Ashish Kamat: It gives me great pleasure to welcome a good friend and colleague, Dr. Wes Kassouf. Wes, welcome. Wes is a Professor of Urologic Oncology and Director of the Urologic Oncology Program at McGill University and has been involved in bladder cancer for many years, ever since I can remember. It's surely an exciting field for bladder cancer nowadays with a lot of activity going on. Tomorrow at GU ASCO at the Plenary Session, you're covering the topic that's on everyone's minds today, which is the options for BCG-unresponsive disease. Could you share some of what your thoughts are on this topic?

Wassim Kassouf: So, just to start, BCG-unresponsive disease, just to make sure everyone's aware of the definition, right now with the revision of the FDA is defined as high-grade recurrence after adequate BCG therapy. Adequate BCG therapy includes an induction course with at least one cycle of maintenance. Now, the exception with that is if you fail with T1, then failing after induction course also qualifies you for BCG-unresponsive disease. Now the other side of it is also BCG relapsing. If you relapse with a high-grade disease within six months of your last BCG dose, if you are a Ta or T1 disease, that's also BCG unresponsive, or within 12 months of the last dose if you relapse with carcinoma in situ.

Now, as you know, there's a big unmet need. The last drug that was approved in this space is valrubicin back in 1998 with an efficacy of a very modest 8% at 30 months. So we're talking about the available options right now looking at what we use based on retrospective evidence and, as well, clinical trial data that came out with the recent FDA approval.

A couple of things. There has been a recent report looking at multi-institutional experience with sequential gemcitabine and docetaxel in that space showing a 52% high-grade recurrence-free survival at two years. That looks promising. Of course, we need prospective validation to make sure it's actually accurate because it's quite a cheap way to achieve acceptable results.

More recently, the FDA has approved pembrolizumab in this space based on a 40% CR of carcinoma in situ at three months, and the majority of which are actually durable at 12 months at approximately 20%. So that's an exciting avenue and approach as well with regards to BCG-unresponsive disease. And a couple of trials that have read out and are right now getting FDA priority review, and we'll see in the next couple of months if they're going to get approved or not. One is the Adstiladrin® and the other one is Vicinium® in that space as well.

Ashish Kamat: Right. Right. So as you mentioned, there's a lot of activity and it was a key thing that you brought up is the definition of BCG-unresponsive disease because prior to that definition there were a lot of trials coming out. The Canadian MCNA Study, for example, were clearly going in front of the regulatory bodies, they couldn't quite understand what the nuances of the disease meant and then with the workshops that we and others had, and you're involved too with the FDA and coming up with this definition. It's clearly a huge improvement to have a clear-cut entry criterion. But today, as you also know, there is a shortage of BCG. Right? So patients are not able to get BCG.

How do you think the shortage of BCG will affect the entry criteria for patients who are going into these BCG-unresponsive studies, whereas you mentioned they have to have an induction and at least one maintenance scores, but they don't have access to the drug?

Wassim Kassouf: It will for sure affect the entry criteria, making them "ineligible" if you want to be quite pure. Now, the shortage of BCG is managed by a few things depending on the guidance of your associations. In Canada, we address the shortage by not just decreasing maintenance but also one option is decreasing the dose. Now, up till now, according to the FDA guidance, they have not talked about dose per se with regards to BCG-unresponsive disease. I suspect they want a full dose, but that's not clarified in the document, but it will definitely limit the accrual of patients on BCG-unresponsive trials if the institution is affected by the shortage.

Ashish Kamat: Yeah, absolutely. And in fact, in some recent conversations, the FDA has actually insisted in a full-dose induction course but are okay with a reduced dose for the maintenance course. And clearly, that's based on not much robust science, but it is the best evidence that we have nowadays, at least from the guidance document.

How do you in your clinical practice plan to counsel patients on options when they have say, CIS, after adequate BCG? So BCG-unresponsive CIS, what's your counseling paradigm?

Wassim Kassouf: A good question. I think the whole BCG-unresponsive population is quite, although we try to homogenize it, it's still heterogeneous in a sense that if we have BCG-unresponsive Ta or CIS, there is enough data to suggest potentially we can delay a radical cystectomy to one year. As such, we can try a salvage intravesical route. However, we always advocate for upfront cystectomy in patients who fail with T1 disease because that's a different beast, and we're quite aware of the consequences of delay. So usually in my practice, anyone who fails with Ta or CIS, I discuss with them a trial of a salvage route before I pull the trigger on cystectomy. Now the salvage route could be either a BCG-interferon or sequential gemcitabine-docetaxel.

Ashish Kamat: You are still using BCG and interferon as a salvage option for these patients?

Wassim Kassouf: We are. In Canada, when we surveyed the country, I would say around 50% of the centers are still using it as a salvage option. However, we do know also the company was producing that will cease to produce it by the end of 2020, so that option will no longer be available. Again, this is data based on the Mike O'Donnell trial, which shows that there's some efficacy in BCG relapse, but not really in BCG refractory, and the critics can call that potentially early induction of BCG could achieve the similar result as well. But we're still using it in that situation particularly in patients who don't want cystectomy.

Ashish Kamat: And now that pembrolizumab has received approval for this patient population, where do you think it will fall in the treatment paradigm?

Wassim Kassouf: Absolutely. So this is the first drug since 1998 that has FDA approval, and if we have access to it, depending where you're working on a government level from reimbursement indication, then anyone would BCG-unresponsive disease should have that discussion about the merits of pembrolizumab with regards to efficacy, balancing it out with the toxicity, of course.

Ashish Kamat: And you raise an important point about the toxicity of a systemic agent. There is talk in the US about being done by medical oncologists, urologists, large groups. What's the sense in the Canadian system as to who would be administering the IO agents for patients with BCG-unresponsive disease?

Wassim Kassouf: Currently, if we evaluate the landscape in Canada, the majority I would say of the centers with the exception of one center, the medical oncologists are administering the drug. So I think it's going to rely a lot on good collaboration, communication, and multi-disciplinary effort, particularly in the space that medical oncologists has not been in there in the past. So I would say they will continue to probably administer the drug intravenously, but the urologists have to play an active role in being on top of managing the patients with regards to failure and when to pull the trigger for other alternative measures.

Ashish Kamat: Right. Again, we've covered a lot of ground in a short time. Any closing thoughts for our audience as we wrap up this conversation?

Wassim Kassouf: Well, I think it's exciting. We're finally seeing a light at the end of the tunnel, particularly in that space. So I think for the next few months I suspect we're going to have probably another one, maybe two drugs that are approved in that space. And at the end of the day is going to be us choosing which will fit the patient most by taking into account treatment intensity, treatment costs, treatment morbidity, particularly in this failed patient population.

Ashish Kamat: Right. As you mentioned early on, it's exciting times and it's a good time for both us and our patients. Once again, thank you so much for taking the time with us. It's always a pleasure.

Wassim Kassouf: Thanks, Ashish.