Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston, Texas. And I'm welcoming today, a friend and colleague, Dr. Girish Kulkarni all the way up from Toronto. Dr. Kulkarni is an Associate Professor in the Division of Urology at Princess Margaret Cancer Center, and has a huge interest in urologic oncology with a specific focus on bladder cancer and has done a lot of work when it comes to the management of patients who have had recurrences after BCG therapy. Girish, you have been instrumental in the editorial that came out, the recent publication for the gene therapy for BCG unresponsive bladder cancer. And I'm so pleased that you were able to accept our invitation to discuss that, and some finer points of the study. The stage is all yours.

Girish Kulkarni: Thank you Ashish again for this invitation. So I'm excited to present some of these data and mainly my comments and opinions on this new therapy for BCG unresponsive nonmuscle-invasive bladder cancer and how it will fit into the treatment paradigm moving forward. So as we all know, BCG unresponsive NMIBC is a very difficult malignancy or disease state to actually treat. These patients are plagued by a very high recurrence rate. Recurrence rates of 70 to 80% at two years. And a significant progression rate in the 20 to 30% range. Up until recently, we didn't have a lot of free man options in this space of if I want to use the old term BCG failures. And I use that term because that's where valrubicin was actually approved in 1998, but for a number of reasons, availability uptake, it just did not permeate into the urologic community.

This year, pembrolizumab was actually approved in the BCG unresponsive nonmuscle-invasive bladder cancer space. So it was the first agent approved in this setting by the FDA, and it is undergoing reviews in different countries for international approvals. So we have some reason to be excited because we have new agents coming into this space. Nevertheless, there's still a very large clinical unmet need for additional therapies in this space. And for this reason, dating back at least eight years, the AUA, the SUO, and the FDA have come together to create guidance on nonmuscle-invasive trial design to help guide industry, and disperse some interest in this previously neglected space. So many of the registration studies are Phase II trials because it's simply not ethical to randomize patients to placebo against a new agent or not pragmatic to randomize, to cystectomy compared to new agents.

So this is where our nadofaragene firadenovec comes in, this is a replication-deficient, recombinant adenovirus. It's vector-based gene therapy instilled intravesically, and went through Phase I and Phase II trials. And this was the pivotal Phase II trial published in 2017 of 40 patients. It was randomized between low and high dose, and ultimately adverse effects were very similar between the low and high dose. So they moved on to a Phase III trial. This was supported by the SUO CTC (Clinical Trials Consortium) and was a single-arm, open-label, repeat-dose clinical trial. So basically patients either with carcinoma in situ or without, meaning they only had papillary disease Ta high-grade or T1 high-grade, received intravesical nadofaragene firadenovec, and they would receive the agent at initial treatment and then every three months up to a year at which point the data was cut off. And that's presented here, but patients did have an opportunity to continue on with treatment for up to four years. And the meat of the data from this study is actually presented in the chart on the left. And you can see patients with carcinoma in situ at three months had a CR of 53%.

So this was the primary endpoint of this study CR at three months in the CIS cohort, but they also were able to report on high-grade recurrence-free survival and the high-grade Ta or T1 without CIS cohort. And at three months, that was quite high at 72.9%. And at the bottom of this chart, you can see the 12 month. So the one-year data of 24% in the CIS only cohort and 44% in the high-grade Ta or T1 without CIS cohort, overall 30%. So these data were very exciting and present another opportunity for treatments for patients with this disease and for urologists experienced surgeons in this disease space.

Now, usually we frown upon comparing studies across studies because of different methodologies in the studies. So epidemiologically, there are problems doing this yet we do it nonetheless. So here's a comparison of the new agents where a lot of data have actually been presented and on the left-hand side intravesical therapies, and on the right-hand side, the systemic therapies, which are the immune checkpoint inhibitors. And I would like to thank my friend, Dr. Peter Black for helping provide this one slide which he has put together. So here you can see the three months CR rates in the intravesical groups on the left-hand side, the nadofaragene, as I reviewed at 53%. Oportuzumab monatox, which is vicinium at 40% at three months. And the IO agents on the right-hand side at 41, 42%.

So generally, pretty good and pretty similar are at three months CR rates. At one year 24% for nadofaragene, 17% oportuzumab. Although that final publication has not come out and 19% for pembrolizumab, again, waiting for that final publication. Atezolizumab, which was SWOG 1605 was closed early for it because of a futility analysis. The main differences I would say in terms of these studies are the grade 3 to grade 5 treatment-related adverse events. So 4% a grade 3 to 5 for the intravesical agents and approximately 15% for the systemic agents. Another big differentiating aspect is actually the treatment intensity. And as I reviewed every quarter for nadofaragene, pembrolizumab is every three weeks in the KEYNOTE-057 study. But realistically we'll probably be using that every six weeks at the double dose that was approved by the FDA. Oportuzumab is very treatment intense with a big burden on patients to come in and frequently one to two weeks in the first 12 weeks and then every two weeks for two years.

So I think there are a number of points to consider when considering these different agents. First for the immune checkpoint inhibitors, as I reviewed, they do have side effects and they are immune-related and sometimes they can be significant. These agents are frequently accessed in larger centers or in cancer centers. So they may not be accessible for a smaller urological practice that isn't in a large city as one concern. In terms of the nadofaragene, urologists are familiar with this treatment modality, and that is intravesical. And patients are also used to this type of treatment because they've received BCG and many of them, or all of them have been unresponsive to BCG. The treatment frequency is very manageable. Problems with this therapy could come in the form of bladder function. Many of these patients do have problems in terms of voiding symptoms and storage symptoms. So these symptoms may actually impact a patient's ability to retain the drug intravascularly for one hour as required. Incontinence can also be an issue in this setting just as it is with BCG to actually get the proper treatment in.

And finally, nadofaragene is gene therapy. And while we are all excited about it, there may be problems in terms of acceptance in the general patient population, because it's gene therapy and a virus vector has been transfected into the bladder, and we don't know the long-term side effects of this form of gene therapy. In terms of oportuzumab, the dosing regimen are reviewed as it can be quite intense, and we are still waiting on final data from that agent.

Part of my commentary was to highlight the outcomes of the nadofaragene study and to discuss where we are with the BCG unresponsive state. But to also highlight or touch on some of the problems with Phase II trials. Now, I understand why we are doing Phase II trials, and I think they're important. And I applaud the FDA and the SCO and the AUA for moving in that direction. It will allow us to move forward in this field. But problems with Phase II studies in general are that they're not randomized. So we don't have a comparative group. So we don't know if a 50% three months CR will be that different from another study, short of just lining them up like I did, which is not statistically kosher. The other issue is endpoint assessment because assessing the primary outcome can be challenging and we only have a single group. So if a bias is introduced into outcome assessment, it won't be evenly spread across groups.

And I reviewed some of those in the commentary, for example, monitoring a positive cytology and a normal bladder with a normal cystoscopy. And then, finally identifying carcinoma in situ a few months downstream can be a problem in terms of effectiveness measurement. In the Lancet Oncology study, however, the authors did a good job of trying to account for this and spent a fair bit of ink in the methods section to review how they assessed and overcame this potential bias such as backdating the time of recurrence in a patient with positive cytology and having strict mandatory 12-month biopsy rules. Finally, when we look at AEs or even patient-reported outcomes and quality of life, the latter of which were not presented. There can be biases introduced in single-arm study. So it makes it hard to compare across studies. If the AEs are assessed at different time points or different criteria are used for the AEs.

So these are just some salient clinical epidemiological points to consider when reading these types of studies. Nevertheless, these are exciting times, we have a new approval for BCG unresponsive nonmuscle-invasive bladder cancer in 2020, that's pembrolizumab. I suspect that nadofaragene will go forth through FDA, and hopefully, it will become another option as will others coming down the pike. So I think we have more options that will come and this will only benefit our patients. And another important fact is that once we can establish a standard in this setting, then we can actually run randomized trials, just like our colleagues in radiation, oncology, and medical oncology have done so well and are lacking in the bladder cancer space. Thank you very much for the opportunity to discuss this paper and my commentary, and I'm happy to chat more.

Ashish Kamat: Thank you so much, Girish. That was a very well put together commentary and discussion on the specific paper. If I might ask you a few questions, but kind of jump in at the end and work my way backward. You mentioned running randomized studies in this space. Are you proposing then that currently, because we have one approved agent, pembrolizumab, trials that are designed starting as off now, should already be considering a competitor, or is that suggestion more based on the feeling that we might have more than one agent approved soon?

Girish Kulkarni: Well, I guess if I was to waffle, I'll be somewhere in the middle. I think we probably have a number that are coming, they've been grandfathered in and they're in the midst of evaluation. And my sense is if they came in early on and started the trials early on, they should be allowed to have the same approval process as agents like pembrolizumab or nadofaragene, or even the vicinium agent. But ultimately I think as a group, we need to come up with a consensus as to which agent or agents should be considered a gold standard. So that in a year, or two, or three, the next type of trial design we will aspire to will be randomized.

Ashish Kamat: Yeah. And that's a perfect segue because that actually brings me into the question that I wanted to ask you next. You know, you showed that nice comparison with the caveat of comparing across different studies, but recognizing that they all looked at very similar patient populations. Numbers that jumped out at most of us that are looking at the data coming out are 40 and 20, right? I mean, most of these agents appear to have a 40-ish% CR rate. And at about a year, the numbers are roughly at 20, which essentially means 80% of patients are not responding to the agent at 12 months.

So with that in mind, how would you counsel a patient that says, well, I want to try an experimental drug in a trial that's coming up, but I don't want to be randomized to an arm where I know that the best case efficacy is about 20%. Would you feel that there's clinical equipoise or do you think that single-arm studies should still be allowed to occur in this space? Because the current agents, at least the data that's coming out, I mean the approved and the ones that might be approved are not robust enough for us to recommend them truly as gold standard.

Girish Kulkarni: Well, I guess the way the Phase IIs have come through are hypothesis testing based on historical CR rate. So the valrubicin CR rates or other retrospective studies. So in the nadofaragene study, for example, their null hypothesis was 27% and they had robust statistical testing to exclude that null. So I think in that setting, we do have enough data to be able to move forward with a randomized trial. We need to at least establish a baseline or a level that allows us to get to the next step.

Ashish Kamat: And moving forward, if we assume that we have three agents approved pembrolizumab, nadofaragene, and oportuzumab, what is your sense as to how you might counsel patients that you see in your practice that show up with BCG unresponsive high-grade bladder cancer?

Girish Kulkarni: So I guess my feeling is that if all three are available and we feel that all three have very similar efficacy, more than likely the intravesical option will be favored by urologists because we're used to using those agents and the treatment frequency and burden is less on patients. But like I said, I think there are a number of patients that just will not be able to handle or manage more intravesical therapies. And if they cannot manage that, then it would most likely move on to the IO agents.

Ashish Kamat: Great. And in closing, if I would ask you to look at potential combination therapies between the agents that we just talked about and other agents that are coming up, what are some of the combination therapies that excite you the most?

Girish Kulkarni: So I think some ideas that we can even combine from these different agents that we have here are intravesical viral therapy or gene therapy, along with systemic immune checkpoint inhibitors to really maximize an immune response and also localize that immune response within the bladder. So I think that is a reasonable option that can be explored and I know that some of the companies are exploring that type of combination right now.

Ashish Kamat: Thank you so much, Girish, for taking the time in sharing with us your insights on this and other ideas related to that topic. You know, we live in crazy times right now, but it's always great to have you and chat with you about bladder cancer. Stay safe and stay well.

Girish Kulkarni: Thank you very much. And thanks for this opportunity to discuss this important field.