The Landscape of Advanced Bladder Cancer: A Review of the Last 30-Years - Cora Sternberg

March 23, 2020

Cora Sternberg joins Alicia Morgans at ASCO GU 2020 and discusses the significant advancements in the treatment of advanced bladder cancer looking back over the last 30 years. MVAC was regulatory approved as the first line treatment in metastatic bladder cancer thirty years ago.  Cora discusses the recent progress that is offering significant improvements in the overall survival for those patients who respond to the treatments.  Only in the past few years have we experienced major opportunities in mostly second-line treatments with the approval of immunotherapy, specifically pembrolizumab and atezolizumab.   Dr. Sternberg highlights the five drugs recently FDA approved for the second and third-line treatments in advanced urothelial carcinoma.  She reviews the advancements including the recent approval of the antibody-drug conjugate, enfortumab vedotin.  


Cora Sternberg MD, FACP Professor Medicine and Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York.  

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: I am so delighted to have here with me today a friend and GU medical oncologist, Dr. Cora Sternberg, who is a Professor of Medicine at Weill Cornell and the Clinical Director of the Englander Institute of Precision Medicine there. Thank you so much for talking with me today.

Cora Sternberg: It's a pleasure, Alicia, to be with you.

Alicia Morgans: Wonderful. So, I have been so excited to hear of your lecture at GU ASCO where you reflected back on the landscape of advanced bladder cancer over the last 30 years to help us understand where we are and where we're going. And I'd love to hear you give us some tidbits from that lecture.

Cora Sternberg: I'd love to do that. I'd love to do that. Well, I talked about the progress. I talked about immunotherapy. We talked about chemotherapy and immunotherapy. I talked about the antibody-drug conjugates and the fibroblast growth factor receptor inhibitors, all of these new advances that have occurred. Because what happened was over the last 30 years, since we developed the MVAC chemotherapy regimen, there really was no great progress at all.

Gemcitabine and platinum were developed but didn't improve survival over MVAC. And we had the high-dose MVAC regimen. But in the last 30 years, we were just blocked. And there was really no second-line regimen or anything. This has changed over the last few years and we now have the approval of five new immuno-therapeutic drugs for advanced bladder cancer.

Most of them were first approved in second-line therapy after a combination of platinum regimens. They were approved in Phase III trials, in Phase I trials, Phase II trials, different ways. It's hard to compare among the different trials but they all showed pretty much similar results. I would say that the response rates are really only about 20 to 25% but when patients respond, they can really live for very long periods of time and have a long duration of response.

So, the immunotherapy has really changed it and I have patients with disease after chemotherapy, with disease in the liver, in the bladder and the lung that's just gone after they've finished. And they finished the immunotherapy three years ago and they're cured, which we haven't seen cures like that before. So, immunotherapy has really changed the landscape.

We also have immunotherapy approved like atezolizumab and pembrolizumab for patients who are what we call cisplatin-Ineligible. They have poor creatinine function or poor hearing, poor performance status. These are patients who can't even get chemotherapy and those patients, we've had very good results with the two different drugs that I just mentioned. And I showed also the longterm follow-up from some of those studies, which was I think really interesting.

The FDA has mandated that we only give those drugs in the cisplatin-ineligible to patients who have PD-L1 positive staining. And the PD-L1 staining has been kind of a problem for everybody. Many different companies have used different techniques, so that was a problem to compare but anyway, that's the way that has gone.

I then spoke about the ESMO plenary session, where they presented what's called IMvigor130 and Enrique Grande was the one who presented it. And it is in the press now with Matt Galsky as the first author.

There was a study of chemotherapy plus atezolizumab immunotherapy and, with that combination, they showed a very interesting improvement in progression-free survival. And it was too early yet to look at the overall survival. It was definitely a trend but it's a little bit too early. So, people were very excited that was a plenary session at ESMO, so we mentioned that.

I also talked about in immunotherapy there are quite a number of other trials that are ongoing that are similar to that looking at the combination of chemotherapy and immunotherapy versus immunotherapy alone. I didn't have time to go through all of them. Many of them haven't even reported out yet, but I did mention the JAVELIN 100 trial, which is called switch maintenance and it's thought to be a prolongation of first-line therapy.

So, patients got between four and six cycles of gemcitabine and a platinum compound. And then if they had either stable disease or PR or CR, they were randomized between avelumab or best supportive care, which is what we usually do with these patients. And we have a press release now from January showing that there's an important improvement in the overall survival with that switch maintenance technology.

So, we'll have to see how this all plays out in the future, whether patients will use and whether providers will pay for the combination of immunotherapy and chemotherapy. Or whether or not the technique will be to choose the best responders to chemotherapy and then give immunotherapy afterward. That's kind of interesting results.

And this echoes what was already presented and was impressed by Matt Galsky, a study with the Hoosier Oncology Group with pembrolizumab. They had fewer patients so they only have progression-free survival, not overall survival. And this study was done with avelumab. It wasn't done with pembrolizumab. I don't know what is going to happen if people are going to switch some around. They really shouldn't. I mean, we have Level 1 evidence of maintenance therapy after chemotherapy with avelumab.

I then went on to talk about the antibody-drug conjugates. So, these are antibodies that are attached to cell surface membranes and then they're able to deliver their payload directly to the cell with having less systemic toxicity. And then went on to talk about enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4. And its payload is very strong chemotherapy which arrives directly to the cell. And we'd heard presentations by Dan Petrylak a few years ago with a 44% overall response rate and a 12% complete response rate subsequently published by Rosenberg.

And this drug is the first Nectin-4 conjugate to actually get approval based on that study. Now, there's a Phase III study that's almost completely enrolled. It's enfortumab vedotin versus investigator's choice such as Taxotere®, Taxol® or vinflunine. This is done in the second-line.

I talked about other exciting results that we heard at ESMO. At ESMO, we heard that 71% of patients actually had a response in shrinkage of the tumor.

Alicia Morgans: Yes.

Cora Sternberg: And these data were updated yesterday in a poster and in a short presentation by Jonathan Rosenberg, again presenting the same patients with the 73% now... shrinkage of patients having a shrinkage of the tumor. And the overall PFS was I believe 12.3 or 12.4 months. And really, really good results. Very exciting. I think that combination with enfortumab vedotin and pembrolizumab is going to go further and probably be evaluated in a Phase III trial.

I also talked about sacituzumab govitecan whose, the antibody, is to Trop-2 and it's got a protease-cleavable attachment to its payload, which is SN-38 which is the active metabolite of irinotecan. And because it's protease-cleavable, it goes into the cell but it also treats cells also in the very close microenvironment.

And what was presented was, in the past, a study was all-comers of epithelial cancers, a subgroup of patients. 45 patients had a 31% response rate and at last year's ESMO, Scott Tagawa presented the results with more than 70% of patients having a response. And that's really exciting data.

And I showed some of these what we call these spider plots in which I would put the two, it was 80 patients from the two different trials that had metastatic urothelial cancer. And showing that these responses are longterm, too. So this is another drug that's also going into Phase III trials and hasn't yet been approved by the FDA. But it's a very exciting drug.

And then, last but not least, I spoke about the FGFR fibroblast growth factor receptor inhibition. And we know that patients that have FGFR 3 maybe even FGFR 1 mutations are our patients who can respond to FGFR inhibition.

And I talked about a trial that had already been presented where they found that the eight-milligram dose was the best dose. And that there was a very high response rate. 40.4% response rate, as I recall. And this drug can cause hyperphosphatemia. But aside from that, if patients have DNA mutations in FGFR, they can respond really well and long-lasting to this drug as well. And erdafitinib has been approved.

I mentioned briefly the combination trials that are going on with rogaratinib and anti-PD-1 checkpoint inhibitors that will be presented at a future meeting. And also the NORSE study was presented at this meeting, the first results of the NORSE study, which is with erdafitinib, an anti-PD-1 inhibition.

We have different classifications for bladder cancer now by molecular classifications. The luminal-papillary and the basal-squamous ones seem to be the ones that respond best to immunotherapy. And the papillary ones are the ones that seem to respond best to the FGFR inhibitors.

And it was thought that patients with papillary and had FGFR positive weren't going to respond to immunotherapy. But there was a paper recently published by Galsky and others looking back at some of the other trials that have already been published and showing that this really isn't true. That, in patients who are FGFR wild-type or FGFR mutated, can respond to immunotherapy as well.

I spoke about a lot of different things at this ...

Alicia Morgans: Yes, you really did and I-

Cora Sternberg: ... Talk.

Alicia Morgans: And I love all of the trials that you're able to really bring to life. And bring forward. And I think to myself now as I listen to you review all of this data... and certainly when I'm in clinic... It's going to be a challenge for some of us... Actually for all of us... To think through the sequencing of these drugs.

Cora Sternberg: Of course.

Alicia Morgans: And how do we best use them in clinic? And this will be true especially as we see combinations come forward. And reflecting a little bit on that Galsky data regarding the FGF patients and immunotherapy, some people are making decisions based on these things when the data is still fresh. So what are you doing in clinic?

Cora Sternberg: The data is still fresh. The other thing is that I also presented the SAUL study, which was a study-

Alicia Morgans: Yes.

Cora Sternberg: ...that we published in European urology this year where we had a thousand patients from 32 countries. And we put in patients who were not able to go into all these registration studies. Patients with poor creatinine clearance down to 15, patients on dialysis, patients with autoimmune disease, patients on steroids.

And what I presented at this year's meeting was we looked at the upper tract tumors. We know pelvic tumors and ureteral tumors as compared to bladder tumors because everyone also thought or was said that those patients who had upper tract tumors didn't respond as well to therapies. And what we found is that the upper tract tumors responded just as well as patients with bladder cancer, too. So that was kind of interesting as well.

Alicia Morgans: That's very interesting. It's very important in these real-world studies or studies like the Galsky study that pulled from completed clinical trials can help us understand when we make decisions based on our presumptions about biology, they actually may not be born out in the clinic.

So, when you see a patient with an FGF mutation or you see a patient with a disease that has progressed after chemotherapy, are you giving them immunotherapy, are you giving them erdafitinib? Now enfortumab vedotin is approved, are you giving them that? Are you putting them on a clinical trial? What are you doing?

Cora Sternberg: Well, I think that I've been working a lot recently with enfortumab vedotin and also with sacituzumab govitecan within the context of clinical trials. I haven't used many of these drugs outside of clinical trials because I was working in Europe for the last years where many of these drugs are not even approved yet in Europe. So, I was only able to give drugs within clinical trials.

But I think that we have tended to go first with immunotherapy in second-line in those patients where it was possible to give immunotherapy. And in second-line immunotherapy, it seems that the PD-L11 testing isn't as important as it is in the platinum-ineligible patients in first-line. So, that has been my tendency if we're talking about not within the context of a clinical trial.

Alicia Morgans: And I think that's the right choice and the Galsky data supports that, that we shouldn't really be using FGF to make decisions about immunotherapy.

Cora Sternberg: Yes.

Alicia Morgans: That's really something that I think we used when we're thinking about erdafitinib. At least that's what I'm doing at this point. But the data is so young. And I appreciate your contribution to the data that we have and the data that will be coming out. And I so appreciate your time ...

Cora Sternberg: Thank you so much.

Alicia Morgans: ... In running through all of this. Thank you.

Cora Sternberg: Hey, it's a pleasure.