this was just basically a list of this table. Then lots of exciting work being done in this disease state. Looking at the top this is the Phase III Nadofaragene firadenovec (Adstiladrin®) trial. There's also a Phase III pembrolizumab plus BCG trial going on. The PANVAC plus BCG. As well as, you can see at the bottom, nivolumab Phase II randomized control trial.

We'll look a little closer at the Nadofaragene firadenovec (Adstiladrin®) Phase III trial. As Chris mentioned at the beginning of our Journal Club this data was presented in February of 2020 at the GU ASCO symposium by Dr. Boorjian from the Mayo Clinic. This was looking at the safety and efficacy of Nadofaragene firadenovec (Adstiladrin®) for patients with high-grade BCG-unresponsive non-muscle-invasive bladder cancer. This is the first results of this Phase III trial, which we looked at on the last slide.

This Phase III trial the primary objective was to evaluate the complete response rate in patients with CIS with or without high-grade Ta or T1 papillary disease at any time after the first installation of Nadofaragene firadenovec (Adstiladrin®). Secondary objectives were to evaluate the durability of the complete response in patients with or without high-grade Ta or T1 disease and to evaluate the rate and durability of high-grade recurrence-free survival in patients with high-grade Ta or papillary T1 disease only.

You can look at this table here by Dr. Boorjian. You can see that the three-month rate overall in 151 patients was 59% high-grade response rate. Subsequently, down to 12 months, 30% overall and 43% for papillary disease, corresponding to 24% for patients with CIS.

Importantly the durability of response in patients who achieved a complete response was also important. You can see that for 35 patients that have papillary disease they had a 12-month durability response rate of 60% and 45% for 55 patients with CIS. So good results, especially in this BCG-refractory group.

Just to finish up the ongoing clinical trials, there are several more going on as well. You can see the durvalumab Phase II single-arm trial is ongoing as well as the atezolizumab Phase II single-arm trial. Both of these trials hoping to report data in the next couple of years. Finally, there's another trial going on looking at intravesical Nadofaragene firadenovec (Adstiladrin®), which should be reporting also in the next couple of years.

So lots of activity in this BCG-unresponsive and refractory disease state. This is important as patients, as Chris mentioned, [inaudible] cystectomy would like to preserve their bladder. This is a high unmet need. We need efficacious treatments to improve clinical outcomes in these patients that recur after BCG who do not want a cystectomy. Certainly, there's large variability in evaluating treatment, which also highlights the need for consistent endpoint reporting. As you could see in this systematic review we discussed they had to do an estimate of recurrence-free survival, disease-free survival, and complete response. We need to streamline how we're reporting these outcomes for comparison. Because, and certainly as we've discussed today, there's promising emerging treatments, such as pembrolizumab and Nadofaragene firadenovec (Adstiladrin®), which have been evaluated for the efficacious and safe options, and convenient administration schedule.

Just to conclude the Journal Club we will discuss a couple of what we think are pertinent questions that the urology and oncology community may have with regards to BCG-unresponsive disease, as well as this paper. I'll ask Chris at this point in time in 2020 what's the optimal treatment approach after BCG?

Christopher Wallis: I think this is one of those nuanced questions. You know there are many urologists out there who have many more years experience than I, but I think there is no single optimal treatment. I think that's the hard part of these discussions with our patients, is it's always about trade-offs and uncertainty. I think we need to know the data and know the options, and layout the options for our patients and let them decide. I think radical cystectomy has to remain on the table and should be discussed with anyone who's got BCG-refractory disease, particularly patients with BCG-refractory CIS.

Given the uncertainty in the data, I think clinical trial enrollment also remains a top option. We don't have a clear preferential choice for patients who want to preserve their bladders. I think enrollment in ongoing trials can both get patients to access to agents they may not otherwise be able to receive, as well as help contribute to the body of knowledge to guide future patients' treatments.

In terms of intravesical therapies, we reviewed a number of those studies in the Journal Club today. I think Nadofaragene firadenovec (Adstiladrin®) is certainly offering promising data but not yet FDA approved. Other intravesical therapies and more traditional approaches using things like mitomycin-C or using gemcitabine and docetaxel, I think are becoming less preferred over time as we get options. Certainly, systemic immunotherapy with pembrolizumab is now FDA approved and should be part of any of these discussions. As we await the trials of durvalumab and atezolizumab we'll, again, have potentially more options, which is great for our patients but potentially makes these discussions even more difficult as there's a clear-cut [inaudible]. There's also no head-to-head trials, which can guide our treatment council.

While efficacy outcomes are important, tolerability is also really important. Probably a large part of why patients are interested in bladder-sparing approaches, rather than radical cystectomy. The next, perhaps, relevant question is what is the tolerability of some of these emerging treatments. The most interesting one, to urologists, may be intravesical Nadofaragene firadenovec (Adstiladrin®).

So I'll ask you, Zach, what can you tell us about the common side effects of Nadofaragene firadenovec (Adstiladrin®)?

Zachary Klaassen: Yeah. I think the biggest thing, in terms of obviously we want efficacy in these patients but we also want tolerability, BCG being commonly associated with cystitis and obviously more commonly more systemic issues in a few percentage of patients.

But looking back at the Nadofaragene firadenovec (Adstiladrin®) trial, from what Dr. Boorjan presented at GU ASCO, this really does look like a very tolerable drug, which is great. This is his adverse event slide from that talk. You can see that any local or systemic adverse event rate was 70%. Not surprising that it's still a treatment, there are going to be some side effects, but if you look at the serious adverse events it was only 1.9%. You can see here in his asterisk that one of these was sepsis, one was syncope, one was hematuria. Grade 3 adverse event rate was only 3.8%. No deaths due to treatment-related adverse events. Similar to the BCG population most common study-related adverse event is irritative voiding symptoms.

I think these patients have all been through BCG, they understand that there's going to be some side effect profile associated with it, but I think it's encouraging results from the Nadofaragene firadenovec (Adstiladrin®) study that this seems to be a very well-tolerated medication and treatment option.

I think as we move forward, and as you mentioned already, looking at efficacy comparisons between Nadofaragene firadenovec (Adstiladrin®), the other FDA approved is VALSTAR®, and now recently with the FDA approval of pembrolizumab we'll be looking at comparing efficacy, but certainly, we can't forget about the tolerability and adverse event profile. At least right now it looks like for Nadofaragene firadenovec (Adstiladrin®) this is quite well-tolerated, which is great.

With that Chris and I will wrap up this Journal Club for UroToday looking at non-muscle-invasive bladder cancer and reviewing this exciting systematic review by Dr. Kamat and colleagues that was recently published in European Urology and Oncology. Thanks so much for your attention.