Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Cora Sternberg, who is a Professor of Medicine at Weill Cornell Medicine and the Clinical Director of the Englander Institute for Precision Medicine. Thank you so much for being here with me today, Dr. Sternberg.

Cora Sternberg: I'm very happy to be here with you Alicia, really happy.

Alicia Morgans: Wonderful. Well, thank you so much. I wanted to speak with you a little bit about the JAVELIN 100 trial. First reviewing its overall schema and findings and the way that it really changed practice for metastatic urothelial cancer patients, and then to think about the updates from ESMO and from GU ASCO 2021. Can you give us a little bit of a brief update or a brief overview of JAVELIN 100?

Cora Sternberg: Sure, Alicia. I'm happy to. I think you know very well that the JAVELIN 100 study is a randomized, phase 3 study, in which patients with locally advanced or metastatic urothelial cancer who had gemcitabine and cisplatin or gemcitabine and carboplatin chemotherapy and who obtained a complete response, a partial response, or stable disease after four to six cycles of treatment, were then randomized between avelumab IV immunotherapy every 2 weeks, versus best supportive care. The primary endpoint was overall survival in all the randomized patients, and then the PD-L1-positive patients. We stratified the patients for their best response to first-line chemotherapy, which was a CR or PR, versus stable disease and their metastatic disease, whether it was visceral versus non-visceral.

So what was happening here was that we chose patients who responded to treatment that had a CR, a PR, or stable disease. We then waited 4 to 10 weeks before the randomization. We repeated the scans to make sure that they maintained that response, so we actually selected out the best patients. And then they were given IV avelumab versus best supportive care.

What we saw in the overall population, if you look at the overall survival, there was a significant benefit for those patients who got avelumab. The hazard ratio was 0.69, which meant at 12 months, it was at 71% versus 58%, and at 18 months, there was 61% surviving versus 44% of the patients. If we look at the PD-L1-positive patient population, the hazard ratio was even more impressive. It was 0.56, and at 12 months, 79% of patients were alive, compared to 60% who didn't receive avelumab. And at 18 months, that was 70% alive, versus 48% who didn't receive avelumab.

Now, we looked at patients who had either gemcitabine and platinum or gemcitabine and carboplatin, and you can see that patients, irrespective if they got platinum or carboplatin, both of these groups did well and had a benefit. This, actually, was what was presented at ESMO. The other thing at ESMO we discussed were things that had to do with, if they got a CR or a PR, whether they got a CR or whether they had a partial response or whether they had stable disease, they all had a benefit from the avelumab immunotherapy.

So, actually, at ESMO, we saw that all of the subgroups, practically, that were looked at, patients with visceral disease versus non-visceral disease, irrespective of age, less than or more than 65 years of age, they all had a benefit with the avelumab. And patients with creatinine clearance more than 60, less than 60, all the patients really benefited from the avelumab. There were many other studies at ESMO, including looking at markers and TMB, tumor mutational burden, was looked at, PD-L1 status was looked at, not any one of these really, predicted by itself, the patients who would do the best, but they were really interesting. We looked at immunologic signatures, different signatures, even those used in renal cancer as well, and what seems that the patients who did the best, were the patients who had an inflamed immunologic signature. That was all seen at ESMO.

Alicia Morgans: This information that you're reviewing for us from ESMO 2020 is actually, I think, so clinically important for us as we, as clinicians, try to help our patients understand what to expect with the addition of avelumab. And just to reiterate, patients who've had cisplatin versus carboplatin, both seem to benefit. Patients who had complete response versus stable disease and partial response, all of these patients seem to benefit whether they had visceral disease or not. So, that's really, really powerful. Thank you for reminding us of that from ESMO 2020, and also just to ensure that all the clinicians out there like me think about that, that none of these are reasons to not try avelumab maintenance if you have a patient who has at least stable disease in the metastatic setting after chemotherapy.

At GU ASCO, the virtual meeting, 2021, you and your team just presented as well, additional analysis to help us understand, as clinicians, whether it's worth moving forward to avelumab or not in this sort of a paradigm, the JAVELIN 100 paradigm. You guys thought about the number of cycles that patients receive of chemotherapy and looked at the association with response. can you tell us a little bit about that?

Cora Sternberg: Yes. That's exactly what we did. We looked here at the baseline characteristics of the duration, or the number of cycles, of a first-line chemotherapy, and a cycle is considered to be every 3 weeks. So if you look at it in quartiles, a quartile being less than 15 weeks of therapy, 15 to 18 weeks of therapy, 18 weeks to 20 weeks, and more than 20 weeks, no matter what quartile we looked at, all of the patients benefited from the avelumab therapy, as opposed to the patients who didn't receive avelumab. I think it's sort of more easy to look at number of cycles of chemotherapy of first-line therapy.

We always think we have to give six cycles of chemotherapy, and I still believe that we do, but we looked at patients who got four cycles, who got five cycles, who got six cycles, and actually, they all benefited, all of them. And if you look at the curves, the hazard ratio for four cycles was 0.69, and for six cycles it was 0.66. These are, again, retrospective analysis, but no matter if they got four cycles or five cycles or six cycles of chemotherapy, either GemCarbo or Gem platinum, they all had a benefit. So I think we'd like to try to give six cycles of chemotherapy when we can, but in those patients where it's absolutely impossible or we can only get in four cycles, those patients also can be switched to avelumab.

I think it's kind of important to remember that many of the patients crossed over from the best supportive care patients who progressed, and even the avelumab arm, over 70% of patients in both arms got subsequent therapies. They primarily got immunotherapy in the best supportive care arm, but many other patients had other kinds of treatments. So, treating early makes a huge difference. In my experience with bladder cancer and urothelial cancer, which goes back to the days of MVAC, if a patient had just a partial response, let's say, they always progressed. And we know that second-line immunotherapy from, for example, the Keynote 45 study, that giving second-line immunotherapy is better than not giving it. But here we have even better results by not waiting until they progress and by selecting out those better patients.

There are some people who think that perhaps giving chemotherapy gives a more mutational burden and more chance of new antigens and more chance of even becoming more inflamed or more chance of changing the microenvironment so that they respond to immunotherapy, so it does make some sense, apart from the fact that we are selecting out those patients who do the best with chemotherapy to be on this trial. So I think that's one of the reasons this trial was so positive.

What's happened is that the guidelines have been changed. They've been changed by the NCCN, they've been changed by ESMO, by AUA, so that now they recommend to give platin-based chemotherapy, followed by maintenance of avelumab to all patients with locally advanced or metastatic urothelial cancer, and I think it's really been practice changing. Before this, for those patients who were platin ineligible, we would give atezolizumab or pembrolizumab upfront, but the people have to be really ineligible for any chemotherapy at all, ineligible for even carboplatin, to go that route at this point to give immunotherapy upfront.

Alicia Morgans: Yeah. I think that I agree with all of those things so completely, and really also would echo your thoughts on ensuring that patients get these lines of therapy. Because we see that when we wait and patients progress, we actually lose a percentage of patients on each line of therapy with each progression, and urothelial carcinoma, it's pretty striking, it's at least half on every line. Depending on the analysis that you look at, about half or more of the patients are unable to proceed with a subsequent line of therapy.

Cora Sternberg: You're absolutely right. 25 to 55%, never get a second line of therapy at all?

Alicia Morgans: Yes. Which is, if we have a setting where we're able to give this right away for those patients who seem to be responding, at least with stable disease and chemotherapy, I wholeheartedly encourage everyone to use this data, try to get these therapies into your patients, because if we wait, we may not have the opportunity. Or at least that's the way that I look at it.

Cora Sternberg: I agree with you 100%. I think this study has really been practice changing, and that's why we're going back and doing all these sub-analyses. Looking at TMB and PD-L1. Neither one of these alone is enough, because everybody benefited, actually, in this study. And we know that PD-L1 is not a perfect biomarker either and neither is TMB, neither have any of these inflammatory signatures, but they all seem to suggest who may respond better or who may survive better, but they all seem to do well, the patients who have had a response or stable disease, anyway.

Alicia Morgans: Well, I love that you're looking into the biology, and I encourage you in the team, as I'm sure you will, to continue to dig into that and help us understand better how this is working and how we can help choose the patients who may have the most benefit. At this point at least, when we look at clinical parameters, when we look at number of cycles, all of these patients seem to benefit. So all of these patients, if they have stable disease or better, should, I think, have the opportunity to consider maintenance avelumab here. And in that way, we can hopefully do the best that we possibly can for these patients. So, as we wrap up, do you have a summary for people regarding JAVELIN and this newer data that you have presented at GU ASCO 2021?

Cora Sternberg: I think that we know that the high mutational complexity and the potential for many new antigens that can trigger an immune response, and perhaps even more so with chemotherapy, is important and it's one of the reasons why immunotherapy has really been so successful for urothelial cancer. But by choosing the patients who respond well to chemotherapy, or even who respond or have stable disease, if they have even four to six cycles, these are all patients who'd do very well with maintenance avelumab. So I think maintenance avelumab has clearly become a standard of care, and we've made great progress with this study, so I'm really happy to have been a part of it. I must say that.

Alicia Morgans: Yes, congratulations to you, to your coauthors, and thank you to all the patients who participated. I really appreciate the efforts that you continue to make, Dr. Sternberg, in this field. I appreciate your time today.

Cora Sternberg: I love speaking to you, and you know that. Thank you, Alicia.