Alicia Morgans: Hi and welcome to continued coverage of LUGPA 2018. I am delighted to have here with me today Dr. Noah Hahn, who's an Associate Professor of Oncology and Urology at Johns Hopkins University. Thank you so much for being here today.

Noah Hahn: Thanks. It's a pleasure to be here.

Alicia Morgans: Great. Well, you're giving a really important talk today to the LUGPA organization all about how we think through complications of immunotherapy and how the urologist specifically can get involved in that, and I'd love to hear some of your thoughts.

Noah Hahn: Sure. It's a great time I think in bladder cancer and urothelial cancer in that in the last four years we've seen some tremendous breakthroughs in advanced disease patients and initially, these were with some modern use of immune therapies targeting PD1 or PDL1/2 receptors that are important for modifying the immune system's response to cancer. And with those breakthroughs that we've seen in advanced disease, naturally, we've wanted to see if we could see bigger benefits by moving up to patients with earlier-stage disease. And there are a number of clinical trials that are ongoing right now, both for patients with disease that invades into the muscle, that traditionally need surgical removal of the bladder, and there are also clinical trials that are looking at patients with non-muscle invasive bladder cancer.

And that's very important because non-muscle invasive bladder cancer is where most bladder cancer is diagnosed. Those trials are looking at both the safety, the clinical benefit, and more importantly the duration of benefit with some of these modern immunotherapies. I think it's an exciting time for bladder cancer, particularly for different disciplines. This intersection between urology, medical oncology, the radiation oncologist, it's bringing us together in a way that we've not done before. We've always worked together, but this is a different way of working together for patients with earlier-stage disease.

Alicia Morgans: You've worked a lot with these checkpoint inhibitors and with other methods of immunotherapy and you work very closely with your urology colleagues. And in fact, we just talked about you having your clinical space in the urologist's clinic at Johns Hopkins. What could you say in terms of thinking through the complications of checkpoint inhibitors or other types of immunotherapy as you think through this multidisciplinary approach to these patients?

Noah Hahn: Sure. I think as a medical oncologist, we're often shaped by our view of toxicity in dealing with patients with advanced metastatic disease. And that's a little bit different than what our urology colleagues see in that many of our patients with advanced disease have already gone through traditional therapies. They've had chemotherapy or other things and they may not have a lot of options left when they started using immune therapy. Either in the first clinical trials or then when these drugs were approved. Their willingness, I think to accept certain side effects is probably a little bit higher than patients with earlier-stage disease that are not used to having what I'll say are systemic side effects. By and large, the immunotherapies, their side effect profile compared to traditional chemotherapy is far superior. We see fewer rates of severe side effects and those side effects are now predictable and typically treatable.

But that being said, they're not side effect free. And so I think we need to respect that. We need to understand what those risks are. And I think we've done that pretty well with our use in advanced disease patients. But as we think about moving into earlier stages of disease, both for the patients and the physicians who treat them, there's a big burden I think on the educational side to teach our patients, colleagues, nurses, everyone who deals with this patient population, how frequently these side effects occur, when they occur, how to pick up on them. And I think more importantly what to do. If these side effects are picked up early, they are generally manageable. There are still some patients though that have severe side effects that, in very rare cases can even be life-threatening. I think we have to respect the side effect profile.

I think as the medical oncologist, we're typically more accustomed to dealing with side effects and how to manage them. And it's not that our urology colleagues are not either because they're very used to handling the surgical side effects, our medical oncologists are not. As we enter into potentially a world where we are having systemic side effects from drugs that we use mixed with surgical expected side effects either before or after the surgery, I think the most important thing for us is to talk to each other, to learn from our strengths and our experiences and to be able to reach out to those who have both a different perspective and maybe a different experience with a particular side effect for these patients.

Alicia Morgans: Absolutely. And that good communication I think should also come with sort of a high level of awareness of what to look for and sometimes what strikes me with some of the complications of immunotherapy is that they can be a bit more subtle in their presentation but still then lead to potentially pretty catastrophic or challenging complications. How do you keep that awareness high when the subtlety may make it difficult to detect these side effects?

Noah Hahn: Well, I think in a weird way, I think the fact that some of the side effects of immunotherapy can be a little bit cryptic in that they can come on at different time points. It's not necessarily like with chemotherapy where if we expect someone to have suppression of their bone marrow, we can expect it earlier with subsequent therapies. We can have patients on immunotherapy that are sailing along for nine months or a year with no side effects and then they can have an autoimmune colitis or something else occur. And I think in a strange way, I think that's a good thing for all of us as a field because it forces us to think. It forces us to think about the patient, the processes that could be going on. And I think it forces us to think about the entire body and all the different disease processes or mechanisms that could be affected by immune therapy.

I think in the long run that's probably a good thing. There's been a lot of advancements as we've seen very, very subspecialized care and centers of excellence and getting very good at very, very focused sort of pathways of disease. But our patients are more than a pathway. And so I think the fact that the side effects in some ways need to keep us all on our toes. I think that's a good thing in the long run for our patients, as long as we are all willing to be open to continuing to think and to be curious about what our patients are telling us. They know their day to day life and their body better than anybody else. And when our patients are telling us that they've been on something for nine months or a year and a half and something is different over the last six weeks, we probably need to listen to them and investigate it to see if there's something there that we are causing.

Alicia Morgans: Absolutely. And I think it's also really important for us to educate our patients on what could be occurring and what to look for as well as educating our colleagues not necessarily just within the GU urology medical oncology realm, but also our colleagues who are hospitalists and our colleagues who are cardiologists or our colleagues who are in the emergency department so that they're all kind of thinking through this because as a team, like you said, really thinking through the more complex systems in our bodies rather than just isolated heart, lungs or bladder is going to be really important as we use these therapies.

Noah Hahn: Yeah, I couldn't agree more. I think it's not just about, we're talking about bladder cancer today and some of the different cross disciplines involved with the care of bladder cancer, but I think what immunotherapy has done in terms of crossing really multiple, multiple different diseases. It's something that all physicians have to be familiar with. They don't have to be the world's expert because there are more and more immunotherapies coming out. There are multiple, multiple combinations and different approaches and some of those have unique side effects that are different than the first wave of PD1 or PDL1 inhibitors. But what it does do to us I think as a healthcare community is it does emphasize and brings up the need for us to work together. And I think that that presents a great opportunity for us that this may just be sort of the tip of the iceberg in terms of we have new therapies now for our cancer patients, but at the same time there are breakthroughs happening in rheumatology, immunology, cardiology, you name it.

And there are just as important breakthroughs happening there that in our oncology world and urology we may not be as familiar with. I think relying on our broader healthcare community as a resource is incredibly important. I think it's just important for us as physicians to be upfront and admit what we don't know and know where to get help. And I think that with the speed of advancements that are happening across the globe, the resources are there. I think it's on us to just reach out to our colleagues who are familiar with things if we're seeing something that we haven't seen before.

Alicia Morgans: Absolutely. Something I remember hearing in residency all the time, lifelong learning. That's what physicians have to be and this is a very clear area in which we need to continue with that process. And one more point that I wanted to ask you about before I ask for your closing thoughts is the concept that these therapies, unlike traditional chemotherapy for example, where we see the side effects actually occurring predominantly during the treatments, these therapies can sometimes cause side effects months after we've actually stopped treatment with these therapies. How do you think through that? And how should urologists in the community kind of maintain this awareness even when a patient is not on an immunotherapy anymore?

Noah Hahn: Well, I think one of the things that comes right to the top of my mind when we talk about potential late side effects or even when patients are off of therapy is it brings up the need for survivorship programs and planning both within institutions, individual practices, individual specialties. And I don't think any of us has the exact answer of how this should be implemented because I think every practice and even in different parts of the country, there are regional differences in resources and how this can be done. But I do think it's our responsibility to work with our patients to continue to be a resource and an advocate for them beyond just the treatment phase of their disease. I think it's important for us to let our patients know if they're finishing therapy and they're entering into a sort of follow up phase where maybe we're not seeing them as often, maybe we're just seeing them for some scans, three months, six months, or even once a year. I think it's important for them to have a number that they know they can call and get a hold of someone.

And for every office that's different. I know for my own practice, our office coordinator is a godsend and I could not function without her. In other practices, there may be nurse practitioners, physician extenders, or other people in the group. But I think the point that you bring up about potential late side effects that can happen even after treatment has finished is an important point as we think about these immunotherapies entering into earlier stage patients and being seen and potentially managed by non-oncologists, either on clinical trial or otherwise.

Alicia Morgans: Great. What are your take-home messages for viewers?

Noah Hahn: Well, I think the immunotherapy breakthroughs that we've seen in bladder cancer in the last few years have been unprecedented. They were the first drugs approved in 30 years for bladder cancer and that's an incredible breakthrough watershed moment for the bladder cancer community. But our work is not done. When we look at patients with advanced disease, the somewhat sobering fact about immunotherapy when it's given by itself is that we're seeing somewhat of a plateau of about maybe 20 to 30% of patients that are getting a big benefit and a durable benefit. But that means the majority of our patients still need other options. I think we are looking at ways to optimize and improve the initial responses seen with immunotherapy as a single agent. And so we will see combination data coming out.

We've already seen that combining two immune therapy medications can increase the response rate. The question is does it increase durability? Is that cost of somewhat short term side effects worth it for longterm gain? We don't know yet. We're hoping that it will, but I think the encouraging thing I think for our patients in the bladder cancer community is that these breakthrough approvals for immune therapy have brought large scale drug development to bladder cancer for good. We may have some trials that come out in the next few years and I'm sure we will that maybe we missed the mark and we don't see as much of improvement as we want, but we have proven without a doubt that patients want to be on clinical trials, that they can accrue to clinical trials and that drugs can be approved if they're successful.

And I think what we're seeing here at this meeting in terms of talking about these immune therapies moving into earlier-stage patients, we're hoping that those benefits will be even bigger. But I think it's still an incredibly exciting and hopeful time for bladder cancer, and we're hoping that very soon we'll have further discussions about further breakthroughs to come.

Alicia Morgans: Absolutely. Well, I couldn't agree more. And I really appreciate your time today. Thank you, Noah.

Noah Hahn: Thanks so much for having me.