Ashish Kamat:  Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston and it's a pleasure to welcome Rian Dickstein who's Chief of Urology at the University of Maryland Baltimore Washington Medical Center and Assistant Professor at the Department of Surgery, UM School of Medicine. Rian, welcome, and thank you for taking the time to join us today.

Rian Dickstein:  Thank you for the opportunity to speak this evening. 

Ashish Kamat:  Rian, you've been very active with vicineum and of course we've seen you present it at the AUA. There's been obviously the approval of pembro earlier this year, and then, you know, there's talk about NATO, which is currently under FDA review. And then the next agent, which is vicineum, is the one that everyone's sort of looking towards and looking for the next update, whether it's going to be approved or not, but obviously not much has been published about it. So we are eagerly awaiting to hear what you have to say today. The stage is yours.

Rian Dickstein:  Okay, great. So yeah, I'm going to present the update on vicineum, otherwise known as oportuzumab monatox. So these are slides that were provided to me by Sesen Bio, the company that produces vicineum.  Just a couple of quick disclosures. I am a paid consultant for Sesen Bio and FerGene.  Well, a little bit of background. As we all know about 75% of all newly diagnosed bladder cancer patients have non-muscle invasive disease and the standard adjuvant therapy for this high-risk disease is intravesical BCG, which is aimed to decrease the risk of recurrence and progression. And about 84% of patients with CIS initially achieve a complete response with BCG, but up to 50% of patients fail to maintain that durable response. So there's a critical need for new bladder sparing therapies in the setting of non-muscle invasive bladder cancer. This is due in part to a limited therapeutic option for patients with BCG unresponsive disease.  Many patients are intolerant of BCG. There's obviously an ongoing BCG shortage and many patients either refuse or are not great candidates for radical cystectomy.

So a little bit about vicineum itself. It's a recombinant fusion protein comprised of an anti-EpCAM antibody, which is linked to a variant pseudomonas exotoxin. The exotoxin mediates tumor cell death by blocking protein synthesis and dying tumor cells display an immunogenic cell death with a response to a neo-antigen known to promote an adaptive T-cell mediated anti-tumor response.

So here's an illustration of the mechanism in action. So the mechanism first, causes direct cell kill. Vicineum selectively targets EpCam on cancer cells, leaving normal cells alone. The protein is uptaken by the cancer cells and the pseudomonas exotoxins release causing an immunogenic cell death, which is triggered by DAMPS. There's neoantigen release, activation of antigen-presenting cells. And then this causes a T-cell immediate immune response, which is the second half of the mechanism.

Now the one downside of this particular drug is the administration and dosing schedule, which is a little bit onerous for some patients, particularly during our coronavirus times that we're living in. It's an intravesical instillation for two hours, twice weekly. There's an induction course for six weeks, followed by maintenance weekly for six weeks. And those patients who were disease-free at three months, receive maintenance every two weeks for up to two years.

So I'm going to present the phase three trial data. This is a phase three single-arm multi-center registrational trial. It was in patients who have BCG unresponsive disease, which is defined as either refractory or relapsing within six months, and these are the majority of patients, or relapsing within six to 11 months.

So here's the breakdown of the cohorts. So 86 patients had CIS that was refractory or occurred within six months of adequate BCG.  Cohort Two had carcinoma in situ, that recurred between six and 11 months of adequate BCG, and that included seven patients and Cohort Three had 40 patients with a papillary tumor that has recurred or is refractory within six months of adequate BCG. The mean age is in the late sixties, early seventies, and these are mostly male patients as one would expect. In terms of prior treatment, these patients had on average about three courses of prior BCG, which is about 15 to 16 instillations of BCG, and on average have had about four prior TURBTs.

In terms of the primary endpoint, there was a three month 40% complete response rate with carcinoma in situ. In terms of the durability of this response, 52% of patients retained the complete response at nine months and 39% at 15 months. In terms of a secondary endpoint, there was a three month 71% recurrence-free survival rate with papillary disease. And in terms of the durability of this response, the median time to recurrence was about 400 days, and there was a 50% probability of remaining recurrence-free for 12 months.

Another secondary endpoint was time to cystectomy. This is a critical endpoint that this study has looked at, and we know that responders have an 88% probability of remaining cystectomy free at three years after starting treatment.

Now, word on safety and tolerability. This is a very, very well tolerated drug. In general, there were a number of patients that did have adverse events. However, the number of patients with serious adverse events was very few and only 3% of patients discontinued therapy due to serious adverse events. So again, on average, these patients did very, very well with this therapy.

Now there are a few additional trials that Sesen Bio has been looking at. The first was a planned confirmatory trial.  In this trial that will enroll BCG refractory patients who received less than adequate BCG. this will represent a broader population of patients to include those with either BCG intolerance or it will also account for patients during the BCG shortage.

It is powered to demonstrate superior efficacy with vicineum versus currently utilized therapies. And it will even include an evaluation of patients who had a delayed response. Off the books on this phase three trial, there was some delayed response seen in some patients who were initially non-responders at three months, and this is very encouraging.

The other trial that the company is performing right now is a combination trial in coordination with the NCI and AstraZeneca. So in this trial, they've combined vicineum with the checkpoint inhibitor durvalumab, and they're evaluating the expression of ligands and interaction with checkpoints and correlating to biomarkers. So we'll look forward to hearing some data from this trial in the future.

So in summary, alternatives to radical cystectomy are needed for the treatment of BCG unresponsive, non-muscle-invasive bladder cancer. Vicineum exhibits a clinically meaningful activity in the BCG unresponsive setting. Vicineum may delay or even mitigate the need for radical cystectomy in BCG unresponsive patients. And finally, despite the intense administration schedule, this is a very well-tolerated therapy with few treatment-related, serious adverse events. Thank you.

Ashish Kamat:  That was great, Rian, thank you so much for providing that summary. So from the data that you presented and, of course, you know, you're very involved with the bladder cancer world and, obviously, you know what's going on with the other agents, how would you compare or contrast the results with vicineum with what's been published with pembrolizumab and nadofaragene gene therapy? 

Rian Dickstein:  Sure. So first I just would like to say that it's really an exciting time in the bladder cancer world, because not only do we have one, but we have multiple new agents, which hasn't been seen for many years in this setting. In general, the data, I think from an efficacy perspective lines up fairly similarly with the other agents, maybe a little less effective, but in general, it falls in the same spectrum. In terms of side effect profile, again, it's an intravesical agent that's very well tolerated, so I think it has at least as good, if not a better side effect profile than the other agents. And again, the one criticism that this therapy has received more so than others, is the onerous administration schedule. It's a lot of visits in a very short amount of time, which may be a lot for patients to handle again, particularly during the COVID setting.

Ashish Kamat:  So, when you look at the CR rates and obviously for papillary disease, a three month CR rate is too early to really make much determination, but if you combine your CR rate with, in the papillary disease now, with the duration of response, what's the Kaplan-Meier estimate for the one year, which is, you know, what clinicians and patients usually ask. So at one year doc, what's the chance I'll be free of recurrence from high-grade disease?

Rian Dickstein:  Let me go back in my slide here. So here you could see at one year there's just around a 50% chance of remaining recurrence free with papillary disease.

Ashish Kamat:  Great. That's what I thought. I just wanted to confirm that. And if you look at the CIS cohort, what do those numbers end up being?

Rian Dickstein:  Sure, again, they reported the three month CR rate of 40%, but if you look at 12 months, it falls right around the 40% mark, and again, at 15 months, it's just under 40%. 

Ashish Kamat:  Now, is this 40% an absolute, or is this 40%, because, essentially half of the patients with CIS who had a CR at three months stayed disease-free and 40% had CR at three months. So is that 20% then? I mean, that's one of the things that I'm...

Rian Dickstein:  Yeah, I believe you are correct. I believe it's the 52% of those who had the initial response.

Ashish Kamat:  Yeah. Okay. So, that's similar to what we see with the other agents as well, because when you look at the CR of X percentage at three months and then do a percentage off that, people tend to get confused a little bit, but most of those numbers are in the 20 to 22% ballpark range. So is that pretty much accurate to say then that vicineum, also is comparable to what we see with NATO and pembro and the roughly 20 ish percent at 12 months?

Rian Dickstein:  I believe so. Yes.

Ashish Kamat:  Okay, great.  And then Rian, you talked about the tolerability of this agent in the patients that you've treated, or charts that you've had a chance to review, any specific side effects that stand out? Anything that is unique to this drug over intravesical administration of any agent per se?

Rian Dickstein:  They had no systemic effects in my experience.  It was all local side effects, such as urgency, frequency, dysuria, and in general, it was better tolerated than BCG itself, so meaning patients had a much easier time with this therapy than they did with prior intravesical therapies.

Ashish Kamat:  That's interesting. So even in patients who've had prior BCG exposure, they found this treatment easier to tolerate than what they have just been through?

Rian Dickstein:  Well, at least that was my experience as an investigator on the trial. That's what patients had reported to me.

Ashish Kamat:  Excellent. So, you know, any insight into where this drug is when it comes to the whole regulatory approval and what to expect from that timeline?

Rian Dickstein:  That's a great question. I know that the company is in active talks with the FDA and has presented multiple times in front of them. We're hoping that within the next year or so, it will get FDA approval, but I think that remains to be seen.

Ashish Kamat:  OK Great. And then as far as the combination studies are concerned, do you know if and when that might get open and available for patients to enroll in?

Rian Dickstein:  So I believe that the combination trial is currently enrolling or it has enrolled, but they haven't given me any details in terms of updates on the trial.

Ashish Kamat:  Okay, great, great. So that was great. Thank you so much for taking the time off in your busy day and spending time with us. In closing, maybe some thoughts from you about this drug and something to share with our audience?

Rian Dickstein:  So in closing, this is a drug that has some significant efficacy in the BCG unresponsive setting. It has little toxicity, very well tolerated. The only again, the downside is the administration schedule, but it is another opportunity that we have for our patients to at least prolong them from having cystectomy, at least, and maybe even having some long-term durable response. Again, it's another alternative to the other agents that are coming out in the market now.

Ashish Kamat:  You know, and it's great, the more options our patients have, the better it is because, as you mentioned, early on, the other drugs, well one's approved, one is likely to be approved. Of course, we don't know if it will be or not, and then if this one gets approved as well, patients can pick and choose, right? I mean, this is a local administration, it has good tolerability. The dosing schedule might be onerous, but if a patient lives close to the office or doesn't mind coming in, that sort of disadvantage is a relatively small price to pay if it gives someone a chance of saving their bladder. And, of course, the immunogenic mechanism in some ways allows for combination therapies too. So yeah, absolutely great times for the bladder cancer community. You see so much activity in this space and, thank you again for taking the time and presenting this to us.

Rian Dickstein:  Absolutely. My pleasure. Thank you for having me.