Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago, in the United States. I'm so excited to have here with me today, two friends and colleagues, Dr. Neeraj Agarwal, who is a Professor of Medicine at the Huntsman Cancer Institute at the University of Utah and Dr. Petros Grivas, who's an Associate Professor of Medicine and a GU Medical Oncologist at the University of Washington in Seattle. Thank you both so much for being here with me today.

Neeraj Agarwal: It's a pleasure, Alicia. Thanks for having me on board. Very nice to see both of you. Dr. Grivas, good friend, and what a morning. Thank you very much.

Alicia Morgans: Thank you.

Petros Grivas: Thanks Alicia for having Dr. Agarwal and myself. We're super excited and looking forward to the discussion today.

Alicia Morgans: Wonderful. So guys, I wanted to talk with you a little bit about the JAVELIN Bladder Data. JAVELIN 100 Bladder Data that really helps to understand this concept of chemotherapy followed by Avelumab maintenance. And the reason this is so important is that this is a little bit of a different approach to therapy. It's a shift in our typical treatment algorithm. And I know the two of you have really delved into how we can actually make this a seamless process within our clinical practices. Before we start on how we actually make that happen and why that's so important, Dr. Grivas, can you review the data for us please?

Petros Grivas: Absolutely. Let me review the JAVELIN Bladder 100 Trial data quickly and then Dr. Agarwal can comment on the unmet need in this landscape. So JAVELIN Bladder 100 trial, to remind the audience, it was a Phase III trial international trial with 700 patients worldwide that randomized these patients to either best supportive care alone or avelumab anti PD-L1 plus best supportive care after chemotherapy in the frontline setting of advanced urothelial cancer, specifically only the patients with either response or stable disease and not those with progression, but only with response stable disease. After induction platinum-based chemotherapy with GEM-CIS or GEM-CARBO were randomized in this trial and they were stratified based on the location of metastasis site of metastasis visceral or non visceral, and based on the best response to induction chemotherapy CRPR stable disease.

The primary endpoint was overall survival and this endpoint was met significantly with a very significant p-value and the hazard ratio of 0.69 in the overall population, regardless of PD-L1 expression, resulting in a difference in the middle of row survival, exceeding seven months in difference, a median overall survival was 21.4 months with avelumab plus best supportive care versus 14.3 months with best supportive care alone in this overall survival was time and measured from the beginning of the trial, which means after the response stable disease to chemotherapy, this overall survival significant benefit was corroborated by significant PFS benefit as well as differences in response rate and also, which have important point, high degree of tolerability Avelumab as a single agent was well-tolerated with no new safety signals and only 7% grade three immune-related adverse events and no grade four or grade five immune-related adverse events of the patient report outcomes, which is a topic of your research and expertise Alicia, and the quality of life data, so that there was no detriment with treatment with avelumab, so the toxicity profile was relevant to that, and there was some trend, but not significant, adjusted trend towards prolongation of time for deterioration, probably reflecting this PFS benefit. So based on the data that I just told you that were presented by Professor Powles at the afternoon session of 2020, and they were published in the New England Journal of Medicine in September 2020, the FDA approved this agent as of end of June 2020, and later the European medicine agency also approved this agent in Europe and this approval followed in multiple countries. So now avelumab switch maintenance after responsible disease with chemotherapy is the standard of care. And it's, I think it's now been implemented with different rates and speed in different parts of the world.

Alicia Morgans: I, I agree with you and I think I'd love to hear from Dr. Agarwal regarding why this is so important in any sort of explanations or additional information you'd like to add to that explanation of the trial.

Neeraj Agarwal: Of course. Before I make a comment on that, I would like to congratulate Dr. Grivas here and Dr. Powles obviously first and senior authors for changing the standard of care in patients with metastatic bladder cancer and especially to Dr. Grivas, when was the last time I saw a faculty who changed practice in medicine before they turned 40 years old? So congratulations, any time I see this paper that reminds me what hard work and aspiration and honesty sincere work can do. So congratulations, Dr. Grivas, we all are very proud of you.

So let me just bring up the context here. We saw three trials, Pembrolizumab upfront being used with chemotherapy, atezolizumab being combined with chemotherapy upfront, and then Durvalumab Tremelimumab double IOIO combination being tested, being compared with chemotherapy. All those trials were not able to meet or show what was expected of them and that's why none of those drugs will pan out in the clinic. With that background, I think the fact that with maintenance Avelumab, as Dr. Grivas said, we are seeing an absolute improvement of seven months in survival benefit in patients with metastatic bladder cancer. I think this is historic. I don't think we have ever seen this magnitude of survival benefit with any drug in the context of metastatic bladder cancer. So are very impressive data indeed.

Now I'd like to come to your question, Dr. Morgans, you are asking me why this is important. We had the pleasure of working together on collating the data which have been reported and how many patients actually receive first-line therapy, second-line therapy, third-line therapy in the context of metastatic bladder cancer. So in the United States, these are the data from U.S., not from any other country, with the caveat that, that are recorded until 2018. So we did not have sacituzumab or enfortumab in the clinic. And if you look at the attrition rate, I thought that was mind-boggling. Out of a hundred patients being diagnosed with bladder cancer more than half did not even receive any treatment. And out of those patients who receive treatment, around 48% patients receive first-line therapy, only 17% patients receive second-line therapy and only 6% patients receive third-line therapy. And that tells me that if we let patients experience disease progression, we lose half of them. So I like to ask Dr. Grivas, with whom we did the study together. What do you think about this attrition rate and how it is going to change or how it should be changed with the recent data on Avelumab?

Petros Grivas: Dr. AgarwaI totally agree with you. I think this is clearly a perfect example of the highly unmet need for patients with advanced urothelial cancer and uniformally fatal in lethal disease. We are all of us seeing patients in the context of academic centers, where there is a selection filter or selection bias, as I call it, aware of patients who may be more fit, are able to travel and come to see us in this [inaudible 00:08:31] expertise centers. However, in the real world, as sometimes we use this term in community practices, in rural areas across the board, the situation may be different. And the proportion of patients who actually get into second and third-line or fourth-line therapy is a lower array and lower frequency and low proportion compared to a large, a reputable academic centers because of multiple reasons. As you said, the patient's [inaudible 00:09:00] has more performance status or degree of medical comorbidities or access to care or, rapid disease course and clinical deterioration.

I think all of these reflect the reasons why you see these attrition rates. And to your point, Neeraj, with the paper we published together with your leadership and Dr. Swami's great work, so that about 20% of patients make it to second-line, then only 6% to third-line. This is very sobering a number, this is really, really, I would say mind boggling, as you mentioned, and we need to do better. I think the development of maintenance strategies definitely helps to increase those numbers because you capture more patients before they fall off the cliff. And I think that's a very important message. And I think this strengthens the message from JAVELIN that is very important to capture these patients before they progress. And that's the one argument to why we should give a switch maintenance immunotherapy. The other point of course, is the development antibody-drug conjugates, as well as [inaudible 00:10:02] that actually shows efficacy and safety in many patients, in the refractory setting. So I think the combination of those factors hopefully will translate in the more patients getting those therapies. And of course, access to therapy is very important and elimination of healthcare disparity so we can improve those numbers and help patients live longer and better.

Alicia Morgans: I completely agree. You know, I think that unfortunately, none of us sitting on this Zoom have the power in community practice to change who gets next-line therapy. And I do think that our colleagues who are in community practice and us, because we contribute to those statistics as well, I think that we're all trying to do the best for our patients in terms of balancing risk and benefit. And my hope is that if we are able to roll right into these next therapies for appropriate patients in the metastatic setting or in the adjutant setting, when we think about the checkmate data, that we will be able to limit these patients who really do fall off that treatment cliff, because that's ultimately what we want to do. And it is easier to get them early on when they have that performance status when they're still going strong from their initial diagnosis.

And we have the opportunity to help them muster that strength, because it can be hard as these patients continue to decline. And do experience these, the complications of their disease. And that's one of the reasons this is so powerful. And as you think about this, what are the barriers to implementation? How can we support ourselves as academics, our community colleagues, patients, of course, as well, to enable them to use this data, to go from the chemotherapy and roll right into Avelumab for this protocol? What are your thoughts, Dr. Agarwal?

Neeraj Agarwal: I think the most important thing for me has always been education and awareness of the data. When we see these data showing this fantastic, wonderfully improved survival benefit in patients who are receiving maintenance therapy with Avelumab, how can I justify not proposing, not suggesting to my patients to not do about these data and not, and why not they should receive this treatment? I think the way I am, after learning about these data, after they were presented by Dr. Powles and Dr. Grivas in last ASCO, I have been telling this to my patients, do not let your disease progress. If your disease progresses, there is a 50% chance, more than 50% chance, that we are going to lose you. So how can you minimize disease progression? I ultimately, majority, vast majority, of patients will experience disease progression, because the disease remains incurable, but how can we minimize, how can we move checkpoint inhibitors? And right now we only have one approved in this setting, which is Avelumab upfront so that patients can receive it without experiencing disease progression. And the next area will be to develop novel, effective adjuvant therapy or new adjuvant therapy. So patients do not develop metastatic disease. I think that is another area I would like to highlight.

Alicia Morgans: Absolutely. Dr. Grivas, what do you see as the main barriers to implementing this data beyond knowledge, which certainly is an issue, but there have to be other barriers that you recognize as well, and we need to help clinicians overcome those. What do you see that those are?

Petros Grivas: I agree totally with Neeraj about the need for education. It can never be enough. In addition to that, there's definitely the issue about access to therapy. If the medication is not available, you cannot get it. And you know, we're here in the U.S. you will have access to many therapies and the medical system that provides these agents most patients. However, it's in many parts of the world, this is not the case. And we know about differences in time until an agent gets approved and also reimbursed. And those issues are not negligible. You know, there are many countries right now that Avelumab may not be available as switch maintenance therapy. So access to care and access to particular therapies, I think is a huge barrier that we, as a community, global community, I would argue, we need to overcome along with healthcare disparities.

The other issue is, would I say that at the provider's gestalt or the other providers experience? And when I talk about that, I also refer to experience that providers have from other tumor types. I have a very high respect and admiration from my colleagues in community oncology practices who take care of multiple tumor types. It's very hard as Neeraj say, to keep up, with just GU cancers, let alone all the other cancer types. So it's hard for them and sometimes their experience in one tumor type may potentially, subconsciously impact the decision, the different tumor type. One example is, the chemotherapy and immunotherapy combination, right? And the data in lung cancer or gastric cancer, head and neck cancer, are different compared to urothelial cancer where the concurrent chemo-immunotherapy combination has not panned out. So far we do not use concurrent chemo IO.

However, as nearest mentioned, we do sequentially chemotherapy followed by IO for those with small cell disease. So I think, education comes to play there. The other factor I think, is a patient preference and patient convenience. Patients may get tired after the end of chemotherapy, they need a break, right? It's like the pandemic, right? They need to get out at some point because they are tired. Having said that, as Neeraj mentioned, it's important, like in the pandemic, you have to educate the patients that we have to be careful and maintain all the health prevention measures. Similarly, in metastatic urothelial cancer, you have to have a dialogue with the patient early on that this disease cannot wait and we have to stay on top of it as much as we can, eventually it will go away.

But in my humble opinion, the earlier you should use maintenance, you make capture more patients and in the absence of a reliable, accurate biomarker, who can tell us, who is going to progression who is not. I think that I would like to offer to all my patients who can safely get immunotherapy, switch maintenance, Avelumab after response, stable disease, to avoid losing some patients in the way. And we know from the JAVELIN Bladder 100 that we had, some patients who did not pass screening, what we call screen fails in oncology because the scans were done later. So, and the median PFS after at the end of chemotherapy is only two months. So I think that's an argument strengthening what Neeraj said about the discuss the dialogue with the patient early on. And, and I think it's a discussion between the provider and the patient overcome those barriers.

Alicia Morgans: I completely agree. You know, I think between education of the clinicians and education that the patients, and of course, encouraging everyone to continue to take this data over time and integrate it into their practices. I think that there should hopefully be very few barriers, because as you said, in similar, in other solid tumors, we are trying at least similar approaches. So this for patients who do not have progression of disease, so stable disease, or better after treatment with chemotherapy, which should always be our first-line therapy approach to patients with metastatic or unresectable locally advanced disease, this is a great option to prevent them from falling off of that treatment cliff that has been so artfully defined by Dr. Agarwal. and of course Dr. Grivas on that paper as well. So as we think about final messages to the audience Dr. Agarwal, what would yours be?

Neeraj Agarwal: We should do everything in our capacity to introduce Avelumab maintenance therapy As soon as we complete chemotherapy with Cisplatin or Carboplatin based combination for the six cycles. I think it's key to start treatment with Avelumab maintenance right after we finished chemotherapy without having to wait for any scans.

Alicia Morgans: Absolutely. Well this is a simple, but a true message. That's coming with a clear survival advantage. So very important, Dr. Grivas, what would yours be?

Petros Grivas: I think we should read very, very careful about implementing what we preach, which is evidence-based medicine and following level of evidence. I think implementation of the level one evidence can result in significant improvements in outcomes. And this, again goes back to education. The other point that I want to mention is that there are always variances and variations, when you think about clinical practice and not all the scenarios being covered in the clinical trials. So the recent publication that I had the honor to go through with Dr. Agarwal, Dr. Powles, Dr. Belmont, and other colleagues, looks at this particular patient populations who may not fit the exact eligibility criteria for JAVELIN 100 trial. And in that particular paper that was just published in Cancer Treatment Reviews with discuss different populations that may not be district definition, and we'll discuss different parameters and elaborations, whether, we think is reasonable or not to extrapolate the data from JAVELIN those specific populations. For example, patients with very poor kidney function, CNS, metastases, VALIC histologies, and other specific population. So I think it's an interesting paper in Cancer Treatment Reviews that was published on March 22nd of this year. And I would welcome feedback from the audience when they read that paper.

Alicia Morgans: Well, thank you. And thank you both for really doing your best to bridge that gap between efficacy in a clinical trial and effectiveness in our clinical practice, because it's only that translation from efficacy in the trial to effectiveness in a real world population that ultimately makes a difference for the people, the men and the women, that we take care of every day. So thank you so much for your time and for your expertise.

Neeraj Agarwal: Thank you very much for having me here.

Petros Grivas: Thank you so much, Alicia and great to discuss with you to Neeraj today.