Outcomes Between Patients With and Without Prior Intravesical BCG, Who Received Immune Checkpoint Inhibitors for Advanced Urothelial Carcinoma - Rafee Talukder & Petros Grivas

May 11, 2022

In this conversation with Alicia Morgans, Rafee Talukder and Petros Grivas share data that investigates comparing the outcomes in patients who received prior intravesical BCG, and those patients who progressed and then required immune checkpoint inhibitors, to see if prior BCG therapy had an effect on the response on immune checkpoint inhibitors. Their hypothesis was, that patients who received BCG in the past would have a negative effect, or a decreased response, with immune checkpoint inhibitors because they've already had some immunomodulation with prior intravesical BCG therapy.


Petros Grivas, MD, Ph.D., Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

Rafee Talukder, MD, Hematology/Oncology Fellow, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Dana-Farber Cancer Institute. I am so pleased to have here with me today, Dr. Rafee Talukder, who is a second year fellow at the University of Washington, where he works with Dr. Petros Grivas, also at the University of Washington, and the Seattle Cancer Care Alliance. Thank you so much, both of you, for being here with me today.

Rafee Talukder: Thank you so much for having us.

Alicia Morgans: Wonderful.

Petros Grivas: Thank you, Alicia.

Alicia Morgans: Wonderful. Thank you both. So I wanted to talk with you a little bit about a poster that you presented at ASCO 2021, really investigating a data set that you put together for patients who have urothelial carcinoma, who received various different kinds of treatments, but really focusing, I think, on those ICIs those checkpoint inhibitors, so that we can understand how those therapies really impact the outcomes of these patients. Now I'm wondering Rafee, if you could tell us a little bit about the importance of the work that you did in this investigation, and what you studied, how you got to where you did?

Rafee Talukder: Sure. And again, thank you for having us on. What we wanted to investigate in this study is, comparing the outcomes in patients who received prior intravesical BCG, and those patients who progressed and then required immune checkpoint inhibitors, to see if prior BCG therapy had an effect on response on immune checkpoint inhibitors.

Rafee Talukder: What we did was, this was a retrospective cohort study with over 1000 patients, from 25 institutions in the United States and Europe. And we whittled it down to 617 patients, that we further characterized those patients that received immune checkpoint inhibitor in the first-line setting, compared to those that received it in the second plus line setting.

Rafee Talukder: The rationale for a trial was, patients who received prior intravesical BCG, even though it's local therapy, there is some data showing intravesical BCG does have some systemic effect on the overall immune system. So our hypothesis was, patients who received BCG in the past, would have negative effect, or a decreased response, with immune checkpoint inhibitor, because they've already had some immunomodulation with prior intravesical BCG therapy.

Alicia Morgans: I think that's such an important question, because we do have patients who receive BCG for their non muscle-invasive disease. And that, previous to the approval of these checkpoint inhibitors, was the real immunologic approach that we used, to try to cure these patients with non muscle-invasive disease. So I think there's a very clear biologic story to tell, between patients who had a good response, or perhaps, who may not have had a good response, to understand how treatment then, with immune check inhibitors, would impact these outcomes. So really important question, and it makes a lot of sense.

Alicia Morgans: I'm wondering, Rafee, could you tell us, what did you find in this analysis?

Rafee Talukder: Right. So just a little bit about the methods and the database. We had over 1000 patients initially, and we whittled that down to about 617 patients that we used for the data. For the overall response rate, and let me clarify. We did subset analysis, looking at patients that got immune checkpoint inhibitors as first-line therapy, compared to those that got immune checkpoint inhibitors in the second plus line. What we found was, there was no difference in overall response rate, overall survival, or progression-free survival, in patients that received BCG in the past, compared to those that did not receive BCG.

Alicia Morgans: So that's really, really interesting, and a little bit unexpected. I would think, that there might be some association there.

Alicia Morgans: Dr. Grivas, what is your take on these findings? What do you think?

Petros Grivas: I think Alicia, as Rafee said, this is an interesting question, because you can hypothesize of patients who may already have received BCG intravesically historically in the past for non muscle-invasive disease, may have some priming of the immune system, may have some potential different response to the checkpoint inhibitors administered later for metastatic urothelial cancer.

Petros Grivas: Having said that, we did not find a significant association with this historical intravesical administration, and response or survival, to checkpoint inhibition, even from metastatic disease.

Petros Grivas: There are different factors to keep in mind here. Why this finding? Number one, there may be some presence of on method confounders. Right? Why the immune system can be influenced by prior BCG, or other factors, and how? And obviously, the time lag. Right? The time frame that has passed between the intravesical BCG administration, and the time frame when the support inhibitor's being given. These patients may have been treated in very different time frames, maybe months or years later, with a different constellation of other factors, host factors, that could impact their immune system. Maybe, prior interim therapies that may have been different.

Petros Grivas: And different disease setting. Right? Localized, non muscle-invasive disease, versus metastatic urothelial cancer. Obviously, the model of administration is different in intervascular BCG and intravenous and use of the inhibitor is different. And obviously, despite that both are under the umbrella of immunotherapy, they're very different immunotherapies, with different mechanisms and functions, and different, I would say, targets. We still got to figure out how BCG works intravesically. Right? But if anything, I think that study at Rafee led, number one, gave us the insight that probably, if you're in the decision making process in the clinic, and you have to think about giving checkpoint inhibition, the receipt of prior BCG may not be part of your decision making, probably may not influence that.

Petros Grivas: And the other question is, what is the implication trial design? And I think, the trial design, and based on our data, intravesical BCG may not need to be a certification factor. Right? And does not appear to be a corrosive factor in those patients. We still are awaiting, I would say, eagerly, the plethora of checkpoint inhibitor trials in non muscle-invasive disease setting. In addition to KEYNOTE-057 and SWOG 1605, at least, in responsive disease, with pembro and atezo, respectively, there are many other trials. Some of them are combining BCG with checkpoint inhibition, in BCG relapsing, or even, BCG naive space. So I think, we're going to find out about this potential addictive effect, or [inaudible 00:07:22] effect down the road. But until that happens, I think, in the metastatic disease setting, decision about checkpoint inhibition should be made, regardless of prior BCG.

Alicia Morgans: I agree. I similarly find it really encouraging. Because we have had thoughts that this needed to be a stratification factor, which could very much alter, of course, our statistical design and our plan. And perhaps, we could use other things that when we find, ultimately, impact outcomes more strongly, more strongly than nothing, which is important, as stratification factors. And we only get so many for a trial. So really important, that this probably, does not have to be one. Or at least, based on this data, is something to really consider strongly, not including.

Alicia Morgans: And I wonder, you mentioned this, and this is one of the thoughts that I had. I'm not sure if you were able to look at it within the dataset presented as a poster. But it's, I think, interesting to wonder, whether prior treatment with BCG, obviously, for patients who relapsed early and then develop metastatic disease, this is a non-response, perhaps, to BCG. But there may be patients who actually have BCG in the distant past, and had non muscle-invasive disease that responded well to that, and then, developed a subsequent urothelial carcinoma, that could then be treated with these immune checkpoint inhibitors.

Alicia Morgans: And so I wonder, if the time and treatment of a separate cancer, that hadn't yet developed, that then became this cancer, that we needed the ICIs for, if that could cause differences too? Because certainly, if patients are relapsing after BCG, they have a different biology, than if they have a subsequent new cancer. Probably, not something that you were able to investigate, in this study at least, is what was presented in the poster, I assume. But is this something you looked at, the timing since that BCG?

Rafee Talukder: Yeah. Alicia, that's a excellent question and observation. So why one of the limitations of the study is, we were not able to calculate the time to ICI initiation, investigating when we started ICI in respect to when they got the BCG therapy. So, yeah. That's a excellent question that unfortunately, we just did not have enough data to collect and investigate.

Alicia Morgans: Every study has its limitations.

Rafee Talukder: Right.

Alicia Morgans: So I did not mean to point out the only one I could find here. But just a question, for future work. We all need future studies to engage in, I'm sure. So, I'd like to hear from both of you then, and I'll ask Rafee first, and then Dr. Grivas. Where do you go from here? What are your next investigations? And how do you use this data going forward, Rafee?

Rafee Talukder: Right. I think that's twofold. First, I think we need to do a better job, and be more cognizant in investigating this, and doing subset analysis of patients that got BCG versus those that didn't, in our current and future trials in investigating, using ICI. The DANUBE trial that either the Phase II investigating durva with tremelimumab, versus chemo in advanced urothelial cancer data, this hub set analysis, which again, didn't show any difference. The ABACUS trial also showed, was similar. But a lot of these trials, when we were doing our due diligence and research, we didn't see that subset analysis. I'm sure they had it, but we just didn't see it. So I think, it'll be important to identify this as an importance subset analysis in our trials, going forward.

Rafee Talukder: And two, I think both you and Petros mentioned, this data is encouraging, showing that patients that did get BCG in the past, should not be precluded from being on these ICI trials, going forward.

Alicia Morgans: Well, thank you, Dr. Talukder, I appreciate that wonderful, wonderful thoughts. Is there anything left for you to say Dr. Grivas?

Petros Grivas: I think Rafee covered it so well, it's hard to add here. But one of the things going forward is obviously, as I mentioned, mining further, the database, and we have many unanswered questions. For example, Rafee and Demetrius, another mentee, are working together in different exercises here.

Petros Grivas: Number one, we're trying to look the potential prognostic value of the site of metastases in patients with metastatic urothelial cancer. How patients fare, depending on the site of metastasis. For example, lymph node disease, versus visual disease. And then, particularly, go granularly, liver versus bone, or combined. I think, I would, and interesting to see, because we have the sense that patients with lymph node only disease do better. Right? Regardless of treatment, chemotherapy, immunotherapy. So we're looking at these questions. And we had an abstract recently in one of the ASCO meetings.

Petros Grivas: The other question that comes up is, what about the time that goes between the end of prior treatment until checkpoint inhibitor is been administered? For example, time of prior platinum chemotherapy. Is that something relevant? Does this impact responsive for inhibition? And these are just examples of what we try to answer, some practical things. And we have this amazing team, with 25 plus institutions, from US and Europe, that have contributed patients. And I think, this can give us an angle of this real world setting. Patients of trials that can compliment or supplement data that we're getting from clinical trials. So the example that Rafee gave us today, is one of many, how we can learn from real world practice. Which I think, is an interesting compliment to what we try to learn from clinical trials. And thank you, Alicia, for giving us opportunity to present that work that Rafee led today.

Alicia Morgans: It is always my pleasure to talk with you and your team, Dr. Grivas, and always something of interest, to see what you, and all of the folks who work with you, are coming up with. Because over time, little by little, abstract by abstract, publication by publication, you're shaping the way that we think about this disease, and it's really, really important work. So thank you both for your time, and for your continued expertise in this area.

Rafee Talukder: Thank you so much.

Petros Grivas: Thank you, Alicia.