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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU Medical Oncologist, and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today a good friend and colleague, Dr. Petros Grivas, who is an Associate Professor of Medicine at the University of Washington, and a GU Medical Oncologist at the Fred Hutchinson Cancer Center in Seattle. Thank you so much for being here with me today, Petros.

Petros Grivas: Thank you, Alicia, for inviting me. It's always a great pleasure to interact and discuss with you.

Alicia Morgans: Wonderful. So, Dr. Grivas, I'd like to talk with you a little bit about some JAVELIN 100 data that was presented at GU ASCO 2021. This was really a subset analysis, or perhaps a pre-planned analysis, you can let us know that, of patients, in terms of the duration of chemotherapy, or the number of cycles of chemotherapy that they receive, and considering whether that was associated with the benefit from treatment with avelumab, can you tell us a little bit about this analysis?

Petros Grivas: Thank you, Alicia. Absolutely. So, just very quickly to remind the audience, JAVELIN Bladder 100 trial, since practice a few months ago, this was a randomized phase three trial in patients who had achieved a response, or stable disease, to induction platinum-based chemotherapy, GemCis or GemCarbo, and they were randomized to avelumab, anti-PD-L1, versus best supportive care alone. The primary endpoint was overall survival, with progression-free survival as a secondary endpoint. This trial met the primary endpoint in all comers in the intent-to-treat population, with a hazard ratio of 0.69, as well in the subset of patients of PD-L1-positive tumors based on [inaudible 00:01:35] Because of the robust overall survival difference, median overall survival was 21.4 months with avelumab, 14.3 months with best supportive care alone. So, more than seven months difference in the median, or less.

And as I mentioned, significant p-value and hazard ratio, this study changed practice. And now, in our clinical practice, in patients with the responsive disease to induction chemotherapy, we will go ahead with switching them to avelumab. One question that came about was does it matter how much chemotherapy the patient received before avelumab? So, does the number of cycles of induction chemo have anything to do with the degree of benefit of avelumab? So we did this analysis, and Dr. Yohann Loriot presented at ASCO GU 2021, and we try to look at a different subset of patients who got four, five, or six cycles of prior induction-based chemotherapy before they went onto the JAVELIN trial, and if they could measure towards, with of course somebody's ability to decrease of benefit different hazard ratios, the benefit with avelumab, as switch maintenance therapy, appears to be relatively consistent across the subset of patients who got four, five, or six cycles.

So, that's something that is relevant and important data, and you may ask me, "Okay, Petros, what do you do in your clinical practice? How many cycles of chemo do you use?" And I can tell you that I base this decision before avelumab starts, mainly based on the benefit-risk pressure on the individual patient, in terms of clinical benefit and toxicity.  Just to give you two extreme examples, and of course, many patients are in the gray area in between.  If I have a patient who has no significant toxicity, they can get through chemo relatively well, and most patients do okay, especially in the first two cycles. And, they have a great response on the CT, I usually do CT after three cycles, just to give me a sense of where we're going. If this ratio of benefit, clinical benefit, and radiologic benefit, compared to the side effect profile, is favorable, I try to boost up to six cycles.  I try to maximize the benefit from chemo. If on the other side of the extreme, you have a patient who is struggling through significant neuropathy, toxicity, blood counts, it's hard to mediate, and has a stable loss on the scans, I may try to stop chemotherapy early on. I may stop at four cycles and then switch to development maintenance as long as there is no progression.

The other question is, do you ever stop before four cycles? And this was not tested in the context of the JAVELIN trial.  But if you asked me, if I have a patient who's getting... barely survives, goes through three cycles, has a stable disease, and suffers from toxicity, would you switch up after three cycles? And in that particular patient, I may do it. It's an extrapolation, it's not based on the data that we know, I want to make this clear, this is just a subjective thought, but that is why I think it's the individual-based scenario, case by case, try to maximize the benefit for chemo. If someone is benefiting from that, then potentially switch a little bit earlier than someone who is struggling through chemo, but not progressed yet.

Alicia Morgans: Yeah. Well, thank you, and thank you for putting that in the context of patient examples. I think that is really helpful. In my clinic, I always do try if the patient is eligible for chemo, I'm aiming for six, but then I do make these adjustments just as you have mentioned. But I appreciate also that you mentioned those patients who really can barely get through one or two cycles. I guess in those patients... are those patients even receiving adequate chemo, to say, that they've received chemo? And imagine that they didn't receive chemo, then we would probably be proceeding with the checkpoint, right? So I think that it is completely reasonable to say, particularly in patients who don't tolerate chemo, that patients did not tolerate chemo, we will move forward with a checkpoint inhibitor for their metastatic disease, which still needs to be treated.

So, I think that is very, very important, and very relevant. Thank you for putting that in the context of patients, because that's how we all think, and it is very, very useful. I'm wondering, there was some chatter just about, or maybe just a question, so when we looked at the analysis within this JAVELIN 100 data, it was pretty clear that four cycles, six cycles, everything looked good. There was some sort of neutrality on five cycles. This is just strange, and I think probably is actually just driven by small numbers, but you were involved in this analysis. What do you think?

Petros Grivas: I totally agree with you, Alicia.  I think it's probably a matter of sample size, and every time you have a big data set, and you start slicing the data into different ways, and many different ways, you may end up with some subset with a lower sample size and low power. So it's almost impossible to solve significant benefit in every single small subset, though, I think it is probably a matter of numbers, and just probably noise. Most patients probably get four shakes in clinical practice, and probably a smaller proportion gets five. I don't think that there is anything with the number five, it's ust probably a small sample size, and the statistical analysis with probably not being powered enough to show differences.

I think it goes back to what we discussed before, I think most patients by cycle four, probably may have declared themselves whether they have significant toxicity, or not. However, sometimes you see more toxicity cumulatively. So, number five, and six are probably the toughest cycles to go through. So I think the decision again is being made based on the benefit-risk on the individual patients. But to answer your question, I would not make too much out of this, five cycles subset.

Alicia Morgans: Thank you. So as we wrap up, I'd love to hear what you are looking forward to learning from the ongoing analysis in the JAVELIN Bladder 100. What do we have to look forward to? Obviously, you are not going to share any data, but what are some of the things that you and the team are interested in looking into, if you are able to share any of those things?

Petros Grivas: Absolutely. Thank you, Alicia. I think there are a lot of data points that we try to extract, and inform the literature. [inaudible] did a great job at ESMO 2020, he presented some interesting biomarker data. I think we should go ahead and publish this data, it's hypothesis-generating. These biomarker data are very interesting, are not changing practice just to be clear, but definitely raising hypotheses to inform future clinical trial designs. I think it will be very interesting to see this data, in the context of other clinical trials, like IMvigor 130, and Dr. Galsky and colleagues, saw some interesting data there with PD-L1, TMB, but we are looking beyond PD-L1 TMB. We were looking at DNA repair, gene mutations, mutational signatures, or gene expression profiling. We looked also at the FC gamma receptor polymorphisms, as well as other signatures looking at angiogenesis, notch pathways, and TGF beta pathways.

I think all of these will be important. So biomarker is a big bucket. The other is quality of life and patient report outcomes. I think we saw the data at ASCO.... I'm sorry, It was actually ESMO 2020. And I think we should publish that data. I know this is one of the areas of your expertise, Alicia, and I think it would be great, when we get this data out, to get your opinion about it, because you are the expert, internationally, I would say, one of the top experts in this field. Also, the other thing that we are looking for, is subsequent therapies. Initially, there was some critique on JAVELIN Bladder 100, that 62% of patients received second lines. And actually, we can talk about your own work in a later interview.

But the reality is that, if you look at historical data and also prospective trial data, only about a half of the patients, or less, make it to the second line, many of them do not make it.  There is significant attrition, because of clinical deterioration, declining health, access to care, other issues. So this 62% of patients, in the observation of best supportive care, who make it to the second line, is actually one of the strengths in the JAVELIN trial.  It is the highest number we have seen probably. And I think we should look into the subsequent therapies, and what is the duration of the subsequent therapy, right? How long does the patient state, and is avelumab immunotherapy potentially impacting, or not, the future of this patient, right? In subsequent lines. So, we are going to keep dissecting the data, and hopefully, we can inform the literature, and discussions, and looking forward to a discussion with you more about that.

Alicia Morgans: That sounds fantastic. Thank you so much. There is clearly so much for us to look forward to, so much activity going on, and I always appreciate your comments, and your expertise, on things like JAVELIN Bladder 100, and all the other things that you are involved with. So, thank you again, Dr. Grivas.

Petros Grivas: Thank you, Alicia, for the time. It's always a pleasure.