Sam Chang: Hi, this is Sam Chang from Nashville, Tennessee, and we are here with world-renowned Professor, Dr. Ashish Kamat, who is a professor at MD Anderson Cancer Center. And we're going to actually have a discussion about making the transition from a clinical trial practice using the medication Adstiladrin and looking at that as we integrate it into everyday use. So Ashish, first of all, thanks so much for spending some time with us.

Ashish Kamat: So Sam, first off, thanks for having me here. And this is a topic that you know so much about and we've talked about so many times. So I feel like I'm sitting here chatting with a friend.

Sam Chang: Yeah. As we are in a very exciting time with obviously the BCG-unresponsive space in non-muscle invasive bladder cancer. And that's expanding to actually all non-muscle invasive bladder cancer. But as you start trying to determine what you're going to treat patients with in this space, how are you rationalizing the decision and how are you integrating Adstiladrin in your practice?

Ashish Kamat: So we have an embarrassment of riches, right, which is great for our patients. And when you talk about Adstiladrin or Nadofaragene as its generic name is, it certainly has a role to play. First off, this was a drug that was studied with the help of the SUO-CTC. It was a well-run study, rigorously looked at, and of course, approved by the FDA and is now actually available commercially and used in the United States. The key data points when you look at Nadofaragene is what is the complete response rate, right? And that's in the 53% range. Keeping in mind that patients were not allowed to be re-induced, unlike some of the newer studies.

Sam Chang: Yes. I was going to ask you about that. Yeah.

Ashish Kamat: Some of the newer studies allowed the patients to be re-induced with the drug, which I think is great because that's what we have learned, the community, it's safe to do that, right? But when Nadofaragene was being studied, we didn't know that. So because of that, the FDA, and of course the SUO-CTC said, "If a patient has no response, they come off the study."

Sam Chang: They came off the study. And basically that's why all the data basically is based upon that initial three-month CR. We don't know what would happen at another repeat treatment, what actually would happen to those people as they were censored out.

Ashish Kamat: Exactly.

Sam Chang: So as you contemplate currently what's available, FDA approved Valrubicin, nobody's using it, check. Chemotherapy options, monotherapy gemcitabine, combination gemcitabine docetaxel. In practice today in the US, at least some are still using mitomycin. So we have chemotherapy options, trials ongoing. Obviously a good time to give a shout-out to Max Cates in his Bridge Trial, that being actually in the BCG-naive population, but people using this in combination. And now we have Adstiladrin along with many clinical trials. So tell me how you integrate Adstiladrin in your clinical practice?

Ashish Kamat: Great question. And this is actually the topic of a full one-and-a-half-day retreat that the International Bladder Cancer Group had just this last August. And how do we actually integrate Adstiladrin and the other drugs? Where do we sequence them in a patient that's BCG-responsive? So in my mind, honestly, one of the huge benefits of Nadofaragene is that it has a CR that's in the 50% range, and you identify that at three months. It's also dosed once every three months, and it's extremely well tolerated.

Sam Chang: Agree.

Ashish Kamat: We know, and we've both been lamenting this along with BCAN and it is bladder cancer awareness month, so it's important for our audience to recognize that a large percentage of patients in the United States have no access to care. So we have all these drugs for people that have access, but there's a large group of people that don't have access, that live in rural areas. So I think that Adstiladrin is perfect for that patient who has to call on his or her grandson or granddaughter to take time off of work to go get treated. This is something we can tell the patient, we can give it to you once every three months. We'll give it to you. If it doesn't work, we'll know right away. And then, to bring up your point about the re-induction, I think in the real world, we all recognize that re-induction or repeat therapy would be appropriate, but to study that, the SUO-CTC actually has a trial where they're looking at a second course of Nadofaragene in patients who've had one course and have not had a response.

Sam Chang: And that's titled ABLE 41, ABLE 40. I'm not sure exactly the terminology.

Ashish Kamat: It's one of those ABLE studies.

Sam Chang: It's one of the ABLE studies. But I think a very important study in terms of evaluating real-world use because in reality, and I'll just say treatment at Vanderbilt, those that we're now evaluating after initially starting their initial course after FDA approval, but availability more recently, we're now evaluating them. And there have been some complete responses and there are those who have not responded, but whose bladders have looked better, less evidence of CIS, fewer locations, etc. That there really is I think a need to see what would happen with a repeat induction course or rather just a repeat course. I don't want to say induction because along those lines, you're going to have treatment. I think for you as you contemplate individuals, are those individuals some that you may prefer, intravesical chemotherapy versus Adstiladrin or is it a 50/50, if all things are equal, how do you kind of balance what's going to actually take place with patients?

Ashish Kamat: There's no one winner. If you look at all the data out there, yes, gem doce appears to be better at 58% at two years, but it's not a prospectively collected data set, right? But with all those limitations, it works really well.

Sam Chang: Absolutely.

Ashish Kamat: Adstiladrin Prospective Trial, no repeat therapy allowed. Same thing with Pembrolizumab. And then of course you have the other drugs that are coming out that are allowing repeat courses, including NAI, which was just approved a few days ago. But there's a pressing need now for us to actually explain all of these to our patients and say, "Well, first of all, this is an immunotherapy or this is a chemotherapy. This is once a week for six weeks. This is once every three months. This is with BCG." Do we have BCG? So it is, again, back to us. I think we got used to the discussion where we told the patient, "Radical cystectomy is the standard of care, nothing else works. Here's a clinical trial."

Now we could tell the patient, "Radical cystectomy is still the standard of care. It is very safe, so long as they're followed by expert urologists to try something, maybe even try two things. This is the data, what would you like to try first?" And if they ask me, "What would you try first as if you were the patient?" I would tell them based on their specifics, would I try gem doce first? Would I try Adstiladrin first or would I go to Pembro even, or would I try one of the other agents that are coming out?

Sam Chang: Well, I love the fact that you have verbalized, and I agree with you 110%, that the vast majority of these patients can, at least with a second line, perhaps even a third line, avoid cystectomy. And these, particularly in my opinion, CIS-TA patients, T1 patients, honestly, I put in a little separate category, that's just kind of my risk stratification internally. But I think the idea of the didactic, dogmatic, we move straight to radical cystectomy. Although in guidelines, there's an understanding that for the vast majority of these patients, we can try another treatment, and now we have options. I love the fact that you used the word "sequencing." We never had sequencing before for non-muscle invasive bladder cancer, because we didn't have options. We tried. There's really no sequencing because things didn't really work.

So to have that capability, and I look forward to studies being done in terms of at least pathophysiologically, what would make sense to do first versus alternatively, et cetera. Hypothetically and theoretically, what do you think long-term success would be better with? So, hypothetically, theoretically, I would think some form of immunotherapy, stimulation of your own body's ability to fight against cancer, would in the long-term trump a chemotherapy, that in my opinion, still needs constant exposure and that type of thing. But we don't really know. We're doing studies to figure it out. Tell me kind of your thought process, long-term versus short-term. Is there an advantage of one over the other?

Ashish Kamat: I think you're absolutely right. And we've learned that from the metastatic setting where we see that tail when you activate the body's own immune system, whether it's the T cells, the helper cells, the natural killer cells, or MHC complexes, whatever you can do. But that's not all patients. There are some patients that, transcriptomically, cannot recruit the immune system, and those patients will need chemotherapy. And as you, again, rightfully verbalized, patients have to be exposed to that chemo once a month. That's why maintenance therapy with chemo is so important. So these are all great research questions that folks that are a lot smarter than I are studying, applying for grants for, and doing work on. But the bottom line is, clinically, you and I, like you said, we can still use clinical parameters to sort of identify which patient will do better with what.

Sam Chang: Right.

Ashish Kamat: So for T1 patients, just like you, over the last 20-plus years, I've gotten more suspicious of T1 than I was when I started. I lump that in my mind as it's almost T2, and I don't want to risk my patient becoming metastatic. And then the TA and CIS, I'm perfectly fine counseling my patient, let's try one. I think this would work best. If the immunotherapy doesn't work, I would go to chemo.

Sam Chang: Chemo, exactly, yeah.

Ashish Kamat: If chemo worked, I would go to immuno. So that's sort of how I think about it.

Sam Chang: Right. And so that's in discussing things with patients, and this is a similar rationale as just as you were saying, now we do have options, and if there seems to be a benefit to one modality type, I'll stay with that modality. If there's evidence of disease recurrence, yeah, let's try a chemotherapy option. That to me only makes sense. And so, many times if I don't have a clinical trial available, it depends on cost for some of our patients, but we always offer them, here are the FDA-approved indications, here are chemotherapy options. And then we talk about it. The scheduling of once a quarter really does impact a lot of my patients that travel hours to come to Nashville to get treatment. And so you weigh that versus the once a week for six weeks for chemotherapy and then maintenance once a month, et cetera.

There can be trade-offs for so many different rationales and that type of thing. Before we finish this, at least from our experience, tolerance of the chemotherapy regimens versus immunotherapy, there are subtle differences. In our patients, that combination of gemcitabine has been a little tougher for our patients to handle. And then you throw in the docetaxel and obviously, logistically, it’s more difficult. The Adstiladrin, we're also quite careful of. This comes obviously quite cold; we need to warm it up, so there are other logistic things. So tell me, are there things in the clinic that you set up separately or differently when you have a chemotherapy combination, say, versus the Adstiladrin? Are there things that you tell your staff or work with your staff about?

Ashish Kamat: Right. I think you and I have the luxury of working at cancer centers where there are protocols in place for all of this. So I won't talk about our experience. It's very straightforward. But what I've learned when I've advised other folks that are looking to start this in their program, the first thing you want to do is check with your hospital and your clinic, what your local regulations are.

There are some hospitals like ours where it comes made up in the pharmacy, it's warmed up in the pharmacy, it comes in a closed system. So our nurses don't have to take any special precautions for gene therapy or chemotherapy. It's streamlined, right? Yes. The gemcitabine, docetaxel occupies a clinic room, but we have centers. But there is feedback that I've gotten from folks who are in good hospitals, but not a cancer center, where they're told, "No, this is gene therapy. You have to go through a completely different set of approvals and regulations." So I don't want to give or mislead people. I think if someone is thinking of setting this up at their place, talk to the folks from the company because I know they have a support system to help you navigate this, but first talk to your own hospital. I think that's critical.

Sam Chang: Right. No, that's actually a really good point, Ashish. With certain new products, say an antibiotic, okay, it's a real antibiotic. It doesn't go through specialty pharmacy. It's okay, it's something we do. But to integrate something like this does take effort, it takes a lift. And at some institutions, it's going to be much more of a lift. So you need to understand that and go through the proper channels to actually, don't over promise early on for patients, because there's going to be some time period to get these new treatments.

Actually, we have lots of biologics now coming along that we're going to need to actually then integrate into our health system. Put your forecasting cap on, as these new products come out, are we going to really be able to prevent progression of these patients to invasive disease, etc.? Are we going to make it more of a chronic disease or are we going to have higher cures? Are we going to combine treatments? Multi-loaded question of what's going to happen? Not necessarily where we go next, but what's going to happen with the combinations? Are we going to actually, if we diagnose a patient with non-muscle invasive disease, are we going to be able to keep that patient in that bucket? Or are we always going to have some patients that we're going to lose to muscle invasive and progression?

Ashish Kamat: So that's the whole goal of what we do. We want patients to be able to preserve their own bladder and not have to lose their bladder, but not at the cost of their lives, not at the expense of their lives. Putting on my forecasting cap, and again, just looking at everything we have, absolutely. The answer to that question is absolutely, we're going to be able to offer a lot more patients the ability to save their bladders, at least for the short term. The question you're asking, the question that's on everybody's mind is, what about the long term? What at five years, right? Because for a patient, 85 years old, three years, five years is a big deal.

Sam Chang: We're good, yes.

Ashish Kamat: For a patient who is 40 years old, how is this going to work? Are we going to have to try different treatments? And I suspect the answer is yes. I think we're going to have multiple treatments. And what's to say that if a particular treatment works today, you can't come back to it? One prime example is when we as a community coined the term BCG unresponsive, it was purely to direct clinical trials. It was never meant to direct clinical decisions. People are making clinical decisions based on it. So folks have looked at whether more BCG might work, and it does.

Sam Chang: No question.

Ashish Kamat: It does, right? So if BCG was used 10 years ago and the patient tried all these other treatments and now has a recurrence, why not just go back to BCG? Who knows? But I think you're right.

Sam Chang: Yeah. That leads to a point of people saying, "Okay, if they didn't respond to BCG, they'll never respond." In reality, time changes things. There's no question. And I would love to know the true denominator of the initial people that we tried to get on trials. Because a few years ago, to get on the newer medications, people needed to be BCG unresponsive, that we re-initiated so that they could enroll in trials and there are clearly some patients that I've got good news, bad news. Bad news, we can't enroll you in your trial, but the good news is we can't find any cancer. And so it does make you think that there's really a lot going on with immunotherapies. And I think the point you made about that percentage of patients that have a long tail, if you look at advanced kidney cancer, if you looked at melanoma, if you look at those different cancer types, solid tumor cancer types, that are treated with immunotherapy, obviously not all respond. In fact, the minority respond.

But when they do and get out to a certain point, we've got people who respond for years and years and years. Kidney cancer patients with metastatic disease that are here 6, 7, 8 years later, that would've never happened before. And so tapping in on who those long responders are would be fantastic. And it gives us a great opportunity to thank you and all your colleagues at Anderson, what they've basically helped develop, Nadofaragene help kind of get it to the next steps and now clinically available for patients. It's incredibly exciting and we really appreciate all your efforts and all the efforts at MD Anderson.

Ashish Kamat: Thank you, Sam, and thank you for all the work you've done on the Guidelines Committee and getting all this message out for people in the community to actually look critically at what's out there. And thank you very much for having me.

Sam Chang: Great, all right. Thanks.