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Petros Grivas: Hello, I'm Petros Grivas. I'm an Associate Professor at the University of Washington, and a Medical Oncologist at The Seattle Cancer Care Alliance, and an associate member of the Fred Hutchinson Cancer Research Center. I am very excited and thrilled today to discuss with my dear friend and colleague, Dr. Alicia Morgans. Dr. Morgans is an Associate Professor at Northwestern University. You know her for her fantastic work in the field of genitourinary cancers across different tumor types, and also in the field of patient-reported outcomes. Alicia, welcome.

Alicia Morgans: Thank you so much, Petros. Happy to be here.

Petros Grivas: It's really amazing to see your work over the years, Alicia, and it is always important to learn from you. I recently came across your very important work presented at ASCO GU 2021 which I think touches upon one of the very important points regarding, what we would call pragmatic studies, in real-world data in patients with advanced urothelial cancer. And I'm referring to your poster regarding treatment patterns in patients with advanced urothelial cancer after discontinuation of the checkpoint inhibitors. Could you tell us a little bit more about the study you presented, and the overall context, and the design, and the results, and the findings of your study?

Alicia Morgans: Sure. Thank you for the opportunity, Petros. We actually performed a retrospective chart review from 26 sites across the US, really tried to get some geographic diversity, and we were able to obtain data from 300 patients who had locally advanced or metastatic urothelial carcinoma. We wanted to do this approach because there have been approaches, and actually we are working on other work, using things like CIHR Medicare and other databases. But each of these databases in isolation can really either exclude younger patients, for example, if we are talking about CIHR Medicare or may have challenges in terms of pulling certain claims data. And we wanted to see if a chart review, sort of deep dive into this data, would give us another view on what's happening in terms of real-world treatment patterns.

So, as I said, 300 patients who had locally advanced or metastatic urothelial cancer were identified, and the records were reviewed. A majority of these patients were older, as you would expect. And we looked at the way that these patients received their first line, or whether they received second-line treatment with PD-L1 or PD-1 inhibitor therapy, and then we looked at the therapies that they received subsequently.

What we found was that about 66% of patients actually received PD-1 or L-1 inhibitor therapy in the first line for their metastatic or locally advanced urothelial carcinoma, with the remaining one-third receiving that, actually as second-line therapy. This in itself, I think, was a little bit surprising to me, because I do always try to think about chemotherapy for this patient population first, especially with the JAVELIN 100 data that we have recently seen, and because we know that patients can respond and can benefit from treatment with chemotherapy. But really two-thirds in this real-world setting were getting it upfront.

Now, I would say that for patients who were getting upfront, these patients were older, and had a generally, slightly poor performance status, than patients who were getting probably chemotherapy upfront, which we would expect. But again, important and interesting information. Of those patients who received therapy, the average time on PD-1 or PD-L1 therapy for those first-line patients was about six months, which was also relatively short. And then, when those patients finished their therapy, about a third, only about a third actually went onto another line of therapy. So two-thirds did not receive any further lines of systemic therapy.

For patients who received their treatment in the second line, so this was PD-L1 therapy after something else in the first line for their locally advanced or metastatic disease, the average duration of therapy with their PD-1 or PD-L1 inhibitor therapy was about five months, and only about 29% of those patients went on to subsequent systemic therapies.

In total, about 20% of these patients who received subsequent systemic therapies actually received another PD-1 or L-1 inhibitor. So 20% of them, or a fifth were actually getting another therapy that there is no data really to say that sequencing these PD-1 or PD-L1 therapies will actually benefit patients, but that is what's happening.

Then I guess the final thing is that there was really no clear winner, so to speak, or predominant therapy that was being used in patients who progress on PD-1 or PD-L1 therapy. There was no clear, well, it's always this taxane, or it's always this, whatever the agent is, really just a smattering of agents with a fifth of patients actually getting another PD-1.

Petros Grivas: Alicia, this is really important data. I was really impressed to hear the number. It's significant attrition. Right?

Alicia Morgans: Yes.

Petros Grivas: In subsequent lines of therapy after checkpoint inhibitor, I was surprised to see that about one-fifth of the patients, to your point, received another checkpoint inhibitor, which as you said, there is no data supporting some sequencing [inaudible] someone's progression on the previous one.

Alicia Morgans: Yeah. I have not really done that actually, in my practice. And that is one of the reasons that these real-world studies can be so eye-opening because we see a view of the way that treatment happens in urothelial carcinoma that is so slanted by what we do in our own practices, and by the guidelines that we contribute to as a field, that we just don't know what is happening in practices.

Now, what we can tell from any of this work is why different clinicians chose to use a different PD-L1 inhibitor. Maybe there was an insurance issue. Maybe there was some thought that there was a toxicity that was happening on a given PD-L1 or PD-1 that would not happen on an alternate one. I don't know the reasons. And that is why sometimes these chart review-type studies, or any claims-based retrospective review, can be challenging. But we know what we see, and the data is that this is happening, and now we, I think as a field, need to understand how to best, I think, think about this practice, and educate either for or against, but perhaps, we kind of need to come down.

I think it is pretty clear that we don't have any data that supports this, but maybe education, maybe further research can help clarify that point.

Petros Grivas: I totally agree with you. And I think education is very important, to your point, Alicia. Discussing the data with colleagues across academic and community oncologists.  There is factually I think, enthusiasm on my part to enroll patients in clinical trials, the same thing that you do. And, if someone has progression on a checkpoint inhibitor, I'm okay with subsequent clinical trials with combinations.

Alicia Morgans: Yes.

Petros Grivas: Immunotherapy, right, if we want to reverse resistance, but I totally agree with you that I would not use a single-agent checkpoint inhibitor sequentially. If someone progressed on a previous trial, I would switch class, and now we have agents approved like enfortumab vedotin that you mentioned, erdafitinib in patients with FGFR2, or FGFR3 mutations or fusion, and obviously, clinical trials, like the sacituzumab govitecan is an agent on clinical trials now. So I think it is important, to your point, to understand the reasons behind this, and also to remove barriers if possible, in terms of access to care, and strategies that can keep patients on treatment are important, like the maintenance setup that you mentioned, because there is significant attrition as we go through the lines of therapy.

Alicia Morgans: Absolutely. And just to that point, the attrition, again, striking in my clinic, I do find usually that we will try to get patients onto the next line of therapy, but again, we have only the slice of patients, or the group of patients that we end up seeing in our clinic, which is not representative of all of the patients across the entire country, or certainly not the entire world. And although I have clinical trials to help try to give these patients some different options, not every practice has that, of course. So there are a lot of differences. And I do think that what this highlights is that there is a need for therapies to be approved and to be available for patients when they progress on these checkpoint inhibitors that are both tolerable and effective. And, as you mentioned, there are several, and hopefully, though the uptake on these agents will increase over time.

Petros Grivas: I totally agree with you on that. I think we need more agents in this disease. We can never have enough, right. And making sure that we educate providers and patients, and making sure we do a good job with toxicity, diagnosis, and management. And of course, understanding again, what has happened in the real world, because as you pointed out so nicely, Alicia, the people who come to see me at Seattle Cancer Care Alliance, and the University of Washington, and come to see you at Northwestern, there are patients who can make it to your clinic and can travel maybe more fee-based, and so there may be some selection factor there.

So, great work. As always, I look forward to seeing this in print, like your many publications, and looking forward to discussing more of your great work, Alicia. Thank you.

Alicia Morgans: Thank you so much, Dr. Grivas. I appreciate your time.