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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, my good friend and colleague, and literally my right hand in everything that I do, NP Brenda Martone, who is a Nurse Practitioner in our clinic and who really helps to manage all of our patients on a day to day basis, and certainly keeps me in line. Thank you so much for being here with me today, Miss Martone.

Brenda Martone: Thank you so much for having me. I'm looking forward to this conversation.

Alicia Morgans: Wonderful. So, Brenda, I wanted to talk with you a little bit about some of the new data that has come out for the treatment of patients who have either unresectable locally advanced or metastatic urothelial carcinoma who are being treated with chemotherapy upfront. The JAVELIN 100 Bladder data was really pretty transformative when it came out, I think it was the summer of 2020. In this data, we found that patients who were treated with chemotherapy and were then eligible to receive maintenance avelumab had an improvement in overall survival of just around seven months, which is so huge for this patient population.

I wanted to talk to you a little bit about the data, but also to talk to you a little bit about how we really operationalize this. So let's start. When you see a new patient with metastatic urothelial carcinoma, what are your first thoughts? Are you trying to give most of these patients chemotherapy at this point, given this data that if we are able to treat them and they have a good response, we can put them on maintenance avelumab, or are you thinking about using checkpoints upfront? Has your thought process changed at all? What are you thinking?

Brenda Martone: In the JAVELIN study, the data is very powerful, and so if patients are chemotherapy-fit, obviously talking to them about the chemotherapy and then adding on the checkpoint inhibitor is important in this setting in terms of delayed progression, overall survival, and tolerability.

Alicia Morgans: I agree with you. I think a few years ago when we learned that upfront checkpoint inhibitors were probably not as effective as cisplatin chemotherapy, we always would go with cisplatin chemotherapy for those patients who were cisplatin eligible. We still tried, in our clinic, to give patients who were still chemo-eligible, carboplatin regimens.

But I think, especially for patients who were staining high for PD-1 or PD-L1, there was always this consideration of whether we might give those patients, particularly the patients who are less fit, a checkpoint inhibitor upfront. But as we have our conversations now, any patient who is chemo eligible, we are really trying to get on chemotherapy.

Some of the other information that I found so powerful, is that if we can even get four cycles into these patients, they seem to do as well as patients who got six cycles of chemotherapy before they started that avelumab maintenance, which was just actually presented at ASCO GU this year. So any amount of chemotherapy that we can get in for those patients is like you said, really quite the focus.

So Brenda, how do you talk to patients when you are starting the treatment course before chemotherapy and thinking about really talking to them, not about one type of treatment, but now sort of a sequence of treatments, and they also have to have at least stable disease after their chemo in order to be really eligible for that maintenance avelumab? How do you present this treatment option to them?

Brenda Martone: Oftentimes I'll tell patients that chemotherapy will be first. They are going to be monitored and will have repeat imaging after the four or six cycles, and as long as their disease is not growing or going to new places, I try to make it something that is understandable for patients. Then we would consider adding this additional therapy as maintenance, given the ability of this therapy to delay disease progression.

Oftentimes, as you mentioned, these are metastatic cancer patients, so we are not going to be able to cure their cancer, so we talk about the fact that the chemotherapy and the treatments can lessen cancer, control cancer, and hopefully allow them more time here with their families and their friends and just being able to live their lives and do those things they find most enjoyable.

Alicia Morgans: I think that makes a lot of sense. And I know that our patients seem to understand when you talk to them about things in exactly that way.

When we started using this approach, I think, in our clinic at least, we had not used a lot of avelumab in the metastatic urothelial carcinoma setting, and I wonder what your experience has been in terms of the side effect profile of avelumab. And you could certainly put it in comparison to other checkpoint inhibitors that we had used a little more commonly. What are your thoughts about that?

Brenda Martone: Well, basically we are seeing that avelumab is actually very well tolerated. With all checkpoint inhibitors, we know there can be some immune-related adverse events. I think in terms of comparing to previous checkpoint inhibitors, I don't think we see the same amount of immune-related events as we would with a CTLA-4 inhibitor, but often, again, they are coming from chemo and going on a checkpoint, so I often will... well, I basically reiterate to them that they should not have nausea, they should not have diarrhea, everything they should not have that was expected with chemo, making sure they understand that these would now be something that we would be very concerned about if they had on this current therapy.

Alicia Morgans: That's such a great point, that when you are going from one treatment type to another treatment type, we have different expectations of the side effects, but we don't always express that to patients. I'm so glad you are on my team and that you do express that because certainly when patients are having shortness of breath, cough skin rash or diarrhea, these are things that we would care about at any time, but the patients may not report if they felt like this was something that just went along with their chemotherapy and their prior therapy, so emphasizing that transition to a new treatment type is a really, really important thing, which you realize. And I'm sure that I appreciate and I'm sure that patients appreciate as they try to understand how that works.

Then in terms of tolerability, as you said, I think we've seen actually quite a tolerable regimen. We have some patients who are on this with no real adverse events, but it is always important, I think, to check for things like thyroid dysfunction, other hypothalamic-pituitary axis dysfunction, and then certainly checking for things like rash, shortness of breath, and diarrhea from colitis would be important.

Any other thoughts or things that you communicate to patients or would want to tell clinicians as they are thinking about this? Because this data, I think, has been really transformative, but as we said, avelumab may not be the most familiar of the checkpoint inhibitors in clinicians' hands at this point. So what else? Anything else that you would want to communicate?

Brenda Martone: I think what's important is for patients to understand the different mechanisms of action. So again, with the chemotherapy, we talk about in general how it works. With the checkpoint inhibitor, I make sure that I stress that it is basically uncloaking cancer and their immune system is going to become more active. Along with that, there is an organ in their body, from their head to their toe, that could potentially become inflamed. And then just making sure, even when our patients come in and they have this little review of systems thing and they mark all their checkboxes, and there can be times when every check box is marked, "no", but when you start with your oral review of systems, you find out more information.

Basically, I start from head to toe and just start with itchy eyes all the way down to the feet and try to get every organ system, so if they come up with a symptom or they say, "Well, I wasn't going to mention this, but I've got this thing on my back," or something. So just always looking for these immune-mediated sorts of side effects so that we can intervene early and have the patient understand when to call us.

Alicia Morgans: Great. Well, that is why you are always so good at picking things up, which makes a lot of sense. And this drug, unlike some of the other checkpoints, is given every two weeks, so I think at the beginning, often we are seeing people every two weeks just to make sure they are doing okay. But then in our clinic, I think we've been able to spread people out to once a month, as long as you feel like, for your clinical practice, that works in terms of the infusion staff being able to notify you and those nurses being able to notify the docs and the nurse practitioners if there are any issues. But every two weeks can be a lot with the NPs or PAs and physicians. If that doesn't work for a practice, it can be altered a little bit as long as the patient is being followed closely in the infusion center.

Thank you so much for going through this. I know we've had a lot of success with really integrating this into our standard of care practice in our urothelial patients and a large part of that success has been you, so I really truly appreciate you sharing your insights and your expertise with us today. Thank you.

Brenda Martone: Thank you. You're very welcome.