Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I am so excited to have here with me today, Dr. Tom Powles, who's a Professor of GU Oncology, as well as the Director of the Barts Cancer Centre in London, in the UK. As well as Dr. Matt Galsky, who is a Professor of Medicine, as well, at Mount Sinai in New York. Thank you both for being here.

Matthew Galsky: Thank you.

Thomas Powles: Alicia, thank you for inviting me.

Alicia Morgans: Wonderful. So, I am really excited today to talk about your ASCO presentation, Dr. Powles, which is the first urothelial carcinoma plenary session at ASCO, actually in the history of all of ASCO, it's the JAVELIN trial. Can you tell us a little bit about why this trial was so important and what you found?

Thomas Powles: That's really sweet of you. I'm really excited and really honored to be doing this bladder conference and Matt, and there were a number of other investigators who have worked on these sorts of projects. In fact, Matt indeed has even done a maintenance type trial. So I think that this is a last piece in a pyramid of a number of people who have contributed towards trying to find a good approach for immune checkpoint inhibitors or other targeted type drugs in urothelial cancer. And so I think that's the first thing to say. The trial itself is a maintenance trial. What I mean by that is we know that frontline chemotherapy is associated with a high response rate. It's great at getting in control of the disease, but that control doesn't last very long. We know that immune checkpoint inhibitors are not that great at getting in control in frontline bladder cancer. But they are quite good at getting long durable responses when responses occur.

So the principle was, let's get in control initially with the chemotherapy. And once we're in control, we've bought some time for the immune therapy to subsequently work. Now you might say, "Well, why not just give immune therapy when the cancer comes back?" And that's what we're currently doing. We give second-line immune checkpoint inhibitors. The problem with that is only a minority of patients historically get second-line therapy. And the second thing is, second-line therapy is pretty aggressive and the cancer grows fast. We're probably intervening too late. So maybe this is a Goldilocks right, where it's not too late, but it's not too early.

And that was the principle of maintenance therapy. We tested the avelumab in this setting which is a PD-L1 inhibitor. It's got an FDA approval in urothelial cancer based off Phase 1b/2 data, a large Phase II study, that Andrea Apolo performed, which had response rates similar to other immune checkpoint inhibitors. The bottom line of the trial is those individuals who had responded or stable disease, four to six cycles of gem/cis or gem/carbo, randomized within 10 weeks of completion of chemotherapy on a one-to-one basis, primary endpoints of OS in the all-comer population and the PD-L1 positive population. In the all-comer population that has a ratio of 0.69 with 21 months overall survival for avelumab 14 months, overall survival, or less supportive care. The results and the PD-L1 positive population, the median survival wasn't reached in the avelumab with a hazard ratio of 0.5.6. Toxicity was in line with what one would expect with avelumab. Subset porous plot analysis showed avelumab outperforming best supportive care in broad subgroups of patients, particularly those types of chemotherapy and response to chemotherapy and the presence of visceral metastasis, which I think is important. And then the majority of patients ended up in our best supportive care got second-line therapy, which suggests that patients did have opportunities to get subsequent therapies, putting the work into context. And so those were the top-line results, and we feel that those are, as you suggested, we haven't seen a survival advantage in frontline UFE or cancer previously. And for that reason, I think the work is attracting attention.

Alicia Morgans: I completely agree. And just to make sure we clarify one point, what percentage of patients approximately more or less did receive a second-line therapy after this if they had not received the avelumab duration?

Matthew Galsky: Best supportive care was about, I think it was 64% received any therapy. But I think 41% of those any therapies were immune checkpoint deficient. And then if you look at those patients who have... All the population, there are many patients who haven't received subsequent therapies for various reasons, durable responses, whatever it may be. And so if you look at those who have progressed, those numbers go up to about 75% of those who have progressed. You see the subsequent there.

Alicia Morgans: I think that that is one of the more compelling parts of this because many people will say, "We have these therapies. We could just use a checkpoint as our patients are progressing." But if we're clearly demonstrating that earlier seems to be better or that we maybe miss an opportunity, that window of opportunity may close if the patient has progressive disease and becomes too ill. Then that's a very compelling reason to act on something like this. At least from my perspective. Doctor Galsky, what do you think about the JAVELIN data, particularly in light of your switch maintenance data that was presented a few years ago? These are sort of similar strategies. What are your thoughts?

Matthew Galsky: So the strategies are really identical. There are a couple of nuances to the trials that are different. One is that we used a placebo-controlled crossover design so that patients received pembrolizumab upon progression. The second is that ours is a randomized Phase II study, not a Phase III study. Obviously a smaller study to generate proof of concept, but not a definitive study like the JAVELIN study. And the third difference is PD-1 versus PD-L1 blockade. So three key differences. With all of those differences, the results line up incredibly well. And the overall survival for patients who were randomized to switch maintenance pembrolizumab was 22 months. It's almost identical to what you see in the experimental arm of the JAVELIN study.

So our primary endpoint was progression-free survival. We saw a significant advantage to PFS. We didn't see an OS benefit. Our crossover rate, the patients who got subsequent immune checkpoint blockade was slightly higher, but not dramatically higher. So one could argue that the lack of OS benefit was because of crossover. It is probably also because our study was underpowered to demonstrate a benefit. Numerically, the outcomes were better for survival in the switch maintenance pembro arm compared to the placebo arm. So all in all, I think there are many more similarities than differences between the studies. And I think the fact that now we have two randomized studies really testing the same concept pointing in the same direction, further reinforces that this is the approach that we should really think about pursuing as standard.

Alicia Morgans: I completely agree. And Doctor Powles, I don't know where things stand in terms of NICE evaluating what is or is not allowed in the UK system, but does this approach then seem to be one that should be considered as a new standard of care when the opportunity presents itself?

Thomas Powles: So I can't predict what the agency will do, but I would imagine people will look at the survival signal and will say for this group of patients, this looks attractive. There were two or three things, which I think are particularly compelling. The first is that the duration of therapy, you're not starting right at the beginning with chemotherapy. And I think that the-- Matt and I maybe can talk about this in a minute, but there was a question about whether you need to give the chemotherapy and immunotherapy together. There was something nice about starting off the completion. If you look at the duration of therapy, therefore, it will be shorter than if you started right at the beginning. And of course, the duration of therapy is important from a cost perspective.

I think also having hitting survival has a ratio in 0.6s-- Organizations like NICE tend to look at that very favorably. NICE tends to, although it has a complex reputation, when you're hitting survival signals, the 0.6s, inevitably they tend to get approved, right? It's only when you're in the 0.8, late 0.7s is where I think one struggles. And I think the debate around that is a complex one and probably not one for today but the overall discussion there is that data looks really compelling for urothelial cancer. And certainly, if I was a patient and I've just recently completed chemotherapy and had stable disease, I wouldn't want to wait until my cancer returns before starting.

Alicia Morgans: I would agree. Absolutely. And Matt, you and I are in a little bit of a different situation where we may be able to get a checkpoint inhibitor through the standard of care here in the United States, even as we wait for a formal recommendation if one is requested of the FDA. What are your thoughts in terms of routine clinical practice? Would you consider using avelumab or perhaps any checkpoint inhibitor right now in a maintenance form after stable or responsive to chemotherapy for patients with metastatic disease?

Matthew Galsky: So I think the level one evidence supports avelumab. I think there's data that's compelling enough to use pembrolizumab in this setting. It's certainly not a data-free zone. I think for the other immune checkpoint inhibitors, it's a data-free zone in this particular setting. Although based on what we know about these drugs, we could extrapolate, but we simply don't have the data.

So I think for those two drugs, I think there's evidence. And I think this clearly warrants a discussion with patients. The concept of stopping treatment in the context of radiographic metastatic disease and sort of waiting until it inevitably progresses has never been something that is easy to explain to patients. It's not received well, that's for sure. And although we want to spare patients from financial toxicity and physical toxicity from our treatments, my experience has been that the balance of those conversations strongly weigh toward doing something right away versus sitting and waiting. So I think this strategy will be embraced and I think we have the data to embrace it.

Alicia Morgans: I agree. And I actually have been fortunate to be able to already incorporate this after the press release into practice, which I just feel very grateful that we've been able to do that through a standard of care. And so Doctor Powles, what are your closing thoughts, final messages to people who are thinking about the JAVELIN study?

Matthew Galsky: Well, I think that coming back to the team effort of the huge number of people who have contributed to this, patients and their families, of course, the previous work, there have been previous maintenance trials, using other drugs, which haven't been successful. And I think that one of the key questions moving forward with this, as I see it, is there is going to be some nice biomarker work, that I think we can do with this, which I think is going to be relevant for the future.

I think we're looking forward to seeing quality of life data in a not too distant future as well. I think that both those pillars are going to be relevant. And then I think the next story, which is a complex one, which is we haven't seen the chemotherapy combination, survival signals yet, for 361 and 130 atezolizumab plus chemotherapy, pembrolizumab plus chemotherapy. And those data are going to be really important because I think only at that point can we put what we see now into a broader context. Clearly those trials, I think will need to hit the survival signal.

And then the next issue is what is going to happen with the monotherapy that atezolizumab and pembrolizumab, but also the DANUBE trial we know hasn't been successful with durva/treme, but there are questions around whether ipi/nivo is going to be successful. And then, of course, the monotherapy data with pembro and then looking in onto the horizon, EV plus pembro looks really active. So I actually can see this being the start of a cascade of choices for patients. And I think we're going to have personalized combination type therapies. And I think we're going to have a plethora of opportunities for our patients. And I really think we're going to push those survival signals as we've seen in prostate and kidney cancer, up into the 30 months in the not too distant future, I hope.

Alicia Morgans: I think that this is a wonderful development for anyone who is living with metastatic urothelial cancer or those who care about those individuals. And I commend you Doctor Powles and your team and all the patients who participated on this wonderful achievement. And I thank both of you for sharing your insights today. Thank you so much.

Thomas Powles: Thank you.