High Grade Non-Muscle Invasive Bladder Cancer and BCG Refractory Patient - Josh Meeks

September 21, 2018

(Length of Discussion: 12 min)

Alicia Morgans and Josh Meeks highlight ongoing trials in non-muscle invasive bladder cancer.  Reviews of SWOG 1602 and 1605, highlight the great work being done in the search for treatment options for patients with this disease, the ultimate hope for patients is to retain their bladder and potentially be cancer-free. 

Joshua J Meeks, MD, Ph.D., is an Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine, as well as Section Chief of Robotic Surgery at the Jesse Brown VA Medical Center

Alicia Morgans, MD, MPH

Read the full video transcript

Dr. Alicia Morgans: Hi, and welcome back to continued 2018 AUA coverage. We have with us today Dr. Josh Meeks, who is an assistant professor of Urology at Northwestern University, Feinberg School of Medicine. Thank you so much for being here with us today. 

Dr. Josh Meeks: Thank you, Alicia, for having me. 

Dr. Alicia Morgans: Of course. We wanted to really talk about non-muscle invasive bladder cancer, particularly BCG refractory patients. It's a challenging clinical space. Can you tell me a little bit about your thoughts on this?

Dr. Josh Meeks: Yeah, I think the real problem starts with BCG in general, and it's a drug that we've used and been successful with for over 40 years. It was mid-1970's when we first started using BCG to treat bladder cancer, and one of the problems is, it was so successful, so early on. And it has been successful ever since. But I'd say we still really don't know why people respond. Why they don't respond. Why response goes down over time. So, it's some very early important questions that we've never really ever figured out. And I think that's kind of why we haven't figured out why people fail. So, really there's been a renaissance and people studying non-muscle invasive disease, and a lot of that's been driven by the medical oncology world. So, you folks have developed very nice therapies and immunotherapy, checkpoint therapy and really that's led to us understanding the immune system better, and so people are now taking that and applying that back to BCG to ask major questions about why BCG works and doesn't work. So, before we get to BCG refractories, I think you have to figure out BCG. Like why it works.

So, one of the main questions in that setting right now is of. It's Robert Svatek’s trial, open about a year ago, the goal for it is to be the biggest trial in non-muscle invasive bladder cancer in North America. It's going to be over 900 patients, and the real questions for that trial is number one, is there a difference in response based on strain. You know nationally, internationally, there's probably two to three major strains. Now only two strains. With Merck's TICE and then Tokyo-172 that's given all across Asia. We don't know if there's a difference in response by strain. And people respond differently, there's some retrospective data that Tokyo may do better in the early phase, but if you give maintenance, Merck may be just as good. Never been compared head to head. So that's one question.

The second question is, if you have immunity before BCG, will you respond better? So there's some data that people who are vaccinated to tuberculosis, and are PPD positive, actually have a better response to BCG long term. Once again, all retrospective data.

Dr. Alicia Morgans: Sure.

Dr. Josh Meeks: So, the three arms of that are people are going to get standard of care of Merck. They're going to get ... The second arm is Tokyo-172, and the third is they get primed three weeks ahead of time with an intradermal dose, and seeing if that ... And then you get Tokyo-172 to see if you have a difference in response. And I think there's a lot of hope that you can amplify response to people by priming them. There's very nice translational questions about response, how do you measure response, so we're going to get a lot of data about people in a very regulated way. And that's kind of been another issue with BCG is that until the 2016 guideline about how we should give it, how you should give it in maintenance settings, I would say that we haven't been as formatted as for example medical oncologists about giving a drug and seeing a response and monitoring the outcome. So, the hope is that this will standardize things a little bit.

Dr. Alicia Morgans: So, agreed. It's really fascinating that BCG was one of our earliest immunotherapies and because of that, potentially, we haven't done all of the correlative work, or understanding the biomarkers that may help us choose patients who are going to respond, or not respond, or even necessarily understanding the specifics about how it's working on really a granular molecular level. So, it sounds like you’re going to be able to dig into this with some of the correlatives on that study.

Dr. Josh Meeks: I mean that's the hope. You know, when we see patients with non-muscle invasive bladder cancer, we start with BCG. And we give them the drug. And most of them respond. But many will still have recurrences. And we don't really know why people get six doses. We always joke that we gave that because the BCG came in a pack of six. That's why we give six. So maybe people don't need six. Maybe sometimes people need more. Now that we're able to monitor the immune system so much better, the hope is that we can almost define that at a better level. And Rob Svatek’s doing a lot of that work, and that's why this trial is so good for him.

The second thing is that we only have one strain available in the U.S. And we probably ... Gosh, I think that was almost four years ago, we had a severe shortage of BCG. 

Dr. Alicia Morgans: Yes.

Dr. Josh Meeks: We had patients getting fractionated doses, like 1/3 dose, they were getting chemotherapy when they shouldn't have. And so, while this isn't a registration trial, the hope is that this is potentially opened the path for having Tokyo be available to patients in the U.S. And there may be people who respond better to Tokyo than to TICE, we just don't know, and the hope is that we can figure that out from this trial.

Dr. Alicia Morgans: That's great. I love the idea of using a cooperative group mechanism to optimize our utilization of a therapy that's been around for a long time, because that's ... Otherwise, these things don't happen. These studies are not done. And I applaud you, and your team at SWOG for helping us get there and bring this to the next level.

Dr. Josh Meeks: That's the whole ... You would hope that in the U.S., this should be ... I think this is open ... You know, like 400 sites now. So the hope would be almost every patient that comes in, that's BCG naïve that would qualify for BCG and be PPD negative, that they could potentially be a candidate for that. And when we talk to our patients especially at Northwestern, universally, everyone's very excited, because there's no losers in this trial. There's no control arm, there's no group that's not going to get BCG. They're all going to get intravesical therapy. The question is are they going to respond differently. And what I've been really impressed with is in the community of patients, they all want to participate, because they want to make an impact on their cancer. And this is their way to do that. They want to fight bladder cancer, and this is their opportunity to do that. They're ready to help us figure it out.

Dr. Alicia Morgans: That's great. Well, Kudos, again. And I really look forward to hearing about that data, and maybe we can chat about it in a year or two, or maybe a few years, but great. Thank you. So, what about the non-muscle invasive BCG refractory crowd though, because that's another sort of heart-wrenching moment, when you find that you need more therapy, the BCG alone did not work. So, what's going on in that space?

Dr. Josh Meeks: That's another very important space for us. As urologists and I think honestly, in medical oncology, that's something that we're going to start working together more on. 

Dr. Alicia Morgans: Yes.

Dr. Josh Meeks: So, I think the first question is defining that population. We found that as we move from 1602 SWOG opened a companion study that was 1605, that was Peter Black, and Parminder Singh study, that's giving IV, atezolizumab, and that's an entryway that if these patients fail 1602, or their tumor comes back, that they then can go onto another trial for them. And, one of the things we've identified is that there's a pretty heterogeneous population of those patients. Meaning that, there's a lot of different BCG given, so first of all, making sure they fit the criteria, but once they do qualify, I think that we're starting to approach them from an IV perspective, trying to figure out maybe they didn't respond because they didn't have a large enough immune response. So, that's a trial where people will get every three-week dose of atezolizumab to see if that will potentially remove the exhaustion from their T-cells and have an immune response. 

That's open across the country and accruing very well. At Northwestern, we have a very rare opportunity to have an investigator initiated trial that we started probably opened a year ago, and it's the only trial in the U.S. where we're giving intravesical pembrolizumab. And, you know the concept there is that as urologists, A, were comfortable giving drugs in the bladder, but B, you know it's expressed on the tumor. So, if you do immunochemistry for the tumors, they strongly ... Many of them will strongly express PDL1 at the tumor level, so there may be an effect just giving it in the bladder.

So there's a phase 1 trial. You know, people get both pembro and BCG for the first six weeks, and then the maintenance is all pembro, because once again we know that if you give BCG a long time, there can be side effects, the hope is that pembro will be a little bit better, and the goal from a preclinical end is that these tumors, you know while BCG works at first, the T-cells may get exhausted.

Dr. Alicia Morgans: Sure.

Dr. Josh Meeks: So, if you can keep that exhaustion down, if you can keep the T-cells working, you may have a prolonged anti-tumor response.

Dr. Alicia Morgans: And you may be able to do it in a tolerable way.

Dr. Josh Meeks: Right.

Dr. Alicia Morgans: Which is really important. So, these patients, again, they don't have muscle-invasive disease, and so toxicity is always something that we need to think about in this population. I know from a infusion standpoint, in the development of some of these studies, some of the concerns that were raised were the toxicities associated with these checkpoint inhibitors. So how do you think through that as you're thinking about these treatments with patients?

Dr. Josh Meeks: The great question, and it's one thing, to your point, if someone's got metastatic disease, they failed chemotherapy, you know, in this space IO has done great, but there is some toxicity associated with it. It's very different than the non-muscle invasive population. These folks, they do have treatment refractory disease, but they have other options. We know that cystectomy will cure most of them, but at a price, with a lot of morbidity. So our goal really is to minimize the toxicity. So, for example, there's patients with colitis, there's people with auto immune disease that if you gave it systemically, you worry about the response, but the hope is if you could direct it right into the bladder, you may actually have just as much treatment response without the toxicity.

So, we're seeing once again, it's a phase 1, so we're escalating the dose, and the hope is that they will respond to it.

Dr. Alicia Morgans: So, it sounds like you've already been able to escalate the dose. And I know we've talked about this before so I know you've been able to escalate the dose. Can you tell me about how that's going? Theoretically, at least, you could think that if your giving BCG and you’re simultaneously giving a checkpoint agent, that you might really augment the toxicity of the BCG, even if you’re not really causing trouble directly with the checkpoint inhibitor. So how are patients tolerating it. It sounds like you've been able to at least increase the dose over time.

Dr. Josh Meeks: Yes, so because it's a phase 1, and the FDA to their credit really wants us to go slow with this, because we don't have a lot of data that this is safe.

Dr. Alicia Morgans: Yes.

Dr. Josh Meeks: And it's really not ... And as a phase 1, it's not even a question of response as much as toxicity.

Dr. Alicia Morgans: Safety, yep.

Dr. Josh Meeks: And we've really not seen a problem so far. I mean, we're ... If you remember pembro was originally 1,2,5 and 10, mgs when we were doing the early phase 1 studies, we're doing the same for the intravesical, so we're through the 2 mg dosing, and so far, we've had no dose-limiting toxicity. So, it seems to be at least pretty tolerable to patients. And not any worse with BCG.

Dr. Alicia Morgans: That's great. Well, it sounds like we've got options coming down the pipe for patients. Or at least studies that will help to define what works and what doesn't work. So that's fantastic. So what closing thoughts do you have on this, and on the studies that are really helping to move forward the non-muscle invasive bladder cancer case, and how we can optimize our treatment?

Dr. Josh Meeks: You know, I think that this is a very bright time for people that are interested in both bladder cancer, as well as in non-muscle invasive bladder cancer. We're definitely benefiting from all the great work that's being done in medical oncology. People who are studying these questions in the metastatic setting. We're learning from one cancer, melanoma, how we can apply those therapies to bladder, and then I think just as people with metastatic disease are getting these treatments, we're moving them to non-muscle invasive disease, so our hope is that people don't need to lose their bladder for a disease that's hopefully treatable. I always think of it as finding the right key to unlock their tumor, and let them be able to retain their bladder, and potentially be cancer-free.

Dr. Alicia Morgans: That's a great message. Thanks so much for your time, Dr. Meeks. And, have a great meeting.

Dr. Josh Meeks: Thanks Alicia.