Alicia Morgans: Hi, I'm so excited to be here at AUA 2022 with Dr. Seth Lerner. And we're going to talk about BCG unresponsive non-muscle invasive disease and bladder cancer. So thank you so much for being here.

Seth Lerner: Happy to be here. Yeah.

Alicia Morgans: Wonderful.

Seth Lerner: It's good to be at a meeting.

Alicia Morgans: It is absolutely good to be at a meeting in person. And so nice to talk to a world's expert on the topic of BCG and responsive disease. Are you really able to sort of help us frame that concept? What is BCG unresponsive non-muscle invasive bladder cancer?

Seth Lerner: Sure. So quite a number of years ago, the FDA approached a group of us because they were struggling with a regulatory pathway for drug development in a state where patients who'd had BCG they recurred with high grade disease and were at high risk for progression the muscle invasive bladder cancer. So you may recall that the last approved drug was Valrubicin in 1998. And prior to the approval of a checkpoint inhibitor, I think in 2016 it was a desert. So we came together and we were asked to define a group of patients for whom BCG would no longer be appropriate therapy because there was data to suggest that more than induction or two induction plus three months of maintenance or two induction courses, BCD didn't really work very well. So I think in 2018 there was guidance published by the FDA.

We wrote a paper and published it in bladder cancer. And the definition is something like this, patients with high grade papillary disease TA or T1 where carcinoma in site two and CIS can be alone or with papillary disease. And patients had to have been treated with induction plus three months of maintenance and get at least five of six and two of three or two induction courses still getting five of six, then two of six. And having recurred with high grade disease now within 12 months of BCG, so that's the definition. And so having done that, the FDA then published their guidance in 2018 and said, "okay in this patient population, you can do single arm clinical trials". Which was for registration, right? So that's kind of ANMA in the world of oncology. But the reason for that was that there was no comparator. In other words, you can't really randomize to Valrubicin because the two year efficacy is less than 10% and there was no other approved agent. So now we have a regulatory pathway, we have a patient population defined and soft to the races in terms of drug development.

Alicia Morgans: And that's so important because this is absolutely a disease that we expect will potentially progress to muscle invasive disease or worse.

Seth Lerner: Right. So that's the problem. I have to add one thing. So patients who have either persistent or recurrent high grade T one disease, so LA appropriate invasion after induction only also meet this definition. So you're right, you look at all of our guidelines are very consistent that this constitutes a high risk group. High risk for what? High risk for progression in developing a muscle invasive bladder cancer. And as you know, once that happens you lose at least 20% maybe a bit more in five year survival probability. And then the juxtaposition of that. So cystectomy is the standard of care and cystectomy is not a trivial operation. Has a 15 to 25% major complication rate, probably at least one and a half to two or 3% surgical related mortality. And so if you can avoid that or delay it, and then I think that we're making a lot of progress for these patients.

Alicia Morgans: I would agree. And I think no one would disagree that we would all like to keep our bladders in place. So just losing your bladder, I think is such a major change in someone's life.

Seth Lerner: Agreed. But you may have heard me say publicly on a number of occasions that cystectomy in this patient population has a 100% complete response rate.

Alicia Morgans: Absolutely. Absolutely.

Seth Lerner: And so it's very effective therapy when used at the right time. But no one would argue that if you can avoid it or delay it safely, then that's a win for our patients.

Alicia Morgans: And that's why we needed a regulatory pathway. So this is I think, wonderful way to set the stage. And can you tell us a little bit about where the regulatory pathway has led us?

Seth Lerner: Yeah, what's really interesting. And a number of us have worked with the FDA in a very collaborative way. That to me has been one of the most exciting things that I've gotten to do in the last decade. So what they've done is they've said, "okay, if you're going to do this single arm trial then the target population is those with CIS". Right? So you resect a papillary tumor. And so you'd start with no evidence of disease. So you're giving edge of it. Well without a control group, you really don't know the true efficacy of your drug or your intervention. With CIS, you biopsy prove it. And its natural history means that it doesn't go away without an intervention, right? So you start with CIS and then generally speaking at either three months or six months or some of the current trials anytime within 12 months, you have to do a biopsy or biopsies of the bladder cytology to verify that your drug has eliminated the CIS.

So drug companies and the NCTN. So we conducted a trial in SWG. There's a great trial going on in Alliance, combining intravesical gemcitabine and pembro. So pembro was approved. Pembrolizumab was approved, I guess January 2020 in this disease state. Exactly this trial design right out of the FDA guidance playbook. And they hit a three month CR rate in the CIS population of 39%. The rub is that at 12 months the durability was only 19% of the overall patient population but, better than Valrubicin and hit all the benchmarks that the FDA had prescribed. And so that was the first sort of drug approval. And then there's a number of clinical trials that had been completed that are under FDA review. And so it's a really exciting time.

Alicia Morgans: Absolutely. And what other approaches are you most excited about?

Seth Lerner: So the field has, and I think we all have to credit Michael O’Donnell at the University of Iowa. His depth of understanding in this disease space in non-invasive bladder cancer is wonderful. So Mike's pioneered double it and sometimes even triplet chemotherapy, intravesical chemotherapy. I also have to give credit to Jim Mancini and his group of Columbia because they've done the same thing. So the current darling so to speak, is a combination of gemcitabine and docetaxel given over a three hour period one and a half hours each. Standard intravesical therapy weekly for six weeks. And then if they respond monthly out to a year. And so the data for this looked very interesting, very exciting as high as a 45 to 50% complete response rate with good durability.

The problem is, both drugs are off label, right? And no one's done a prospective study. However, Max Kates and at Hopkins, I forget the cooperative group sorry Max. Has an approved trial that's going to run through the NCTN. So CTE, NCI of looking at this in BCG naive patients.

The topic of what we're talking about today in BCG  unresponsive, most people are using this combination off trial. Off label obviously. However the recommendation would be if you have access to a clinical trial, try to put the patients in that. So this combination I think, has been a windfall for our patients. Gives them another option. Pembro obviously is another option. And then everybody's excited about N803, which denial 15 super agonists. Sam Chang presented the clinical trial date at GU ASCO and their complete response rate at any time I think over a six month period looks really good, durability looks good, minimal sort of toxicity or acceptable toxicity. And then I have to, we've participated in and we've had funding from FKD for the intravesical ad interferon trial. This is the brain child of Colin Dinny and MD Anderson. And the beauty about that is its once a quarter.

Alicia Morgans: Yeah.

Seth Lerner: And they've been under regulatory review for quite some time. And we're all sort of waiting to see what happens there.

Alicia Morgans: Well, there's a lot of excitement and a lot going on. Clearly. I'd love to hear just your sort of final thoughts. What is your message to the listeners about this population of BCG and response of non muscle invasive bladder cancer?

Seth Lerner: Yeah. So as someone who's devoted most of my career to bladder and upper tract cancer. I find this a patient population that's incredibly challenging in the following way, is how can you figure out which patients need to really get on with definitive treatment and radical cystectomy, if they're fit for a cystectomy. Versus those that can have another run at a trial. Well certainly patients with CIS or CIS and resected TA disease. T1 disease, there's some great data from Josh Meeks from Northwestern about the molecular subtypes of T1 and trying to understand predictive biomarkers there. So trying to sort out that patient population is really tricky and. But we've got some options now, and it's been incredibly rewarding to put patients on

Alicia Morgans: I could not agree more and I sincerely appreciate your time and your expertise. Thank you.

Seth Lerner: Thanks, Alicia. Good to talk to you.