Updates on Bladder Cancer Clinical Trials ASCO GU 2020 - Matthew Galsky
February 26, 2020
Matthew Galsky, MD Director of Genitourinary Medical Oncology, Tisch Cancer Institute, Professor of Medicine, Mount Sinai
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.
Read: ASCO GU 2020: New Standards in First-Line Therapy for Advanced Disease
Read: ESMO 2019: IMvigor130: Efficacy and Safety from a Phase 3 Study of Atezolizumab as Monotherapy or Combined with Platinum-based Chemotherapy versus Chemotherapy Alone in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma
Alicia Morgans: Hi, I'm so excited to have here with me today, Dr. Matt Galsky, who is a Professor of Medicine at Mount Sinai. Thank you so much for being here.
Matthew Galsky: Thank you.
Alicia Morgans: So I wanted to speak with you today a little bit about all of the data that's been coming out in metastatic bladder cancer or urothelial cancer. So I know you've been really integrally involved in some of this work and certainly, as an expert in the field, have some perspective over how we think about this. But what are your thoughts, and I'd like to focus the conversation really on the idea of using chemotherapy in eligible patients and thinking about maintenance immunotherapy.
Matthew Galsky: So we have two classes of drugs, actually more than two classes now, but we have two classes of drugs approved as of around 2016 that work via different mechanisms of action. We have immune checkpoint blockade and we have chemotherapy, which we've had for decades.
Alicia Morgans: Yes.
Matthew Galsky: And so the logical question is should we combine these? And if so, how? There are really two main strategies for combination treatment. You can give all the drugs together or you can give them sequentially. And if you give them sequentially, you could give them right after another in a switch maintenance fashion. And so trials were designed to try and address these questions many years ago and we're just starting to see those trials read out now.
Alicia Morgans: So IMvigor130 was recently reported and published. So what are your thoughts? How do you think about this and set up with the trial design and all of that just to make sure everyone's on the same page.
Matthew Galsky: So IMvigor130 tested two concepts. One concept, is there a role for atezolizumab monotherapy in the frontline setting in all-comers with metastatic urothelial cancer, that is patients eligible and ineligible for cisplatin-based chemotherapy? And the concept of whether or not we should give chemotherapy and atezolizumab together versus chemotherapy alone. It's that latter question that was the primary analysis. And if that analysis showed a benefit for the combination treatment, then per the testing hierarchy, the question about whether or not monotherapy has a role versus chemo alone could be addressed. We only have the answer, or at least part of the answer, from the trial so far based on the combination question. There was a co-primary endpoint of progression-free survival and overall survival. We have the final PFS analysis showing that chemotherapy plus atezolizumab improves PFS compared to standard of care chemotherapy alone.
That was statistically significant. The clinical significance of that improvement is of question. It's mild to modest. Overall survival has shown a similar trend toward a benefit in terms of the effect size and at the interim analysis, the P-value, which is less than 0.5 if you look at the P-value, but since it's an interim analysis it didn't meet the threshold to reach statistical significance. The effect size is pretty similar in the 0.82 range. And so there seems to be a trend toward a benefit with combination treatment versus chemotherapy alone based on the study so far.
Alicia Morgans: So just to remind everyone, too. The IMvigor130 study, as well as the pembrolizumab study, is what gave us the indication that we should not be using immunotherapy as a primary agent in patients who are cisplatin or chemotherapy eligible, first-line. And just to make sure that everyone's clear on that.
Matthew Galsky: So, a very important point. Two important points. One, that KEYNOTE-361, a similarly designed study with some nuances, has not read out yet. And so the combination of these two studies should really inform practice. Ideally, they should go in the same direction, so that we'll have two randomized studies supporting the same approach. But the other point that you make is incredibly relevant because both of these trials change practice even before they completed accrual and were read out, which is really pretty unprecedented.
Alicia Morgans: Yes, absolutely. So there was also an avelumab study only reported in a press release at this point, but can you tell us a little bit about that study? And it seems like things are going in a similar direction in terms of the effect there.8
Matthew Galsky: So with the JAVELIN 100 Bladder study is a study that randomized patients, who had at least stable disease after first-line platinum-based chemotherapy for metastatic urothelial cancer, to switch maintenance avelumab PD-L1 inhibitor op versus observation. As you know, our standard treatment after initial chemotherapy in patients who have at least stable disease after about six cycles is really to stop treatment and to monitor. And these patients are destined to progress at some point. And so there's really been a need to fill that space, to see if we can use a treatment that has a favorable risk-benefit ratio in that setting. And so that's what was tested in the avelumab study. We had previously done a randomized Phase II study of similar design with pembrolizumab showing a PFS benefit in the switch maintenance setting. And the avelumab study recently was reported in a press release to show an improvement in overall survival in that setting. This is really the first, I think, first-line metastatic urothelial cancer study to show a survival benefit with the addition of a novel agent. And so we're obviously eagerly awaiting the data.
Alicia Morgans: Absolutely. So how are you thinking about these trials in your day to day clinical practice? Are you putting patients immediately on immunotherapy or checkpoint inhibitors after chemotherapy? What are you doing?
Matthew Galsky: So I think it's important to recognize that the switch maintenance setting is a bit different than the concurrent upfront setting in that there are certain patients who don't make it to the switch maintenance question. Because, unfortunately, they progress before six to eight cycles of initial chemotherapy. And so that strategy probably is not going to be applicable to all our patients. And if we start everyone on chemotherapy that's recognizing that some patients will progress before the maintenance setting and might get immune checkpoint blockade at that point anyway. So obviously, we need to wait to see the data. For now, I'm not using combination strategies upfront. I think the maintenance approach is attractive, but I do think that there's a population of patients who are probably good candidates for monotherapy with immune checkpoint blockade upfront. And I don't think that we should ignore that in what the biomarkers are telling us, because clearly in a subset of patients these treatments work incredibly well and can be incredibly well tolerated.
Alicia Morgans: But I do think that your point about patient selection is one that's necessary to answer so that we can figure out, you know... Those patients who had chemotherapy up front and had progression and then did not go on to the JAVELIN study were really kind of declaring themselves at that point and would per standard of care on progression then they weren't included.
Matthew Galsky: And I think the one question about that strategy then is, are there going to be some patients that miss the opportunity for immune checkpoint blockade because they progress unfortunately so quickly that they don't get a chance at their next line of treatment? And that's the one thing that I still worry a little bit about, the maintenance oppression.
Alicia Morgans: I agree, 100 percent. I think some real-world data suggests that with each line of therapy, about half of patients fall off. And so that's why I think even the radiographic progression-free survival data from IMvigor130 is really interesting because if you can ensure that those patients are getting the treatment that they need from the get-go, you hopefully will lose fewer patients as we go line to line.
Matthew Galsky: Absolutely. And we see that when you look at the survival curves, and I think that's another great point, that all of the story isn't told in the hazard ratios. And we see very interesting survival curves with monotherapy versus combination. And there are patients who clearly are not benefiting from monotherapy early on who, when we give combination therapy, that portion of the survival curve is eliminated. Even though you don't impact the hazard ratio as impressively, you do eliminate the subset of patients who would have been given one class of drugs versus the other, not respond, and unfortunately progress very rapidly.
Alicia Morgans: Absolutely. So the goal will always be to shift the survival curve. This seems to be a step in the right direction with more to come. I'm looking forward to it. I'm sure you are too.
Matthew Galsky: Absolutely.
Alicia Morgans: What would your take-home message be from all of this?
Matthew Galsky: So the take-home message is that the landscape is changing rapidly. It's quite possible in six months that we'll have three standard first-line treatments for metastatic urothelial cancer, without comparative head-to-head data. And we'll have to decide with our patients what the best strategy is for them.
Alicia Morgans: That's going to be a challenge, I'm sure. We'll have to have you on to talk about that when the time comes. But thank you so much for sharing your expertise.
Matthew Galsky: Thank you.