Perioperative Systemic Therapies for Muscle-Invasive Bladder Cancer - Jacqueline Brown
February 3, 2025
Jacqueline Brown joins Sam Chang to discuss perioperative systemic therapies for muscle invasive bladder cancer. The discussion highlights recent advances, including the NIAGARA trial combining chemotherapy with durvalumab, and emerging data on antibody-drug conjugates like enfortumab vedotin in the perioperative setting. Dr. Brown emphasizes the importance of balancing treatment intensification with safety, particularly in the curative setting, and discusses ongoing phase 3 trials exploring various combination approaches. The conversation explores the potential future role of systemic therapies possibly replacing surgery, with Dr. Brown emphasizing the need for better biomarkers to identify patients who might safely avoid cystectomy. They discuss the challenges of implementing combination therapies while managing toxicities, and the importance of tailoring treatment intensity based on patient response and biomarker data.
Biographies:
Jacqueline Brown, MD, Medical Oncologist, Assistant Professor, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center Nashville, TN
Biographies:
Jacqueline Brown, MD, Medical Oncologist, Assistant Professor, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center Nashville, TN
Related Content:
SUO 2024: Emerging Perioperative Systemic Therapy
ESMO 2024: Randomized Phase 3 Trial of Neoadjuvant Durvalumab plus Chemotherapy Followed by Radical Cystectomy and Adjuvant Durvalumab in Muscle-Invasive Bladder Cancer (NIAGARA)
ESMO 2024: Invited Discussant: A Randomized Phase 3 Trial of Neoadjuvant Durvalumab plus Chemotherapy Followed by Radical Cystectomy and Adjuvant Durvalumab in Muscle-Invasive Bladder Cancer (NIAGARA)
SUO 2024: Emerging Perioperative Systemic Therapy
ESMO 2024: Randomized Phase 3 Trial of Neoadjuvant Durvalumab plus Chemotherapy Followed by Radical Cystectomy and Adjuvant Durvalumab in Muscle-Invasive Bladder Cancer (NIAGARA)
ESMO 2024: Invited Discussant: A Randomized Phase 3 Trial of Neoadjuvant Durvalumab plus Chemotherapy Followed by Radical Cystectomy and Adjuvant Durvalumab in Muscle-Invasive Bladder Cancer (NIAGARA)
Read the Full Video Transcript
Sam Chang: Hi. I'm Sam Chang. I'm a Urologist in Nashville, Tennessee, and we are quite fortunate to have Dr. Jackie Brown from Emory University. She's at the Winship Cancer Institute there, and she gave a wonderful presentation at the SUO 2024 meeting focusing on actually perioperative systemic interventions for urothelial carcinoma.
And so we're quite fortunate to have Dr. Brown with us today, as she gives us the highlights of her presentation. And Dr. Brown allowed me to call her Jackie. So I want to say welcome, Jackie, and thank you so much for spending some time with us.
Jacqueline Brown: Thanks for having me, Sam. I am excited to get to do some highlights from my talk at the SUO bladder cancer course on some pretty exciting current and upcoming changes in the way that we use systemic therapies to manage muscle invasive bladder cancer. Before we get started, I just wanted to refresh all of us on what our goals are as we treat muscle invasive bladder cancer.
We want to avoid overtreating patients who could be cured with fewer modalities. And at the same time, as we focus on decreasing toxicities and morbidity, we really also want to avoid undertreatment in patients who could be cured with escalation of therapy. And then lastly, we want to avoid cystectomy in those who have incurable micrometastatic disease. That's the worst outcome of all in my opinion sometimes.
So I've pulled out a few of the highlights of the whirlwind tour from my talk at SUO. I think we have to spend a little bit of time talking about the phase 3 data from the NIAGARA trial. This was presented at ESMO in 2024, so fairly recently. This was a trial looking at patients with muscle invasive bladder cancer who had a creatinine clearance of at least 40.
And they were randomized to get gemcitabine plus cisplatin (standard four cycles of neoadjuvant chemotherapy) with or without durvalumab, which is a checkpoint inhibitor that inhibits PD-L1. Patients went on to receive their radical cystectomy, and if they were randomized to the durva arm, they ended up getting eight more cycles of durvalumab in the adjuvant setting.
There were dual primary endpoints of event-free survival as well as pathologic CR rate. And then OS was, of course, important as well. Now, the path CR rate here ended up being about 37% with durva, gem, and cisplatin, compared to about 27% with chemotherapy alone. I have just pulled out that this study did meet its primary endpoint of event-free survival, and it also met its secondary endpoint for overall survival.
What you can see here is we’ve got a hazard ratio of 0.75. That was significant with a P value there of 0.01. So the argument at ESMO was that this is practice-changing data. There are a couple of things I want to point out here. This study allowed a pretty real-world population. Patients could have this creatinine clearance of as low as 40. A lot of studies stop it at 60. These are actually similar to the patients we treat. And in those patients, that allowed for split-dose cisplatin, which in clinical practice we do all the time. Also, patients with N1 nodal disease were allowed.
Another really important consideration here is that the neoadjuvant and the adjuvant components were a package deal. If patients were enrolled in the gem/cis plus durva arm, they got the four cycles. And then they did get the durvalumab regardless of what was found at the time of cystectomy. I think that's really important relative to how we use adjuvant nivolumab right now and how we select patients for that.
And it’s not for everybody. It’s only based on pathologic findings at the time of surgery. And there are two ongoing phase 3 studies, the ENERGIZE study and KEYNOTE-866. And it's a little bit more complicated, but just suffice to say that both of these are looking at chemo plus perioperative immunotherapy. It’s nivolumab with ENERGIZE; it’s pembrolizumab with KEYNOTE, and we will be really awaiting those results to understand what the role for perioperative chemoimmunotherapy is for our patients.
I wanted to highlight some of the data looking at perioperative EV monotherapy. So probably most of us are aware that EV, or enfortumab vedotin, is a nectin-4 targeting antibody-drug conjugate. It’s really revolutionized the way that we treat metastatic disease, first as monotherapy in the third-line setting and more recently in the first-line setting in combination with pembrolizumab in all patients with metastatic disease, regardless of their cisplatin eligibility status.
So these two cohorts from EV-103 were looking at patients with muscle invasive bladder cancer being treated with curative intent. Cohort H looked at neoadjuvant EV. These were cis-ineligible patients, and they got three cycles of EV prior to cystectomy. These are small studies. This was 22 patients. You can see a path CR rate here of about 36%, and all patients ended up proceeding to their radical cystectomy.
EV-103 cohort L looked at perioperative EV. So these patients also cis-eligible, they ended up getting three cycles in the neoadjuvant setting and six more cycles of EV in the adjuvant setting. Fifty-one patients were enrolled. That path CR rate was 34%. And again, what we saw here is that EV didn’t prevent any patients from going on to get their radical cystectomy.
We have three phase 3 perioperative EV with immunotherapy studies that are ongoing, and we really anxiously await these results. I just wanted to highlight these so we all know what to keep our eyes on. We have EV 303 and EV 304 across the top of the page. So EV 303 is looking at a cisplatin-ineligible population. And these patients were randomized to either perioperative pembro monotherapy, surgery alone, or perioperative pembro plus EV.
EV-304 is in a cisplatin-eligible population. And so these patients were randomized to either perioperative EV pembro versus neoadjuvant gemcitabine and cisplatin. And then lastly, VOLGA is a phase 3 study, and they are looking at an intensified immunotherapy approach with EV. So patients with muscle invasive bladder cancer are randomized to one of three arms. We have EV with durva and tremelimumab.
So you’ve got the combination of the checkpoint inhibitor, the PD-L1 agent, as well as Treme, which is a CTLA-4 inhibitor. The next arm is EV with durva. So again, that antibody-drug conjugate plus a single-agent immunotherapy. And then a third of the patients went on to receive just cystectomy as a standard current 2025 patient who’s not eligible for cisplatin would.
So very briefly highlighting some other high points of recent data and upcoming data. So we talked about EV. EV is a nectin-4 targeting antibody-drug conjugate. I want to highlight two other ADCs. We’ve got sacituzumab govitecan. This is an antibody-drug conjugate that targets anti-Trop-2. It’s an SN-38 payload. So this is a derivative of irinotecan. This was studied in the neoadjuvant setting in the SURE-01 study.
This had some promising efficacy. However, I wanted to highlight, for the purposes of our very short presentation today, of those first eight patients (of the total of 21 who were enrolled in this study), 75% of those eight patients—so six of them—had grade 2 or 3 neutropenia. And there was a death from neutropenic sepsis that prevented a patient from going on to get their cystectomy. This led to mandated dose reduction and G-CSF.
I think this really highlights that we have to be careful because we’re treating patients for cure, and we can’t let our advances in systemic therapy lead to adverse events that prevent that from happening. We’ve got Disitamab vedotin. This is an antibody-drug conjugate that targets HER2. It’s an MMA payload, very similar or actually identical to EV.
And so there was a study—very small, 12 patients—and only 10 of these patients were evaluable for efficacy, very recently presented at big ASCO in 2024. But of these patients who are HER2 or HER2 two or three positive, eight of 10 had a pathologic CR when treated with this antibody-drug conjugate combined with toripalimab, which is another checkpoint inhibitor.
Again, tiny numbers, biomarker-selected. But it’s hard to ignore very promising prelim data like that. And then lastly, I just have to mention TAR-200. A urology audience is going to be familiar with this. This is the gemcitabine pretzel that slowly releases gemcitabine into the bladder over time. It’s been investigated and continues to be investigated in the neoadjuvant setting in the SunRISE-4 study.
So it is not a comparison trial. But there are two arms, one looking at TAR-200 with cetrelimab (another PD-L1 agent) and the second arm just looking at cetrelimab monotherapy. I just want to highlight the 53 patients so far who have been treated with TAR-200 with cetrelimab, and as neoadjuvant therapy, that path CR rate was 42%.
A benefit of TAR-200 is that it’s mostly local symptoms. I deal in high-risk drugs all the time. And so to have a drug that mostly causes local symptoms as opposed to game-changing systemic symptoms is a very big deal. Of course, when you combine it with a checkpoint inhibitor, you lose that local-only selection.
And so lastly, a few take-home messages. We talked about NIAGARA, and this is potentially practice changing. But I still have questions about how to implement it in clinical practice. EV has been practice changing in the management of metastatic disease. And so these studies where we combine it with immunotherapy in the perioperative setting are very anxiously awaited.
We’ve got other drugs—the ADCs—enfortumab vedotin that targets HER2, sacituzumab govitecan that targets Trop-2, and also local therapies like TAR-200. Data with all of those is coming in and is very thought-provoking. And then lastly, the neoadjuvant setting is a great time to look at new drugs because you’re able to get tissue at the start and tissue with the cystectomy and really see how active these drugs are.
But that burden of safety is intensified because we’re treating these patients with curative intent, and we as medical oncologists don’t want to get in the way of that. So thank you for listening.
Sam Chang: Jackie, that was a wonderful overview. I love how now with all the systemic options, we still use neoadjuvant adjuvant. But the utilization of the word perioperative has really taken hold with treatments, I think smartly, probably by the pharmaceutical companies looking at the combination of the agents being used prior to therapy—prior to localized therapy—and then afterwards.
As we look at the effectiveness of these systemic treatments, a question that’s been raised to the urologists is, are we going to get to the point where we’re really not going to need to do cystectomies anymore? That’s a point that obviously the surgeons are like, oh, there’s no way, that’s not really possible.
But as these pathologic CRs increase in frequency and we’re better able to really determine who has a CR with whatever circulating tumor DNA, repeat biopsies, whatever we decide—MRI imaging—what do you think about truly in the near future, the systemic therapies replacing localized therapies, or will we always need to do localized therapy as well?
Jacqueline Brown: I think that’s a great question. And that’s right. That is the holy grail. That is what our patients want. That is what every patient that I meet with asks me, “Maybe do I just need you, Jackie?” And I say, “Not today, but I see where you’re at and there’s lots of cool research happening to that end, my friend.” And so we’ve had really interesting work.
Matt Galsky, Dan Geynisman up at Fox Chase, who have looked at that exact question: can we treat patients with good systemic therapy? And in those patients who have a great response, who have that clinical CR, can we forego cystectomy? Right now and in the trials that we have presented that have shown this as proof of concept, they have been very promising, and a very, very small number of patients has gone on to have metastatic disease.
With that said, if you have one patient who goes on to metastatic disease, that’s one patient too many for most of us. So it’s a balance of efficacy and also trying to meet patients where they’re at. I have patients who meet me and say, “I will not lose my bladder, what can you do for me?” So as long as we’re having at-future-state risk-benefit discussions with our patients, then I think that there is a place for this research to continue and for potentially for it to come into the clinical treatment realm.
I think something we’re going to need is good biomarkers. It’s got to be a lot more in my mind than just the clinical CRs that we’ve had so far in the data. We have had—when we think about Matt Gorsky’s study—we define clinical CR, I believe it was with cystoscopy. There might have been some random biopsies there, and it was imaging.
I don’t believe that incorporated circulating tumor DNA in blood. I don’t believe it incorporated ctDNA in urine. And I think for us to continue having these studies, we’re going to be incorporating those biomarkers. And we are adjusting to the rapidly changing technology that we all have, to figure out what do we use now. And I think that’s a really smart application for it.
So I hope there is a future where I am obsolete in this realm. Believe it or not, or I’m not obsolete. I guess you’d be obsolete, Sam.
Sam Chang: I was going to say this: you are much, much further away from being obsolete than I am. We can figure it out from the get-go for sure. But as you talk about those things, the importance of the biomarkers, I think, is really essential, as you say, to determine clearly a combination of risk stratification and then also response to therapy.
And then whether or not we need to continue therapy, deescalate therapy, et cetera. As you look at these combinations of chemotherapy and IO therapy, and now we’ve got obviously the addition of the ADCs, it strikes me a little bit that early on—and this, again, is your urologist take—early on, the combination for advanced disease, metastatic advanced, the combination of chemotherapy and IO did not seem to be beneficial combining them.
But now we get these perioperative regimens where there seems to be maybe not a synergistic effect, but at least an additive effect of the combining of these. And it might be that you’re continuing therapy afterwards, et cetera, around the localized therapy. So as you look forward, clearly combination therapies are going to be important.
Are we going to be stacking them all together— the CTLA-4, the checkpoint inhibitors, the ADCs, chemotherapy? Are we all going to bundle all of them, or are we going to be able to better risk stratify and actually then tailor treatments? What do you think we’re going to be doing?
Jacqueline Brown: That’s a great question. We’ve got—just to draw a parallel from the metastatic setting—we’ve got data from the DAD and the DAD-IO trial from Brad McGregor at Dana-Farber. So that’s combination of—this is metastatic, but it’s enfortumab vedotin plus sacituzumab govitecan plus, can we throw a checkpoint inhibitor in there as well? And what kind of toxicity do we get along with efficacy?
And so as we have more and more drugs, there is a ceiling to how toxic these things are. And ultimately, I think the stacking in the curative intent setting will also be limited by—we have to deliver these patients to surgery ready to rock. I always tell my patients my goal is three to four cycles of whatever neoadjuvant chemo I’m choosing for them. I said, but if you get one in and it really beats you up, then we’ve gotten one in and that was better than zero.
Two was better than one because ultimately the big show is your surgery, and I’m doing my best prior. So we’re going to be limited in the stacking of toxicities. And I have questions. NIAGARA data combining platinum doublet chemotherapy with immunotherapy—there’s something there, and there’s been debate as to whether, when we talk about checkpoint inhibition and muscle invasive bladder cancer, maybe the PD-L1 weren’t quite as active.
We have the data from IMvigor010 with atezolizumab that was negative. The NIAGARA data would speak otherwise. And we’re seeing it combined. And to your point, maybe not synergistic, maybe it’s additive, but I think that it’s intriguing. And yet I can’t help but wonder, since the—again—metastatic setting has changed so much with our antibody-drug conjugates, are we going to have a new wave shortly where this was great, it was a new benchmark, and what happens next?
So I don’t think we’ll be able to combine everything, just limited by toxicity and needing to get through a major surgery. And I do wonder if we’re on the cusp of a change of regime, similar to the metastatic setting. You bring up—I’ll say one other thing, which is, as we talk about stacking, there’s stacking of individual drugs in a regimen, and then there’s also stacking of the perioperative treatment.
There’s the neoadjuvant component. There’s the adjuvant component. And should everybody get everything? And in NIAGARA, all patients, regardless of what happened to them at the time of surgery—if they had a path CR, they got eight adjuvant cycles of durva. If they had a T3 tumor remaining, they got eight cycles. Everybody got it.
And so I am really thinking hard about how I implement that in my own practice. I think if someone has a path CR and then you treat them with three cycles of durvalumab and maybe they’re the patient who gets a terrible immune-related hepatitis or, God forbid, that they got a myocarditis or something life-threatening to them, we’re going to wish we hadn’t done that, particularly when maybe their disease was cured with the neoadjuvant treatment and surgery.
So I think this is where those biomarkers are going to come in. I think this is where it’s really important that we as a community are enrolling to trials like Modern, which is looking at ctDNA post-cystectomy and figuring out: should patients be getting—if they’re positive, should they get—we know that that’s a marker of minimal residual disease.
So they’re randomized to the one year of nivolumab or intensified immunotherapy—nivolumab plus relatlimab, which is a LAG-3 inhibitor. And if they’re negative, maybe you’re cured. And maybe that one year of nivolumab we would give you is going to be overkill. And any toxicity incurred is one toxicity too many.
Sam Chang: Too much.
Jacqueline Brown: And so that person, if you’re negative, they’re getting randomized to the one year of nivolumab or surveillance. So I think that’s going to be really important data for us. And I do wonder when we get those results if that will be practice changing.
Sam Chang: Now, really important points. The clinical data is so exciting. But then the real-world application is going to be really important, just as you said, because it will—and you’re always clouded by your own individual patients. As you just pointed out, what about that patient in the third or fourth cycle of adjuvant therapy that all of a sudden has some type of -itis that didn’t have to happen maybe so—
Jacqueline Brown: It didn’t.
Sam Chang: Exactly. Now, Jackie, thank you so much. The presentation of the SUO was so well received, was obviously so timely. And we really appreciate you giving us the highlights for UroToday and look forward to doing it again and look forward to having you on the UroToday Show with us and being able to highlight the work that you are doing at Emory, and I know how you and the urology team there work so closely.
And so well together, and it’s really a testament to how great a program you guys have. So thanks for spending some time with us.
Jacqueline Brown: Thanks for your time, Sam. Appreciate the invite.
Sam Chang: Hi. I'm Sam Chang. I'm a Urologist in Nashville, Tennessee, and we are quite fortunate to have Dr. Jackie Brown from Emory University. She's at the Winship Cancer Institute there, and she gave a wonderful presentation at the SUO 2024 meeting focusing on actually perioperative systemic interventions for urothelial carcinoma.
And so we're quite fortunate to have Dr. Brown with us today, as she gives us the highlights of her presentation. And Dr. Brown allowed me to call her Jackie. So I want to say welcome, Jackie, and thank you so much for spending some time with us.
Jacqueline Brown: Thanks for having me, Sam. I am excited to get to do some highlights from my talk at the SUO bladder cancer course on some pretty exciting current and upcoming changes in the way that we use systemic therapies to manage muscle invasive bladder cancer. Before we get started, I just wanted to refresh all of us on what our goals are as we treat muscle invasive bladder cancer.
We want to avoid overtreating patients who could be cured with fewer modalities. And at the same time, as we focus on decreasing toxicities and morbidity, we really also want to avoid undertreatment in patients who could be cured with escalation of therapy. And then lastly, we want to avoid cystectomy in those who have incurable micrometastatic disease. That's the worst outcome of all in my opinion sometimes.
So I've pulled out a few of the highlights of the whirlwind tour from my talk at SUO. I think we have to spend a little bit of time talking about the phase 3 data from the NIAGARA trial. This was presented at ESMO in 2024, so fairly recently. This was a trial looking at patients with muscle invasive bladder cancer who had a creatinine clearance of at least 40.
And they were randomized to get gemcitabine plus cisplatin (standard four cycles of neoadjuvant chemotherapy) with or without durvalumab, which is a checkpoint inhibitor that inhibits PD-L1. Patients went on to receive their radical cystectomy, and if they were randomized to the durva arm, they ended up getting eight more cycles of durvalumab in the adjuvant setting.
There were dual primary endpoints of event-free survival as well as pathologic CR rate. And then OS was, of course, important as well. Now, the path CR rate here ended up being about 37% with durva, gem, and cisplatin, compared to about 27% with chemotherapy alone. I have just pulled out that this study did meet its primary endpoint of event-free survival, and it also met its secondary endpoint for overall survival.
What you can see here is we’ve got a hazard ratio of 0.75. That was significant with a P value there of 0.01. So the argument at ESMO was that this is practice-changing data. There are a couple of things I want to point out here. This study allowed a pretty real-world population. Patients could have this creatinine clearance of as low as 40. A lot of studies stop it at 60. These are actually similar to the patients we treat. And in those patients, that allowed for split-dose cisplatin, which in clinical practice we do all the time. Also, patients with N1 nodal disease were allowed.
Another really important consideration here is that the neoadjuvant and the adjuvant components were a package deal. If patients were enrolled in the gem/cis plus durva arm, they got the four cycles. And then they did get the durvalumab regardless of what was found at the time of cystectomy. I think that's really important relative to how we use adjuvant nivolumab right now and how we select patients for that.
And it’s not for everybody. It’s only based on pathologic findings at the time of surgery. And there are two ongoing phase 3 studies, the ENERGIZE study and KEYNOTE-866. And it's a little bit more complicated, but just suffice to say that both of these are looking at chemo plus perioperative immunotherapy. It’s nivolumab with ENERGIZE; it’s pembrolizumab with KEYNOTE, and we will be really awaiting those results to understand what the role for perioperative chemoimmunotherapy is for our patients.
I wanted to highlight some of the data looking at perioperative EV monotherapy. So probably most of us are aware that EV, or enfortumab vedotin, is a nectin-4 targeting antibody-drug conjugate. It’s really revolutionized the way that we treat metastatic disease, first as monotherapy in the third-line setting and more recently in the first-line setting in combination with pembrolizumab in all patients with metastatic disease, regardless of their cisplatin eligibility status.
So these two cohorts from EV-103 were looking at patients with muscle invasive bladder cancer being treated with curative intent. Cohort H looked at neoadjuvant EV. These were cis-ineligible patients, and they got three cycles of EV prior to cystectomy. These are small studies. This was 22 patients. You can see a path CR rate here of about 36%, and all patients ended up proceeding to their radical cystectomy.
EV-103 cohort L looked at perioperative EV. So these patients also cis-eligible, they ended up getting three cycles in the neoadjuvant setting and six more cycles of EV in the adjuvant setting. Fifty-one patients were enrolled. That path CR rate was 34%. And again, what we saw here is that EV didn’t prevent any patients from going on to get their radical cystectomy.
We have three phase 3 perioperative EV with immunotherapy studies that are ongoing, and we really anxiously await these results. I just wanted to highlight these so we all know what to keep our eyes on. We have EV 303 and EV 304 across the top of the page. So EV 303 is looking at a cisplatin-ineligible population. And these patients were randomized to either perioperative pembro monotherapy, surgery alone, or perioperative pembro plus EV.
EV-304 is in a cisplatin-eligible population. And so these patients were randomized to either perioperative EV pembro versus neoadjuvant gemcitabine and cisplatin. And then lastly, VOLGA is a phase 3 study, and they are looking at an intensified immunotherapy approach with EV. So patients with muscle invasive bladder cancer are randomized to one of three arms. We have EV with durva and tremelimumab.
So you’ve got the combination of the checkpoint inhibitor, the PD-L1 agent, as well as Treme, which is a CTLA-4 inhibitor. The next arm is EV with durva. So again, that antibody-drug conjugate plus a single-agent immunotherapy. And then a third of the patients went on to receive just cystectomy as a standard current 2025 patient who’s not eligible for cisplatin would.
So very briefly highlighting some other high points of recent data and upcoming data. So we talked about EV. EV is a nectin-4 targeting antibody-drug conjugate. I want to highlight two other ADCs. We’ve got sacituzumab govitecan. This is an antibody-drug conjugate that targets anti-Trop-2. It’s an SN-38 payload. So this is a derivative of irinotecan. This was studied in the neoadjuvant setting in the SURE-01 study.
This had some promising efficacy. However, I wanted to highlight, for the purposes of our very short presentation today, of those first eight patients (of the total of 21 who were enrolled in this study), 75% of those eight patients—so six of them—had grade 2 or 3 neutropenia. And there was a death from neutropenic sepsis that prevented a patient from going on to get their cystectomy. This led to mandated dose reduction and G-CSF.
I think this really highlights that we have to be careful because we’re treating patients for cure, and we can’t let our advances in systemic therapy lead to adverse events that prevent that from happening. We’ve got Disitamab vedotin. This is an antibody-drug conjugate that targets HER2. It’s an MMA payload, very similar or actually identical to EV.
And so there was a study—very small, 12 patients—and only 10 of these patients were evaluable for efficacy, very recently presented at big ASCO in 2024. But of these patients who are HER2 or HER2 two or three positive, eight of 10 had a pathologic CR when treated with this antibody-drug conjugate combined with toripalimab, which is another checkpoint inhibitor.
Again, tiny numbers, biomarker-selected. But it’s hard to ignore very promising prelim data like that. And then lastly, I just have to mention TAR-200. A urology audience is going to be familiar with this. This is the gemcitabine pretzel that slowly releases gemcitabine into the bladder over time. It’s been investigated and continues to be investigated in the neoadjuvant setting in the SunRISE-4 study.
So it is not a comparison trial. But there are two arms, one looking at TAR-200 with cetrelimab (another PD-L1 agent) and the second arm just looking at cetrelimab monotherapy. I just want to highlight the 53 patients so far who have been treated with TAR-200 with cetrelimab, and as neoadjuvant therapy, that path CR rate was 42%.
A benefit of TAR-200 is that it’s mostly local symptoms. I deal in high-risk drugs all the time. And so to have a drug that mostly causes local symptoms as opposed to game-changing systemic symptoms is a very big deal. Of course, when you combine it with a checkpoint inhibitor, you lose that local-only selection.
And so lastly, a few take-home messages. We talked about NIAGARA, and this is potentially practice changing. But I still have questions about how to implement it in clinical practice. EV has been practice changing in the management of metastatic disease. And so these studies where we combine it with immunotherapy in the perioperative setting are very anxiously awaited.
We’ve got other drugs—the ADCs—enfortumab vedotin that targets HER2, sacituzumab govitecan that targets Trop-2, and also local therapies like TAR-200. Data with all of those is coming in and is very thought-provoking. And then lastly, the neoadjuvant setting is a great time to look at new drugs because you’re able to get tissue at the start and tissue with the cystectomy and really see how active these drugs are.
But that burden of safety is intensified because we’re treating these patients with curative intent, and we as medical oncologists don’t want to get in the way of that. So thank you for listening.
Sam Chang: Jackie, that was a wonderful overview. I love how now with all the systemic options, we still use neoadjuvant adjuvant. But the utilization of the word perioperative has really taken hold with treatments, I think smartly, probably by the pharmaceutical companies looking at the combination of the agents being used prior to therapy—prior to localized therapy—and then afterwards.
As we look at the effectiveness of these systemic treatments, a question that’s been raised to the urologists is, are we going to get to the point where we’re really not going to need to do cystectomies anymore? That’s a point that obviously the surgeons are like, oh, there’s no way, that’s not really possible.
But as these pathologic CRs increase in frequency and we’re better able to really determine who has a CR with whatever circulating tumor DNA, repeat biopsies, whatever we decide—MRI imaging—what do you think about truly in the near future, the systemic therapies replacing localized therapies, or will we always need to do localized therapy as well?
Jacqueline Brown: I think that’s a great question. And that’s right. That is the holy grail. That is what our patients want. That is what every patient that I meet with asks me, “Maybe do I just need you, Jackie?” And I say, “Not today, but I see where you’re at and there’s lots of cool research happening to that end, my friend.” And so we’ve had really interesting work.
Matt Galsky, Dan Geynisman up at Fox Chase, who have looked at that exact question: can we treat patients with good systemic therapy? And in those patients who have a great response, who have that clinical CR, can we forego cystectomy? Right now and in the trials that we have presented that have shown this as proof of concept, they have been very promising, and a very, very small number of patients has gone on to have metastatic disease.
With that said, if you have one patient who goes on to metastatic disease, that’s one patient too many for most of us. So it’s a balance of efficacy and also trying to meet patients where they’re at. I have patients who meet me and say, “I will not lose my bladder, what can you do for me?” So as long as we’re having at-future-state risk-benefit discussions with our patients, then I think that there is a place for this research to continue and for potentially for it to come into the clinical treatment realm.
I think something we’re going to need is good biomarkers. It’s got to be a lot more in my mind than just the clinical CRs that we’ve had so far in the data. We have had—when we think about Matt Gorsky’s study—we define clinical CR, I believe it was with cystoscopy. There might have been some random biopsies there, and it was imaging.
I don’t believe that incorporated circulating tumor DNA in blood. I don’t believe it incorporated ctDNA in urine. And I think for us to continue having these studies, we’re going to be incorporating those biomarkers. And we are adjusting to the rapidly changing technology that we all have, to figure out what do we use now. And I think that’s a really smart application for it.
So I hope there is a future where I am obsolete in this realm. Believe it or not, or I’m not obsolete. I guess you’d be obsolete, Sam.
Sam Chang: I was going to say this: you are much, much further away from being obsolete than I am. We can figure it out from the get-go for sure. But as you talk about those things, the importance of the biomarkers, I think, is really essential, as you say, to determine clearly a combination of risk stratification and then also response to therapy.
And then whether or not we need to continue therapy, deescalate therapy, et cetera. As you look at these combinations of chemotherapy and IO therapy, and now we’ve got obviously the addition of the ADCs, it strikes me a little bit that early on—and this, again, is your urologist take—early on, the combination for advanced disease, metastatic advanced, the combination of chemotherapy and IO did not seem to be beneficial combining them.
But now we get these perioperative regimens where there seems to be maybe not a synergistic effect, but at least an additive effect of the combining of these. And it might be that you’re continuing therapy afterwards, et cetera, around the localized therapy. So as you look forward, clearly combination therapies are going to be important.
Are we going to be stacking them all together— the CTLA-4, the checkpoint inhibitors, the ADCs, chemotherapy? Are we all going to bundle all of them, or are we going to be able to better risk stratify and actually then tailor treatments? What do you think we’re going to be doing?
Jacqueline Brown: That’s a great question. We’ve got—just to draw a parallel from the metastatic setting—we’ve got data from the DAD and the DAD-IO trial from Brad McGregor at Dana-Farber. So that’s combination of—this is metastatic, but it’s enfortumab vedotin plus sacituzumab govitecan plus, can we throw a checkpoint inhibitor in there as well? And what kind of toxicity do we get along with efficacy?
And so as we have more and more drugs, there is a ceiling to how toxic these things are. And ultimately, I think the stacking in the curative intent setting will also be limited by—we have to deliver these patients to surgery ready to rock. I always tell my patients my goal is three to four cycles of whatever neoadjuvant chemo I’m choosing for them. I said, but if you get one in and it really beats you up, then we’ve gotten one in and that was better than zero.
Two was better than one because ultimately the big show is your surgery, and I’m doing my best prior. So we’re going to be limited in the stacking of toxicities. And I have questions. NIAGARA data combining platinum doublet chemotherapy with immunotherapy—there’s something there, and there’s been debate as to whether, when we talk about checkpoint inhibition and muscle invasive bladder cancer, maybe the PD-L1 weren’t quite as active.
We have the data from IMvigor010 with atezolizumab that was negative. The NIAGARA data would speak otherwise. And we’re seeing it combined. And to your point, maybe not synergistic, maybe it’s additive, but I think that it’s intriguing. And yet I can’t help but wonder, since the—again—metastatic setting has changed so much with our antibody-drug conjugates, are we going to have a new wave shortly where this was great, it was a new benchmark, and what happens next?
So I don’t think we’ll be able to combine everything, just limited by toxicity and needing to get through a major surgery. And I do wonder if we’re on the cusp of a change of regime, similar to the metastatic setting. You bring up—I’ll say one other thing, which is, as we talk about stacking, there’s stacking of individual drugs in a regimen, and then there’s also stacking of the perioperative treatment.
There’s the neoadjuvant component. There’s the adjuvant component. And should everybody get everything? And in NIAGARA, all patients, regardless of what happened to them at the time of surgery—if they had a path CR, they got eight adjuvant cycles of durva. If they had a T3 tumor remaining, they got eight cycles. Everybody got it.
And so I am really thinking hard about how I implement that in my own practice. I think if someone has a path CR and then you treat them with three cycles of durvalumab and maybe they’re the patient who gets a terrible immune-related hepatitis or, God forbid, that they got a myocarditis or something life-threatening to them, we’re going to wish we hadn’t done that, particularly when maybe their disease was cured with the neoadjuvant treatment and surgery.
So I think this is where those biomarkers are going to come in. I think this is where it’s really important that we as a community are enrolling to trials like Modern, which is looking at ctDNA post-cystectomy and figuring out: should patients be getting—if they’re positive, should they get—we know that that’s a marker of minimal residual disease.
So they’re randomized to the one year of nivolumab or intensified immunotherapy—nivolumab plus relatlimab, which is a LAG-3 inhibitor. And if they’re negative, maybe you’re cured. And maybe that one year of nivolumab we would give you is going to be overkill. And any toxicity incurred is one toxicity too many.
Sam Chang: Too much.
Jacqueline Brown: And so that person, if you’re negative, they’re getting randomized to the one year of nivolumab or surveillance. So I think that’s going to be really important data for us. And I do wonder when we get those results if that will be practice changing.
Sam Chang: Now, really important points. The clinical data is so exciting. But then the real-world application is going to be really important, just as you said, because it will—and you’re always clouded by your own individual patients. As you just pointed out, what about that patient in the third or fourth cycle of adjuvant therapy that all of a sudden has some type of -itis that didn’t have to happen maybe so—
Jacqueline Brown: It didn’t.
Sam Chang: Exactly. Now, Jackie, thank you so much. The presentation of the SUO was so well received, was obviously so timely. And we really appreciate you giving us the highlights for UroToday and look forward to doing it again and look forward to having you on the UroToday Show with us and being able to highlight the work that you are doing at Emory, and I know how you and the urology team there work so closely.
And so well together, and it’s really a testament to how great a program you guys have. So thanks for spending some time with us.
Jacqueline Brown: Thanks for your time, Sam. Appreciate the invite.