Treatments in Development for Muscle-invasive Bladder Cancer - Min Yuen Teo
January 15, 2020
Min Yuen Teo, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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.
A Pilot Safety Study and Single Arm Phase II Study of Gemcitabine and Cisplatin With Atezolizumab (MPDL3280A) in Patients With Metastatic and Muscle Invasive Bladder Cancer, Respectively
Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (Ambassador) Versus Observation
A Pilot Study to Evaluate the Safety of Neoadjuvant Nivolumab Alone or in Combination With Ipilimumab for Cisplatin-Ineligible Patients With Muscle Invasive Bladder Cancer (CA209-9DJ)
Study of Nivolumab in Combination With Ipilimumab or Standard of Care Chemotherapy Compared to the Standard of Care Chemotherapy Alone in Treatment of Participants With Untreated Inoperable or Metastatic Urothelial Cancer (CheckMate901)
Alicia Morgans: Hi, I'm so excited to have here with me today Dr. Min Yuen Teo, who is a medical oncologist at Memorial Sloan-Kettering, and a bladder cancer specialist. Thank you so much for talking with me today.
Min Yuen Teo: Thank you for having me.
Alicia Morgans: Wonderful. So I wanted to talk with you about some of the trials in progress that your group has been working on, and some of the unmet needs in bladder cancer that you're really helping to address. Can you explain some of that to me, and the real need for some of these trials that we're working on to advance the field?
Min Yuen Teo: Right. So the field bladder cancer medical management has really changed quite a lot, has been quite exciting in the last couple of years, really. But there's still a few areas which have a huge amount of unmet need, a lot of ongoing exciting work that's being done. So these areas, you can break it down into three main areas.
So we have the optimal management of patients with non-metastatic muscle-invasive bladder cancer. This is the space where these patients are at a higher risk of developing metastatic disease, so optimized treatment can reduce that then lead to long-term survival benefits. And there's also the need of patients who developed metastatic disease, what is the best first-line treatment for them. And lastly, there will always be a substantial subset of patients who have progressive disease, a refractory disease in treatment. And that is also, albeit a relatively small population, but a highly lethal disease stage where a lot of work has to be done to significantly improve their quality of life and survival.
Alicia Morgans: Absolutely. So one of the areas of prime interest though, among these areas has really been the neoadjuvant setting. And I know you have some trials that you're working on in that particular area, a new regiment prior to cystectomy.
Min Yuen Teo: Right, so that has always been an area of major interest for myself and for our group. So there are basically three themes we have, ourselves and various other groups in other major institutions around the country and around the world have been working on.
So one of the main themes is how to build on, how to improve the efficacy of cisplatin-based chemotherapy. So variants go up in looking at combining new agents into this intensification of the chemotherapy, and one of the recent trends, where a lot of activity has been going on would be the addition of an immune checkpoint inhibitor in that space.
And the second theme that we have been exploring is for patients with cisplatin-ineligible muscle-invasive bladder cancer. These represent a pretty substantial subset, depends on some analysis, it ranges from 25 to easily close to 50% of our patients, muscle-invasive bladder cancer, which means it is a pretty substantial cohort who are not eligible for life-prolonging cisplatin-based chemotherapy. And so far there's no effective systemic therapy for this cohort. So we have been doing a lot of work in this realm, and in fact, this has been one of my major research focuses at the moment, and [inaudible]. And the third thing would be on bladder preservation. While the adequate treatment required radical cystectomy, is there a possibility where a subset of these patients could preserve their bladder as losing the bladder is an extremely life-altering experience, which has a significant impact on your quality of life.
So these are three major themes, and myself and my colleagues in the bladder group within the unit have been working on various aspects.
So what I've been working on, we do have an investigator-initiated study using immune checkpoint inhibitors as a new adjuvant therapy. I know other groups in Europe and in the UK have published their early data showing the efficacy in this realm, what we are doing is trying to bring it a step further.
So in addition to monotherapy, we are trying to build, to see, given the activities from combined treatment, from nivolumab and ipilimumab in the metastatic setting, our trial is designed with multiple cohorts in mind with increasing intensification of the treatment. We just have completed our first cohort in single-agent nivolumab. That's minimal toxicity, as seen from the other identical trials in this space.
The second cohort would look at the addition of ipilimumab at a six-week interval, identical to what they have seen in the metastatic non-small cell lung cancer literature, where the six weeks interval does not significantly compromise efficacy.
And the third cohort would be the standard ipilimumab every three weeks. So it will be like a progressively intensified treatment with progressively increased risk of toxicity to see which might be the best middle ground to take with acceptable toxicity while improving the outcomes of these patients.
Alicia Morgans: So this is a neoadjuvant therapy though?
Min Yuen Teo: Correct.
Alicia Morgans: So for how long are patients receiving treatment before cystectomy? Because I think one of the concerns historically has been for those patients who are not cisplatin-eligible, we don't want to delay their time to cystectomy. This is sometimes an interesting or challenging concept because surgeons often do need at least six weeks or sometimes a little more to get the patient onto the schedule. So there is some time to give a therapy, especially if it's an effective one. But how many weeks of therapy is your study giving patients who are not cisplatin-eligible before cystectomy?
Min Yuen Teo: So that's an extremely good question, and that was one of the main concerns during the development of the study. So first of all, for the duration of treatment, there were two considerations. First, we tried to mimic the cisplatin-eligible approach so that the duration of treatment would be comparable to patients who are undergoing cisplatin-based chemotherapy.
And secondly, given the data from the metastatic setting showing that the time to maximum response is approximately eight to 10 weeks, so that is the duration of the treatment as well.
So it depends on the cohorts. On average, you're talking about nine to 11 weeks of systemic therapy, and for the assess, if treatment would significantly interfere with a patient's ability to undergo cystectomy, given that one of the biggest concerns so far with ipilimumab across all disease types is a risk of gastrointestinal toxicities, and cystectomies always require an ileal conduit in your bladder, which required a GI tract for reconstructions.
So in fact, the primary endpoint was designed to look at the patient's ability to get the cystectomy in a timely and safe manner. So efficacies, like pathologic responses, and the instances of survival, those are the secondary endpoints, but our primary concern is to ensure that these patients, especially in the subsequent cohorts, that they're able to get the surgery without severe toxicities which will cause them to miss the opportunity for curative treatment.
Alicia Morgans: Okay. And that makes sense. I think it's important, I think for clinicians to know too, as we hopefully are able to move forward with these treatments, that these are not therapies that are expected to have detrimental effects on wound healing and things like that. With chemotherapy, we always have to kind of make a buffer after you finish your chemotherapy. You do need to have a little recovery period before you can move into surgery, because of the concern for effects on healing or the risk of infection.
It's really interesting to think about the effects of ipilimumab particularly, or the ipi/nivo combination, potentially causing colitis, and then potentially causing poor outcomes in terms of new bladder or ostomy formation. That's a really insightful thing to think of on the front end. And so I appreciate that you brought that up and that you and the team are thinking about that as a particular piece that you're assessing as you're thinking about moving this therapy forward.
Min Yuen Teo: Our urology colleagues are very supportive of the concept, and there is definitely the concern, even you might not necessarily need high-grade colitis and even low-grade colitis or any GI toxicity could theoretically impact the ability to form a stoma on your bladder. And that's something that our urology colleagues are actively involved in and perspectively looking at as part of the trial.
Alicia Morgans: That's really important. What other trials are you moving forward in your group? This one's very, very exciting. What other trials are you moving forward in this setting?
Min Yuen Teo: So as I mentioned, we are very interested in the perioperative space. So we have trials examining different of those main themes. So for those patients who are cisplatin-ineligible, we have been examining cisplatin gemcitabine plus atezolizumab combination. So the trial is ongoing, it's close to completion. We don't have any readout yet, but the fact that it was designed as a two-stage, we were able to kind of move on to a two-stage that was a promising development.
And another trial that we have been very interested in, which is run through the Alliance Group led by my colleague, Dr. Iyer is a biomarker selector trial for patients who are eligible for cisplatin, with an aim for bladder preservation.
So that's a very interesting trial conceptually. It really builds on a lot of our group's observation. So our goal has always been interested in how cancer genomics could interact with therapeutic outcomes. So one of our observations with the last few years is that especially alterations in DNA damage repair and response genes like ERCC2, BRCA1s, 2s, and ATMs and so on and so forth, could be associated in [inaudible] platinum and even in immune checkpoint inhibitor sensitivity, at least from some retrospective work, correlation work that we have done in the neoadjuvant space presently, these alterations have been associated with a higher rate of pathologic complete response.
So this trial kind of opened in a large number of sites across the country. It's interesting, it's designed in such a sense that everyone would receive systemic chemotherapy with dose-dense cisplatin, gemcitabine, and concurrently the lab would be running targeted genomic sequencing to see if there are any alterations in these genes.
If we see any alteration of any of these DNA damage and repair and response genes, and post-chemotherapy cystoscopy shows no clinical evidence of disease, these patients would bypass cystectomy and go on observation with the hope that they would not have any further recurrence. And yet at the same time, they're able to preserve their bladder.
This could potentially represent a fairly substantial minority of patients, at least based on our group's work. It could involve easily 20 to 25% of patients with muscle-invasive bladder cancer. So it's not insubstantial. And for those patients who do not have any of these alterations, they would go on to get a radical cystectomy or chemoradiotherapy. And this would also serve as a large sample size, which would help us learn what are the other factors that lead to their cisplatin resistance, or if there are any other factors which could predict their response to treatment.
So from a clinical perspective, there's a lot of potential for patients, and there's a lot of room to study how the further interaction between cancer genomics and outcome.
Alicia Morgans: Absolutely. Well I am always excited to hear what you and your group are up to, and you're really, I would say, pushing the boundaries of what we know and what we can do for patients with muscle-invasive bladder cancer, it sounds like from the neoadjuvant setting all the way through bladder preservation-type settings. And so I'm excited to continue to hear more. I really appreciate you taking the time to share with me today.
Min Yuen Teo: You're welcome. Thank you.