Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so thrilled to have here with me today, Dr. Cora Sternberg, who is a Professor of Medicine and a medical oncologist at Weill Cornell in New York. She is also the Clinical Director of the Englander Institute for Precision Medicine, as well as being an investigator on the JAVELIN trial. Thank you so much for being here with us today, Dr. Sternberg.

Cora Sternberg: Hello, Alicia. It's a pleasure to be with you and with UroToday. I'm very excited to talk about the JAVELIN trial, which was actually on the plenary session at the last ASCO meeting. And although they said this was the first time we had a urothelial cancer trial plenary, it was actually the second one, because about 10 years ago, the SWOG trial with MVAC chemotherapy in the neoadjuvant setting was a plenary session also. But having said that, I think the fact that this was on a plenary session and patients with advanced metastatic disease is extremely important and we have exciting, new, practice-changing information.

In the JAVELIN trial, we treated patients with cisplatin and gemcitabine, or carboplatin and gemcitabine. And patients were treated between four and six cycles of chemotherapy. And those patients who had a complete response, a partial response, or stable disease with what we call standard first-line chemotherapy, and then had a treatment-free interval of between four to 10 weeks, we repeated the CT scans, were then put on this trial. So 700 patients were randomized on this trial on a one-to-one basis. If they were stable after receiving first-line chemotherapy to either receiving avelumab, 10 milligrams per kilogram, every two weeks or best supportive care alone, there was no placebo in this trial. And the primary endpoint was overall survival in this study.

Alicia Morgans: Great. So is this something that you feel as we think about the results of this trial, do you feel like the JAVELIN study is something that will ultimately affect the standard of care that we deliver for metastatic urothelial cancer patients?

Cora Sternberg: Absolutely. Because what we saw in terms of overall survival, there was a difference between those patients who got treated right away with immunotherapy, with checkpoint inhibition, as opposed to not receiving and waiting until they progressed, was a hazard ratio of 0.69. That means that with avelumab at 18 months, 61% were alive as compared to 44% on the best supportive care alone. And in my experience, perhaps with the exception of a few patients who obtain complete remission, and particularly complete remission in just lymph node disease. But if patients have liver disease or extensive lung disease, if you leave those patients in a partial remission or just stable disease, those patients will progress. And by treating them with immunotherapy immediately afterward, the results I think are really remarkable showing such a difference in overall survival. And I think that we can't ignore those results.

I think Betsy Plimack, as a discussant of the JAVELIN trial, put everything into extremely good perspective, showing that by giving switch maintenance and first treating patients with chemotherapy and then treating patients with immunotherapy, that the median was about 25 months, as opposed to what she considered the combination of all three. We're still waiting for the results of, I believe it's called IMvigor130, in which atezolizumab was given together with chemotherapy and we have results on progression-free survival, but we don't have any overall survival data yet on that. And there was a recent press release on pembrolizumab in a combination trial, which didn't meet its primary endpoint of radiologic progression-free survival. So we've had some interesting other results with the combination of a checkpoint inhibitor and chemotherapy. But this technique of switch maintenance, giving chemotherapy to get the best result positive, and then taking those patients, that are good patients, and then giving them immunotherapy shows that we can really prolong overall survival.

And this seems to be irrespective of PD-L1 status as well. Both patients that are PD-L1 positive, they did extremely well. And those who are PD-L1, just the intent, not positive in the attempt to treat population also had an important improvement in overall survival. And I think this is particularly important, as I mentioned for the patients who have PR or stable disease, these patients all progress. And in the past, I've only seen them progress. And I haven't seen this kind of survival benefit in the past.

Alicia Morgans: So as you mentioned, this is an incredibly exciting study that I think will absolutely change the standard of care, has already affected the way I deliver care in my practice. But there have been several disappointing studies in urothelial cancer when it comes to checkpoint inhibition in the recent past. And I know you don't have a crystal ball and you may or may not be able to tell us why this was, but from your perspective, what are some of the reasons that some of these studies, particularly in the adjuvant setting, may not have been positive, whereas this approach seemed to be a winning strategy?

Cora Sternberg: Well, the adjuvant setting is in patients who have had a cystectomy, that's a completely different set of patients completely. And we only have data from the trial that Maha Hussain presented with atezolizumab adjuvant therapy at this year's ASCO. And we haven't seen that paper yet, but I participated in that trial, and in that trial, adjuvant atezolizumab was given as compared to the best supportive care. And what was seen there, was clearly, absolutely no difference in overall survival or progression-free survival by giving adjuvant atezolizumab. There's also the AMBASSADOR trial Andrea Apolo is running with pembrolizumab and we don't have those data yet. And there's another trial with nivolumab. So we have the data from one trial that are clearly negative. Nobody knows if giving in the adjuvant setting means that there's not as much tumor around, if the tumor has been removed, but patients are selected for those studies that had neoadjuvant chemotherapy and still had a remaining tumor at the time of cystectomy or lymph node-positive disease, or patients who were absolutely ineligible for neoadjuvant chemotherapy. So many of the patients may not have had as much tumor burden around may explain some of the reasons why the adjuvant hasn't worked as well.

That's completely different than this switch-maintenance or giving immunotherapy in combination with chemotherapy. This is a new strategy, this switch-maintenance. There is a smaller trial with pembrolizumab that Matt Galsky has presented with the Hoosier Oncology Group. There's about 50 patients in each arm. And in that study, they did give IV placebo and they did cross over everyone to IV pembrolizumab when they progressed. So that was a small Phase II randomized trial, which suggested in terms of radiological progression-free survival, a benefit with pembrolizumab, but that's not Level I evidence like we have from this large JAVELIN trial with 700 patients.

And I think that having a 700 patient trial and that overall survival was better with avelumab versus control in every one of the prespecified subgroups that were evaluated, whether or not they'd received cisplatin or carboplatin, or whether or not they had a PR or stable disease with their first-line induction therapy. I think this means that first-line maintenance will become a new standard of care for advanced urothelial cancer. And I think this was a very, very important presentation, which should soon be published in the New England Journal of Medicine as well.

Alicia Morgans: Wonderful. So as an investigator on this trial, and as someone who's really thought a lot about how to best care for patients with urothelial cancer, what are your comments in terms of the JAVELIN trial and the message that you would send to listeners regarding the data?

Cora Sternberg: I think the data show that the safety profile as first-line maintenance was manageable. It can be that the patients who respond well to chemotherapy, or those patients who are in better condition and who do well, and they maintain their response, are the ones who are also going to respond to immunotherapy as well. And we are selecting the better patients in this trial, patients with progressive disease were not even eligible for this trial. And we know that's at least 15% of patients who don't respond to chemotherapy. So patients who don't respond to chemotherapy are ones who probably don't respond to immunotherapy either. So this trial did select out the better patients, but I think that if you have the better patients who had a good response to chemotherapy, and then if you give them maintenance treatment with immunotherapy, you have a chance of really improving their survival. And I think this will become a new standard of care for advanced urothelial cancer.

Alicia Morgans: I completely agree, and I sincerely appreciate your time, your efforts on the trial, and your commentary today. Thank you so much.

Cora Sternberg: Thank you so much, Alicia.