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Petros Grivas: Good morning. I'm Petros Grivas. I'm a medical oncologist and professor at University of Washington Fred Hutch Cancer Center in Seattle. I'm very excited to be here with one of the amazing contributors to the great successes we have seen in bladder cancer over the years, especially the non-muscle invasive bladder cancer, Dr. Sia Daneshmand, who is a professor at USC in Los Angeles. Sia, welcome.

Siamak Daneshmand: Thank you, Petros. It's always a pleasure to talk to you.

Petros Grivas: Thanks so much for your great work, my friend, in the field. It's impressive to see how the field has been evolving. I remember you and me were talking when I was back in Cleveland almost 10 years ago, and we were discussing the need for improvements and new agents, and there we are a decade later and we talk about the plethora of agents. So may I start asking you about the BCG unresponsive non-muscle invasive bladder cancer? We have had a series of agents that have been approved recently, a couple of more coming up in the pipeline. Can you drive us through briefly that evolving landscape?

Siamak Daneshmand: Yeah, absolutely. Thanks, Petros. So, as you said, there's been an explosion of new developments in non-muscle invasive bladder cancer. We have several new FDA-approved agents and some on the way. So it's kind of an exciting time for us researchers and clinical trialists in this arena.

For years we did not really have any new drugs or developments at all, and we were using BCG, and BCG refractory patients were going to cystectomy. Most of them, that was our recommendation. Now, we had valrubicin that was FDA-approved, but very poor one and two-year results. Eventually, it was less than 10% long-term in terms of efficacy and there really wasn't much happening until Pembro got approved in this setting for CIS with or without papillary disease as BCG refractory. That was one of the first new drugs that got FDA approved in this setting. But using checkpoint inhibitors, of course, we have a lot of experience with that in more advanced disease. We really needed more intravesical treatments that don't have the systemic potential side effects of the checkpoint inhibitors, and there have been a lot of developments in that area.

Before I get to the FDA-approved ones, I want to mention we've been using the doublet chemotherapy gemcitabine and docetaxel, and still in use, quite effective in this setting, pretty well-tolerated. There's some retrospective data that suggests its efficacy is quite good even out to two years, and we are working on some prospective trials to both validate the results of gem/doce and also start to do some comparison studies to other drugs. So we've been using gem/doce, and just recently Anktiva, or the IL-15 superagonist, nogapendekin was approved. And that's been in use, that's used with BCG in a BCG-unresponsive space. And, of course, Adstiladrin that was approved before that that we'll be discussing. That's nadofaragene firadenovec. And now, we're beginning to look at, like I said, combination trials, comparison trials, to get some clue about sequencing events.

And just a very brief mention of things to come. We have TAR-200. There's a lot of excitement with the intravesical gemcitabine releasing device that is on FDA fast track. We've had great results on the Phase III trial, SunRISe-1, and then the cretostimogene grenadenorepvec in BOND-003, also showing great efficacy in this setting. Also FDA fast track. So more exciting drugs to come.

Petros Grivas: I'm very impressed, Sia, not only with your great work in the field, but also your ability to pronounce these long names very well.

Siamak Daneshmand: Yeah. Yeah, it takes practice.

Petros Grivas: My joke is these words are long but not Greek, but still you can do it very well.

Siamak Daneshmand: True.

Petros Grivas: It's exciting to see the progress in the field, as you said, Sia, with the number of agents, most of them intravesical, as you mentioned, and of course intravenous Pembrolizumab as one of those options.

And, of course, with the many intravesical options, most of those patients having more touchpoints with our colleagues and friends in urology, more options to be given intravesically. In that regard, the question comes is one agent better than the other? Is there a need for combination treatment, intravesically or intravesical plus systemic? So in that context, I know you have been leading a large trial trying to ask this question. So tell us about your trial in progress that you presented at ASCO.

Siamak Daneshmand: Like you said, now we're beginning to look at combination therapies. Despite all these new therapies and the excitement we've had, there's still an unmet need because there is degradation of response as you move forward beyond the one year, six months, one year or two years, of course we want a prolonged response for these patients. And that's where the combination therapies come and you have to be thoughtful about which combinations you choose and how you're doing these comparisons. So ABLE-22 is the study that was presented at ASCO. This is again in the BCG unresponsive, non-muscle invasive bladder cancer. These are patients who have CIS with or without papillary disease who have not responded to the BCG induction and at least one maintenance dose, so the classic definition of BCG unresponsive disease.

So these patients are randomized. This is a randomized trial, which is great, which is what we've been hoping for all this time. Moving away from the Phase Twos, these patients are randomized to Nadofaragene Firadenovec or Adstiladrin alone versus Adstiladrin plus gemcitabine and docetaxel versus Adstiladrin with Pembrolizumab. So it's a two to two to one randomization. One would be the Pembro plus nadofaragene firadenovec, and trying to see if we can improve on the results of Nado at one year, two years. So the primary endpoint's going to be CR.

It's a pretty nimble and quick trial. It's 250 patients across the whole trial. And these are, again, the classic sort of BCG unresponsive patients. Obviously, no evidence of prior muscle invasive disease. They have to have their TURBT within 70 days of enrollment. Very typical enrollment criteria. So we're excited about this trial. I think this is one of the few that is testing the combination therapy of one of the FDA approved drugs. So it is exciting to see this. And like I said, we need 250 participants and it's going to be open in about a hundred to 150 sites across the US and also Europe and Australia and Canada as well.

Petros Grivas: That's impressive that you got this study up and running, Sia. And just to clarify, the pembrolizumab is intravenous?

Siamak Daneshmand: Yes, yes. Not intravesical. Good point.

Petros Grivas: So it's pretty much a combination of among FDA approved options, sounds like. And it's interesting that you are able to at least combine those agents that are used in clinical practice. Intravesical, non-intravesical chemotherapy, intravenous pembrolizumab are kind of the menu of options. So you're looking at these combinations to see if there is a winner there. And the sample size, as you mentioned, is not too large. So do you think you can still tease out any potential difference in terms of efficacy?

Siamak Daneshmand: Yeah, it's a good point. I think we can. We know what the results are for Nado alone based on the Phase Two trial, the CS-103 that showed us about a 25% one-year CR rate. The initial CR rate is 53%, but out to one year you get to 24-25%. So we're really hoping to improve on that, and I don't think it'll take too many patients to show that the combination therapy with gemcitabine and docetaxel will improve on that. So obviously a lot of work has gone into the statistics. If it's a two-to-two-to-one randomization, I think we'll get an early signal on the Pembro plus Adstiladrin. And we're hoping that the other combination, the one with the gemcitabine and docetaxel will sort of be the winner here.

One of the concerns about adding agents to an already difficult intravesical treatment is the toxicity. But I would remind folks that Adstiladrin is given once every three months. We know the safety profile of Nadofaragene quite well. It's very well tolerated. We know the toxicity of gemcitabine docetaxel which is also very well tolerated. And, in terms of additional visits and stuff, if we're just doing quarterly administration of Nadofaragene, hopefully it won't add that much burden to the patients getting these treatments. So I think it's a pretty well-designed trial and hopefully it'll add to what we already are doing. If we're doing gemcitabine docetaxel for this BCG unresponsive space, we're just adding Adstiladrin. So I'm pretty excited about this.

Petros Grivas: That's very exciting. I hope the trial will give us some helpful results to help our patients in this particular setting.
Last quick questions, Sia. I know it's, I would say, a relatively large trial in terms of the number of patients. So are you going to collect also some quality of life report outcomes as well?

Siamak Daneshmand: Yeah, definitely. That's a great point. And I think all of these trials going forward have some of that PRO component built into it. It's very important because everyone wants to know what is the toxicity of these treatments. Even BCG, we want to know. We've been using it for so long, we know what it is, but we want numerical values so that we can counsel our patients better about these new agents and what the side effect profile is. So part of these, of course, will be patient-related outcome measures and how well it's tolerated. Especially when you start to combine therapies, there is a bit of unknown there. Maybe there is some additional toxicity we don't know about. I really don't think so. Mechanism of action is very, very different for all these drugs. I don't think we'll have mounting toxicities. But yeah, important.

Petros Grivas: That sounds great. And I promise you that's the last question. What about biomarkers? Are you going to look at something in the tissue, in the urine, in the blood?

Siamak Daneshmand: Definitely. So we do have some exploratory endpoints in the study. We're looking at PD-L1 and PD-1 in blood and urine from screening to the end of the treatment. We probably will do some additional urine studies yet to be determined. So I think that those are also exciting new avenues to look for markers of response. So yes, they are planned.

Petros Grivas: That's exciting. Congratulations to you and your team. I know there are many investigators involved, research staff. To do a trial like this takes not a village but a whole world, and you have international sites.

Siamak Daneshmand: Yeah. There'll be international sites. They're not open yet, but we're hoping they'll open soon. We have a few sites open in the US already, and I almost have it open on my site. I'm excited. Now you've encouraged me to make a phone call to make sure it's getting open soon, but that should be happening.

Petros Grivas: Always motivated to open trials sooner across, I think, cancer centers. That's a goal we have globally.

Siamak Daneshmand: Yeah.

Petros Grivas: So I appreciate you, Sia, and really looking forward to the results as the trial accrues and matures. Hopefully, can learn a lot to help our patients. I appreciate your time today and everything that you do in the field.

Siamak Daneshmand: Thank you, Petros. It was an absolute pleasure. Thanks so much.

Petros Grivas: Thank you.

Siamak Daneshmand: Take care.