Time to End of Next-Line Therapy in the JAVELIN Bladder 100 - Petros Grivas

June 9, 2021

This conversation with Alicia Morgans, MD, MPH, Petros Grivas, MD, PhD, highlights a post hoc analysis of the JAVELIN Bladder 100 trial which further characterizes the efficacy of avelumab first-line maintenance of time to end of next-line therapy. In JAVELIN Bladder 100, eligible patients had unresectable locally advanced or metastatic urothelial carcinoma without disease progression with 4 to 6 cycles of first-line gemcitabine + either cisplatin or carboplatin. Avelumab is approved for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy. Dr. Grivas suggests the data highlighted here provide further evidence in support of the significant benefits of administering switch maintenance avelumab in patients in the first-line setting.


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.

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, and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a great friend, and colleague Dr. Petros Grivas, who's an Associate Professor, and the Clinical Director of the GU Cancer Program, at the University of Washington. Thank you so much for being here today, Dr. Grivas.

Petros Grivas: Thank you so much, Alicia, for having me. As always, a great pleasure to discuss this with you.

Alicia Morgans: Wonderful. Well, thank you for being here to talk about JAVELIN Bladder 100. I think we are really excited about this data. Honestly, it's been some of the most practice-changing data that I've had, actually in recent years, related to urothelial carcinoma. And I wanted to talk with you a little bit about your ASCO 2021 updates, and new data presentation. Could you share with us a little bit about that?

Petros Grivas: Absolutely Alicia. Thank you so much for highlighting this work, and your great questions as always. As a mission that we have, in the JAVELIN Bladder 100 Program, with professor Powels, and many other great colleagues, and the company would like to enrich the answers to important questions. We keep analyzing and dissecting the data as much as we can, so we can inform the answers to those questions.

In this particular abstract that I'm going to present here at ASCO 2021. We are very excited about this meeting, despite being virtual, it is a great opportunity to connect with a scientific community, and colleagues. We try to answer the question, whether avelumab as a switch maintenance therapy in advanced urothelial cancer in patients with response, or stable disease [inaudible 00:01:43] based chemotherapy would have any association with time to the completion of the next line of therapy in patients who had progression, and went to second-line therapy, whether this time, from randomization until end of next planned therapy was different between the two.

And this is because we could not have exact data, Alicia, on the PFS-2, meaning we didn't have exactly the progression time, and the time of the start of subsequent post-trial therapy, until its completion. So we could not answer the particular question of PFS-2. However, we had data until the end of next line of therapy. So we calculated this interval, from randomization until the end of next line therapy, to see if there was any association there. And interestingly enough, when we look at the analysis, and we of course look at different subsets, we found that avelumab was significantly associated with a longer time, prolonged time to the end of second-line therapy. And if you look at the particular data here, the hazard ratio for the avelumab best supportive care arm was 0.67. And the median time to end of the next line of therapy was 14.8 months, median for the avelumab arm and 9.2 months.

So about, you can argue, five and a half months difference between the two. And the Kaplan Myers curves separate early on. I would say probably about two months, and they stay separated, suggesting that avelumab maintenance therapy, is associated with prolongation until the end of the next line therapy. Again, measured from randomization, which again is an important limitation of the study, because we could not dissect specifically the duration of the second-line therapy, per se. However, I think this data provides further evidence in support of the significant benefits of administering switch maintenance avelumab in patients in the first-line setting, [inaudible 00:03:52] it responds or stable disease to platinum-based chemotherapy.

And in addition to this dataset, I want to highlight a couple of other abstracts we are going to present. One is work we did looking at different clinical, and genomic elect collateralized subsets of patients. And I think it's an interesting separate poster we have, as well as the data we looked specifically at the time interval between the end of chemotherapy, and the initiation of avelumab. And we looked at whether the time interval plays a role or not. I think all the data will show, suggesting that avelumab switch maintenance therapy appears to benefit patients across the board, regardless of how you slice and dice the data. It seems to be a significant benefit, more or less with variable degrees of benefit across different subsets of patients.

Alicia Morgans: That's so interesting Dr. Grivas. I'd love to hear your thoughts on whether avelumab actually makes patients have a longer period of time until they need that next therapy. Or is there... Is it possible that avelumab changes their tolerance of disease progression? We don't always get scans if patients do not develop symptoms, for example, and perhaps patients who had the best supportive care were getting scans earlier than those patients with avelumab because they were developing symptomatic progression. What do you think was going on there? What was the cause of this long time period?

Petros Grivas: It's a great question, Alicia. As I mentioned before, we would love to have this granular data, and measure time to progression, or progression-free survival, between the time points of starting of the second-line therapy, and the end of second-line therapy, but we did not have exactly those dates. It was very difficult to, dissect specifically this PFS-2, as I call it. However, I think of it all, the data tells you, at least in my humble opinion, that if you think about, the [inaudible 00:05:54] packets right, of the first-line therapy, from the beginning of chemotherapy, and then maintenance avelumab, overall appears to at least impact overall a positive outcome in those patients.

In our particular analysis, when we measure the time from trial randomization post-chemo, and then the end of line therapy people overall had a long time to that. I think it might be a plethora of different reasons for that.

Probably one of the main explanations that, because of the longer PFS, PFS-1, on avelumab, people had a long time until progression, and of course longer overall survival. Now, what we do not know for sure was whether these potentially may have impacted the effectiveness of second-line therapy. This is hard to tell. But overall, if you look at the quality of life in patient-reported outcomes data, avelumab was associated with no detriment. The quality of life of these patients, was as good as best supportive care, and that it was a trend, not statistically significant, but a clear trend, towards prolongation of the time to clinical deterioration. Probably because of delayed progression in those patients. You may impact in a positive way, their quality of life to some degree.

I don't think we have a crystal clear answer, because again, we don't have the PFS-2 data. But overall I think these data sets are to the totality of the data. If I can use that term, that tells us that switch maintenance avelumab is true, the standard of care in the first-line therapy of advanced urothelial cancer, in those with a response or stable disease to platinum-based chemo.

Alicia Morgans: I completely agree with you. I think that there have been few studies that have so rapidly changed my standard of care in practice. Avelumab immediately became the plan for those patients who had stable disease, or better, after chemotherapy for their initial treatment for metastatic disease. And this is not a small population, at least in my clinic, and I'm sure in yours. There are many patients to whom this applies. What I think is really interesting though, is that to the point of the question that I asked, I've thought about this, and asking why for a lot of different questions in medicine. And, at some point I had an attending who said to me, ''it's important to understand why, and that's why we continue to do research, but at the end of the day, the data is the data''.

And we don't necessarily know why this is better than that, or the biologic rationale, for example, or, what is the... How do we pull this apart, and understand exactly who these patients are? But in general, overall, this is what the data shows, and that's what the data shows here. And I do think that is very powerful. And of course, when we add that on, or layer that on to the survival advantage, that is very clearly occurring, with those patients who receive avelumab in a setting, versus best supportive care. This is a seven-month survival advantage for a patient population, that has metastatic urothelial carcinoma.

To me, that is not something we have even had the luxury of discussing in the past. This is incredibly powerful data. And of course, I look to understand why, and how we can, even if we understand the why, sometimes we can augment the why. And we can, for those patients who are not helped, find other methods of helping them, that's step two. But I'm really excited to hear that you guys are putting this out at least so that we can start to investigate the why.

Petros, as you think about this presentation, what are the take-home messages that you really want people to have as they take this home? Think about it, and then try to use avelumab in this maintenance setting, in their clinical practices.

Petros Grivas: Alicia a great point, as you said. And I think figuring out the why is very important, practically and theoretically. To your point, we keep trying to answer those questions. We have [inaudible 00:10:02] preparation, looking at biomarkers, and molecular biomarkers studies in the JAVELIN Bladder 100 study. And also, in these different subsets of patients, we will look at the time between the end of chemotherapy, and initiation of avelumab. We will look at the prior duration of chemo, the number of cycles, and also whether a prior chemotherapy regimen or prior response to chemotherapy, for stable disease, whether all these matters.

My take-home point is, taking into account all of the above questions, the take-home is that it is very hard to your point, to find clinical trials in solid tumor oncology across the board, with such clinically significant improvement, not just statistically significant, but clinically significant improvement in overall survival, and progression-free survival, and corroborating that with, no deterioration in the quality of life, and maybe trend towards improvement in some metrics. Because it's so difficult, I think that the standard of care has changed, as you mentioned. I definitely recommend and encourage the colleagues to utilize switch maintenance immunotherapy with avelumab, based on level one evidence, in those with a response or stable disease. That, regardless of what chemotherapy regimen was used in the platinum-based chemotherapy phase, what response [inaudible] I mean response stable disease specifically. If you have progression, [inaudible 00:11:28] this does not apply.

And, also, I would say that overall the data appeared to be robust, in an era where about two-thirds of patients in this particular trial, in the best supportive care alone arm received second-line therapy. Which I think is a strength of the study, because real-world evidence suggests that only about 20% of patients, and not 63% get second-line therapy. So, I think overall, because we do not have a reliable biomarker, to predict who is going to relapse quickly or slower. I'm afraid of under-treating patients. So, at the cost of potentially over-treating a few, I prefer to avoid under-treating many more. I use avelumab maintenance in patients with response to stable disease, again, based on level one evidence in that particular trial.

Alicia Morgans: I completely agree. And I would just emphasize also, to all listening, that with each sort of progression event that patients with urothelial carcinoma experience, patients will fall off of being fit for treatment. And this may be something that you as a clinician think, oh, that doesn't happen to me. I mean, at first, I thought to myself, well, of course, I treat everyone who has progression. I just give them the next line of therapy. But, real-world data suggests that at least half of patients, at each line of progression, do not actually get any other therapy that is disease directed, and known to prolong survival. And if we can do this upfront with maintenance treatment, I really think that we are going to be putting our patients in a better situation.

Obviously, it's FDA-approved in this realm, and it does prolong survival, but it also then gives us the opportunity to keep patients that are, in an intact, and hopefully relatively good performance set of state so that when they do have progression, we can give them the next line, and the next line, and the next. And hopefully, we can improve our outcomes for these patients, who really truly need anything we can do for them.

I'm so grateful to you, Dr. Grivas, for continuing to push the envelope, continuing to make your way, and make our way as a field, in urothelial carcinoma treatment. Thank you so much for your time, for your expertise, your passion, and for taking care of these patients. Thank you, Dr. Grivas.

Petros Grivas: Thank you so much, Alicia. This is great news for our patients. This is an example of great teamwork, with investigators all over the globe. It's great to keep pushing forward the needle to help patients living longer with better quality of life. And, thank you so much for having me today.