Charles Ryan: Hello from ASCO 2019. I’m delighted, today, to be joined by Dr. Jonathan Rosenberg who is chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center. Thank you for joining us, Jonathan. Today, we’re going to talk about your phase three trial in bladder cancer, CALGB 90601. This is a study that looked at bevacizumab plus standard chemotherapy. You’re presenting it here. A big important study, tell us about the results.

Jonathan Rosenberg: So this trial enrolled 506 patients. They were randomly assigned to either gemcitabine, cisplatin, bevacizumab, or gemcitabine, cisplatin, placebo. This study was based on phase two data from two single-arm trials, one of them gemcitabine, cisplatin, bevacizumab, other with gemcitabine, cisplatin… I’m sorry, gemcitabine carboplatin and bevacizumab. And they both showed better than expected outcomes compared to what we might expect with standard gemcitabine and cisplatin chemotherapy, or gemcitabine and carboplatin chemotherapy. In fact, both clinical trials showed a 4-5 month improvement in overall survival compared to historical controls.

So this provided the rationale to move forward. Also, angiogenesis is known to be a negative prognostic indicator of bladder cancer and that the addition of anti-angiogenic agents to chemotherapy and preclinical models actually leads to improved tumor regression and improved outcomes in animal models. So the randomized phase three trial was started in 2009. It accrued over five years and accrued 500 patients in that time period. Patients were treated with a combination of chemotherapy plus bevacizumab placebo for six cycles.

Then, if they had an ongoing response or stable disease, they were able to continue on bevacizumab and placebo. The trial was designed to look at overall survival as the primary endpoint, and progression-free survival greater than or equal to grade three adverse events, and objective response rate were secondary endpoints. Unfortunately, the trial was negative. The hazard ratio for overall survival was .87 and the P value was not significant.

It was designed to detect a hazard ratio of 0.74. We obviously, unfortunately, missed the mark. Interestingly enough, progression-free survival with the three-drug regimen, gemcitabine, cisplatin, and bevacizumab, was actually better longer than gemcitabine cisplatin placebo with a hazard ratio of .75 and a significant P value. But the Delta, the difference, between the two arms was only 1.1 months. So not necessarily a clinically significant difference in the setting of a secondary endpoint in a first-line clinical trial.

Charles Ryan: What’s striking is from the time that you designed that study, and you looked at that initial phase two data and executed the phase three trials you have, a lot has changed in bladder cancer.

Jonathan Rosenberg: Right, exactly.

Charles Ryan: So the natural question is, if PFS is positive, even if it’s a minor amount, was subsequent therapy the issue that may have affected the survival endpoint? Do we know that yet?

Jonathan Rosenberg: So we don’t have complete data on that yet, and we’re still looking at that question, but my sense is that very few patients actually received immune checkpoint inhibitors, which would be the major class of agents that came into use after 2014.

Charles Ryan: Okay.

Jonathan Rosenberg: Because of that time of the study when it went on, only a small fraction of patients actually went on to receive immunotherapy. And so it’s unlikely that that really led to those results.

Charles Ryan: Okay.

Jonathan Rosenberg: We also saw that you know, the combination was what you’d expect with adding bevacizumab to chemotherapy. You had some more cardiac events, maybe less severe events, add some more cytopenias, particularly thrombocytopenia. You had hypertension and proteinuria. But it didn’t seem to be a toxicity problem that a regimen, overall, in general, was well tolerated.

Charles Ryan: I see.

Jonathan Rosenberg: So, you know, this study was designed in an era when there was a lot of nihilism about completing randomized phase three bladder cancer trials. There was a history and a legacy of multiple failed clinical trials in advanced bladder cancer. So the US Intergroup Mechanism, the cooperative groups really managed to pull it together and accrue this trial. And while the trial was negative, just doing that, in itself, was an enormous achievement and I think may have changed the mindset of people. Suddenly, when we had interesting new drugs, in addition to what we’ve been testing, allowed people to realize that, well, we can actually accrue these clinical trials.

Charles Ryan: Right. You and I work closely together in the cooperative group system and we’re both big advocates for it. My perspective is even though it’s a negative trial, we’re still going to learn a lot about bladder cancer from this study. I’m going to ask you about that in a second. But the other thing is just to congratulate you and to really praise the cooperative group system, which is able to ask the questions that industry is not answering. Not asking, rather.

Jonathan Rosenberg: Right.

Charles Ryan: We didn’t know what the answer was going to be when we started this study many, many years ago. So instead of calling this a failure, we say, “Well, that question, the answer is no. But we know it now.” So where do you go from here, in terms of what you’re going to tell us about bladder cancer moving forward?

Jonathan Rosenberg: Well, I think I just want to make one quick point that the phase two data looked really promising.

Charles Ryan: Yeah.

Jonathan Rosenberg: So it really shows the importance of confirmatory phase three trials. That phase two studies are not really able to look at overall survival and that’s why we need good phase three clinical trials. And so if we had changed practice based on phase two data, we would have been exposing patients to an agent that is not adding to their care in general.

Charles Ryan: With some cost and some risk.

Jonathan Rosenberg: Exactly. So it just highlights the importance of doing this. And as we get larger, single-arm phase two trials where we’re getting accelerated approval of drugs, based on those data, the confirmatory trials really are important to understand what the contribution of the actual treatment is to the patient benefit.

Charles Ryan: Mm-hmm (affirmative).

Jonathan Rosenberg: Because we’ve known that the pretreatment prognostic factors for bladder cancer are actually very important in determining the outcome of a phase two trial. You can have a combination or a drug that looks spectacular if you have patients with lymph node only metastasis. You can have a combination that looks terrible for patients who have liver metastasis. They may be the exact same or it may be that the one that looked worse is actually better. But you’ll never know unless you actually do the trial.

So I think it’s very important that we did this. We are going to learn a lot from this trial, actually. We do have a DOD grant focusing on untangling the biology of bladder cancer in the metastatic setting. We’re looking at DNA mutations. We’re looking at RNA expression profiles, and expression subtypes, immune subtypes, angiogenesis signatures, as well as extreme responders, as well as really developing a catalog of chemosensitivity mutations. There’s ample data out there, nowadays, suggesting that there are at least some bladder cancers that have exuberant responses to cisplatin-based chemotherapy.

We’re developing data that’s actually allowing us to identify those patients. In fact, there are clinical trials that are occurring both nationally and regionally to answer that question and allow us to see whether or not we can identify an exquisitely sensitive population to chemotherapy. So hopefully, we’ll learn information about that. It also will serve as an important control group when we analyze the data from the randomized phase three trials that are adding immunotherapy to chemotherapy in bladder cancer or immunotherapy therapy alone. Because we’ll have an analogous data set in a chemotherapy only population of about, you know, 250 patients on the control arm that you can then use as a historical comparator. Another data set of chemotherapy-treated patients for us to understand the biology.

Charles Ryan: So here’s a great example where an NIH sponsored trial, although negative for its primary endpoint, may end up helping bladder cancer patients in the future because of the prognostic work that you’ll be able to do, the biomarker work that you’ll be able to do. Really important work. This is hard, this takes a long time, it requires a lot of patience, and a lot of patients. Your work is really appreciated. And I think that, as I’m listening to talk, I’m also thinking for all the excitement about immunotherapy and other targeted therapies in bladder cancer, chemotherapy is not going away. So we need to continue to focus on how we can make it better.

Jonathan Rosenberg: Right. There are a small proportion of patients who are cured with chemotherapy with this disease, about 10%. We see that in the data, there is a plateau in the curve. And actually, you know, given the historical lack of ability to accrue studies, we minimized the sample size, which means we’re going to have to maximize the number of events. In fact, there’s a group of patients that never dies of bladder cancer on these trials. And so that kind of matched up. And that’s why the trial took so long to read out because there is a tail on the curve with chemotherapy.

Charles Ryan: That good problem of people doing well.

Jonathan Rosenberg: Right. A small percentage, albeit. We need to raise that bar.

Charles Ryan: I wanted to switch and ask you, Jonathan, about enfortumab vedotin. Some exciting new therapy developments in bladder cancer. Tell us about the work that you’ve been involved in there.

Jonathan Rosenberg: So since 2014, I’ve been involved in the enfortumab vedotin program with the phase one study and now in the phase two study. It’s an antibody-drug conjugate targeting a molecule called Nectin-4, which was expressed on probably 99% of bladder cancers. And at a high level, at about 95% or higher. So the concept behind antibody-drug conjugates, as people know, is that the tumor overexpresses the antigen, the antibody binds, gets internalized, the set of toxin gets released, in this case, MMAE, or Monomethyl auristatin E. An antimicrotubule agent goes on to kill the cells and hopefully the patients benefit. So in the phase one study that we conducted, about 40% of patients had objective responses, which, in a phase one trial, in multiply refractory, heavily treated patients-

Charles Ryan: Heavily treated patients, right.

Jonathan Rosenberg: -is really kind of astounding. So we replicated that and repeated that, essentially, in a prospective cohort phase two setting with patients previously treated with both Platinum chemotherapy and immunotherapy. The results that were presented at ASCO by my colleague, Dr. Petrylak, show that the response rate is almost identical in the phase two study, and that the median survival appears to be about a year, if not a little bit longer. That many of these responses are, in fact, quite deep with 12% of patients having complete responses, which we really haven’t seen in the checkpoint-refractory, platinum-refractory, or patient population. The FDA, about a year ago, labeled this in FDA breakthrough therapy. So we’re hoping to see that it will be up for accelerated approval sometime in the next 12 to who knows how many months.

Charles Ryan: Exciting. And this would be most likely an approval in Platinum-refractory?

Jonathan Rosenberg: It will be platinum-refractory and checkpoint-refractory because that really is their unmet medical need at this time. There are patients who might be candidates for another recently approved drug, erdafitinib, who have FGFR receptor alterations. But those patients are a small minority, whereas this seems applicable to most patients. And so now we have two different types of targeted therapies, in addition to immunotherapy, and in addition to chemotherapy. Whereas five years ago, we really had none of this.

Charles Ryan: Wow.

Jonathan Rosenberg: It’s quite an amazing change.

Charles Ryan: Yes, yes. It’s really great to see all the success coming for patients with bladder cancer, and really all the deep thinking that you’re doing around it, in terms of figuring out who are the patients who are going to benefit from this, and how to push clinical outcomes even further. So thank you for joining us.

Jonathan Rosenberg: Thank you very much.

Charles Ryan: Pleasure.

Jonathan Rosenberg: Appreciate it.