Emerging Neoadjuvant Combinations for Muscle-Invasive Bladder Cancer - Mamta Parikh
December 6, 2024
Mamta Parikh explores emerging combination therapies for muscle-invasive bladder cancer. Dr. Parikh details several ongoing trials evaluating various treatment combinations, including checkpoint inhibitors with chemotherapy, antibody-drug conjugates, and intravesical therapies in both cisplatin-eligible and ineligible patients. The conversation highlights the practice-changing potential of the NIAGARA study and anticipates results from multiple phase III trials that could further reshape treatment approaches. The dialogue emphasizes critical questions about appropriate endpoints for evaluating treatment success, the evolving role of cisplatin eligibility in treatment decisions, and the increasing challenge of convincing patients to proceed with radical cystectomy following dramatic responses to new therapies, underscoring the need for long-term follow-up data to guide treatment decisions.
Biographies:
Mamta Parikh, MD, MS, Medical Oncologist, UC Davis Health, Davis, CA
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:
Mamta Parikh, MD, MS, Medical Oncologist, UC Davis Health, Davis, CA
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
Read the Full Video Transcript
Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University. And we're quite fortunate, actually, to have a leading medical oncologist in urothelial carcinoma. Dr. Mamta Parikh is an associate professor at UC Davis in oncology. And she recently gave a presentation at the SUO 2024 winter meeting focusing on emerging combination neoadjuvant therapies for bladder cancer. And so we've asked her to give highlights of that presentation. And we're quite fortunate to have her here today.
Mamta Parikh: Thanks so much, Dr. Chang. Glad to be here. It's a privilege to speak today about my presentation at SUO, which was on emerging therapeutics regarding combination therapy in the neoadjuvant setting. And after many years of research, we're finally moving the needle in the muscle-invasive bladder cancer space.
A lot of this is based on the use of checkpoint inhibitors in cisplatin-ineligible patients. And that has led to a lot of study of combination approaches in the muscle-invasive space. And the first of the trials that we have results on is the NIAGARA study. This phase III trial looked at patients who had cisplatin-eligible muscle-invasive bladder cancer that was clinically T2 or higher. And they could have N1 disease as well.
And these patients were randomized to receive durvalumab plus gemcitabine plus cisplatin for four cycles or gemcitabine plus cisplatin alone prior to radical cystectomy. They did go on to receive adjuvant durvalumab in the experimental arm and no treatment in the control arm. This study had a dual primary endpoint of pathologic complete response.
And that did not reach statistical significance, though it was numerically higher in the durvalumab plus gemcitabine plus cisplatin arm. The other endpoint of event-free survival did reach statistical significance. And the hazard ratio was 0.69. And a secondary endpoint of overall survival also met statistical significance and was superior in the durvalumab plus gemcitabine plus cisplatin arm.
So this is likely a practice-changing study. The contribution of neoadjuvant therapy and adjuvant therapy is not entirely clear, as the control arm did not allow adjuvant treatment. And the other thing to keep in mind is that there are multiple ongoing phase III studies in this space that are likely to result in the next year or so that may change the landscape even further.
So the KEYNOTE-866 and ENERGIZE trials are looking at a very similar approach to NIAGARA, but they are looking at the addition of pembrolizumab in the case of KEYNOTE-866 and nivolumab in the case of ENERGIZE. In addition to that, the EV-304 study is a highly anticipated trial. This is looking at an antibody-drug conjugate, enfortumab vedotin, which targets Nectin-4, in combination with pembrolizumab.
And this will be compared to gemcitabine plus cisplatin. And this is based on studies in the metastatic space that have really established enfortumab vedotin plus pembrolizumab as a standard of care. And so all of these trials may change our use of neoadjuvant therapy for cisplatin-eligible patients.
But there's also a lot of studies going on in the cisplatin-ineligible space, where to date radical cystectomy has been the standard of care. The EV-103 study had an arm called cohort H. And in that arm, muscle-invasive bladder cancer patients were treated with enfortumab vedotin for three cycles prior to radical cystectomy.
The pathologic complete response rate for those patients was 36%. And that has triggered two phase III studies looking at enfortumab vedotin plus immune checkpoint inhibitors in cisplatin-ineligible patients. So the EV-303 study is looking at enfortumab vedotin plus pembrolizumab versus pembrolizumab versus observation prior to radical cystectomy.
And the VOLGA study is looking at durvalumab, the anti-PD-L1 studied in NIAGARA, plus tremelimumab, which is an anti-CTLA4 antibody, plus enfortumab vedotin versus durvalumab plus enfortumab vedotin versus observation again. So these studies are very exciting phase III studies in cisplatin-ineligible patients.
And in addition, the SURE-01 study looked at sacituzumab govitecan for four cycles. This is an anti-TROP2 antibody-drug conjugate. Prior to radical cystectomy, patients were treated with this antibody-drug conjugate. And the pathologic complete response rate was about 37%.
Of note, there was an amendment required because there was significant toxicity seen with sacituzumab govitecan, so the dose had to be reduced. But nevertheless, there is an ongoing phase II study of sacituzumab govitecan plus pembrolizumab. There is also an approach of looking at targeted therapies that appreciate the preponderance of immunohistochemical expression or mutations in bladder cancer.
And so the RC48-C017 study looked at an anti-HER2 antibody-drug conjugate called disitamab vedotin plus toripalimab, another anti-PD-1 inhibitor. And this study showed a pathologic complete response rate of 83% in patients that had highly expressing HER2 positivity. And in addition, there is an ongoing study called the SOGUG-NEOWIN study.
This is looking at patients with FGFR2 and 3 mutations, for which erdafitinib has shown efficacy in the metastatic setting. But in muscle-invasive bladder cancer, this will be studied as is erdafitinib as a single agent or in combination with cetrelimab prior to radical cystectomy. In addition to these studies in cisplatin-ineligible patients that involve targeted therapies, there's also a very provocative approach of looking at intravesical therapy plus immune checkpoint inhibitors.
So the SunRISe-4 trial presented some of their interim data at ESMO this year, and there were 53 patients that were treated with TAR-200, which is an intravesical special delivery system of gemcitabine in combination with cetrelimab, a PD-1 antibody. And in the 53 patients that were treated with the combination, the pathologic complete response rate was 42%. About 13% of patients had to discontinue due to treatment-related adverse events, and immune-related adverse events that were greater than or equal to grade 3 were seen in 6% of patients.
Another intravesical combination looked at cretostimogene, which is an oncolytic viral immunotherapy. And this study looked at the combination of cretostimogene intravesically with two doses of nivolumab. And this was done by Dr. Lee's group at Mayo. And what we saw here is in 21 patients, there was a pathologic complete response rate of 42% and a 1-year relapse-free survival of 70%.
And there were no grade 3 treatment-related adverse events or immune-related adverse events reported in this study. So in summary, for cisplatin-eligible patients, we do believe that NIAGARA may be practice-changing. The contribution of neoadjuvant-adjuvant treatment still remains in question, and more studies are likely required to evaluate that question.
There are also more studies in cisplatin-eligible patients that are likely to result soon that may further change our practice. And then in cisplatin-ineligible patients, there's a lot of work being done. There are a number of immune checkpoint inhibitor plus antibody-drug conjugate combinations under study. There are studies looking at targeted therapy plus checkpoint inhibitors, which brings to mind the practicality of doing this kind of immunohistochemical staining or next-generation sequencing prior to starting neoadjuvant therapy.
And then finally, the combination of checkpoint inhibitors and intravesical therapy is very interesting, but it must be noted that the SunRISe-2 study that is looking at intravesical TAR-200 plus cetrelimab versus chemoradiation for patients appropriate for trimodal therapy was halted early for lack of efficacy. So it's unclear if we will be moving forward with intravesical plus checkpoint inhibitor combinations. But nevertheless, there's a lot of excitement in this space. Thank you.
Sam Chang: That was just a wonderful summary, Dr. Parikh, of a constantly evolving field. As a urologic surgeon—well, actually, you've got really smart urologic surgeons at Davis. As a more standard urologic surgeon, the wealth of studies of combination therapies can be overwhelming for us, especially as we garner data from the metastatic setting that looks so exciting.
I think the first message that we may want to emphasize is, look, we've got neoadjuvant studies going on. We can't immediately extrapolate in the metastatic setting to the neoadjuvant setting. Would you agree with that?
Mamta Parikh: I do agree with that. I think that we are seeing some of the same trends. As you probably know, the CheckMate 901 study that looked at gemcitabine plus cisplatin plus nivolumab also was superior to gemcitabine plus cisplatin in the metastatic setting. But it's a very different patient population.
And so it is very important that these studies are being conducted in patients with muscle-invasive disease. And the real question will be whether cisplatin eligibility remains a true split point for patients with muscle-invasive disease, because the combination of enfortumab vedotin plus pembrolizumab, if positive, may change that paradigm altogether.
Sam Chang: Yeah. You basically answered that question I was going to follow up with. Is that really going to be a fork in the road? We've, as a field, hung our hats on the importance of cisplatin eligibility in terms of benefit and response. And then we've shifted to a platinum eligibility. And now, does it make any difference at all with these possible combinations being superior to any chemotherapy that we had?
So as we look at these different trials with combination therapies, and clearly, it seems that a combination is going to be important. Could it be a combination of an ADC plus a checkpoint plus perhaps a TKI?
These different combinations. Intravesical treatment, all these combinations. As you look at these data in a neoadjuvant setting or perhaps even in a curative setting for non-metastatic disease, tell me, in these studies, what you think will be the most important primary endpoint.
Is it this pathologic CR? Is it going to be overall survival? Clearly, it's a tough target for us because we know that a pathologic CR really requires a cystectomy. Otherwise, we're getting clinical CRs and we have some concerns. So tell me what your thoughts are about endpoints and how we are going to determine what's going to win out.
Mamta Parikh: Yeah. I think that is probably the most important question facing us as a community in this muscle-invasive space. What we saw in the NIAGARA study is the pathologic complete response rate actually did not meet statistically significant superiority, and yet overall survival was extended in this study. Event-free survival was extended.
There is the reality of doing phase II studies and needing an endpoint that can allow us to move forward into larger phase IIIs because I think everybody agrees that in phase III studies, we should be having at least one endpoint that involves survival. I think that's very important. But I think the role of pathologic complete response is really in question right now.
And I would like to see more rigorous standards for what defines pathologic complete response and its association with overall survival in our new era of all these new treatments that are emerging. We know that checkpoint inhibitors work very differently than chemotherapy in terms of durability of response. And so I think that these more long-term endpoints are going to become more important.
Sam Chang: And basically may help us then truly decide what our initial treatment should be. And obviously, important for all of us then will be, like everything is sequencing then afterwards, and timing of any type of local consolidation therapy, be it radiation, be it cystectomy, et cetera. So no. Dr. Parikh, the presentation at the SUO was obviously very well received as this field continues to evolve over time. So we want to thank you very much for your presentation. And we look forward to, in a year or two, as some of these studies mature, where we're going next in this field.
Mamta Parikh: Yes. I think the only other thing I wanted to mention is I think we have to be on the lookout in all of these phase III studies on the rate of patients actually getting to radical cystectomy. We are starting to see patients declining radical cystectomy, and we don't know yet truly if that is a safe approach. And so I think that's going to affect the survival endpoints but also may affect how we design trials moving forward.
Sam Chang: I think that's really a key point. And in all honesty, it is becoming increasingly more difficult as, honestly, the treatments get better, to persuade patients that—and even for us to really have that clinical equipoise—that it really is better to remove your bladder. It really is when there have been some dramatic responses with some of these regimens. So I think that improvement in evaluation of really what that pathologic CR will translate into.
So hopefully, we'll have long-term follow-up of those patients in some of these studies to give us an idea that, hey, it is safe prior to bladder removal or radiation that these patients have truly responded and that they do OK for years. So that will be, I think, increasingly important for sure as these treatments become more effective. So thank you once again, Dr. Parikh. And we hope that we can do this again, seriously, in a year or two, because I know there'll be more and more data regarding the impact and change in our therapies.
Mamta Parikh: Agreed. Thank you, Dr. Chang.
Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University. And we're quite fortunate, actually, to have a leading medical oncologist in urothelial carcinoma. Dr. Mamta Parikh is an associate professor at UC Davis in oncology. And she recently gave a presentation at the SUO 2024 winter meeting focusing on emerging combination neoadjuvant therapies for bladder cancer. And so we've asked her to give highlights of that presentation. And we're quite fortunate to have her here today.
Mamta Parikh: Thanks so much, Dr. Chang. Glad to be here. It's a privilege to speak today about my presentation at SUO, which was on emerging therapeutics regarding combination therapy in the neoadjuvant setting. And after many years of research, we're finally moving the needle in the muscle-invasive bladder cancer space.
A lot of this is based on the use of checkpoint inhibitors in cisplatin-ineligible patients. And that has led to a lot of study of combination approaches in the muscle-invasive space. And the first of the trials that we have results on is the NIAGARA study. This phase III trial looked at patients who had cisplatin-eligible muscle-invasive bladder cancer that was clinically T2 or higher. And they could have N1 disease as well.
And these patients were randomized to receive durvalumab plus gemcitabine plus cisplatin for four cycles or gemcitabine plus cisplatin alone prior to radical cystectomy. They did go on to receive adjuvant durvalumab in the experimental arm and no treatment in the control arm. This study had a dual primary endpoint of pathologic complete response.
And that did not reach statistical significance, though it was numerically higher in the durvalumab plus gemcitabine plus cisplatin arm. The other endpoint of event-free survival did reach statistical significance. And the hazard ratio was 0.69. And a secondary endpoint of overall survival also met statistical significance and was superior in the durvalumab plus gemcitabine plus cisplatin arm.
So this is likely a practice-changing study. The contribution of neoadjuvant therapy and adjuvant therapy is not entirely clear, as the control arm did not allow adjuvant treatment. And the other thing to keep in mind is that there are multiple ongoing phase III studies in this space that are likely to result in the next year or so that may change the landscape even further.
So the KEYNOTE-866 and ENERGIZE trials are looking at a very similar approach to NIAGARA, but they are looking at the addition of pembrolizumab in the case of KEYNOTE-866 and nivolumab in the case of ENERGIZE. In addition to that, the EV-304 study is a highly anticipated trial. This is looking at an antibody-drug conjugate, enfortumab vedotin, which targets Nectin-4, in combination with pembrolizumab.
And this will be compared to gemcitabine plus cisplatin. And this is based on studies in the metastatic space that have really established enfortumab vedotin plus pembrolizumab as a standard of care. And so all of these trials may change our use of neoadjuvant therapy for cisplatin-eligible patients.
But there's also a lot of studies going on in the cisplatin-ineligible space, where to date radical cystectomy has been the standard of care. The EV-103 study had an arm called cohort H. And in that arm, muscle-invasive bladder cancer patients were treated with enfortumab vedotin for three cycles prior to radical cystectomy.
The pathologic complete response rate for those patients was 36%. And that has triggered two phase III studies looking at enfortumab vedotin plus immune checkpoint inhibitors in cisplatin-ineligible patients. So the EV-303 study is looking at enfortumab vedotin plus pembrolizumab versus pembrolizumab versus observation prior to radical cystectomy.
And the VOLGA study is looking at durvalumab, the anti-PD-L1 studied in NIAGARA, plus tremelimumab, which is an anti-CTLA4 antibody, plus enfortumab vedotin versus durvalumab plus enfortumab vedotin versus observation again. So these studies are very exciting phase III studies in cisplatin-ineligible patients.
And in addition, the SURE-01 study looked at sacituzumab govitecan for four cycles. This is an anti-TROP2 antibody-drug conjugate. Prior to radical cystectomy, patients were treated with this antibody-drug conjugate. And the pathologic complete response rate was about 37%.
Of note, there was an amendment required because there was significant toxicity seen with sacituzumab govitecan, so the dose had to be reduced. But nevertheless, there is an ongoing phase II study of sacituzumab govitecan plus pembrolizumab. There is also an approach of looking at targeted therapies that appreciate the preponderance of immunohistochemical expression or mutations in bladder cancer.
And so the RC48-C017 study looked at an anti-HER2 antibody-drug conjugate called disitamab vedotin plus toripalimab, another anti-PD-1 inhibitor. And this study showed a pathologic complete response rate of 83% in patients that had highly expressing HER2 positivity. And in addition, there is an ongoing study called the SOGUG-NEOWIN study.
This is looking at patients with FGFR2 and 3 mutations, for which erdafitinib has shown efficacy in the metastatic setting. But in muscle-invasive bladder cancer, this will be studied as is erdafitinib as a single agent or in combination with cetrelimab prior to radical cystectomy. In addition to these studies in cisplatin-ineligible patients that involve targeted therapies, there's also a very provocative approach of looking at intravesical therapy plus immune checkpoint inhibitors.
So the SunRISe-4 trial presented some of their interim data at ESMO this year, and there were 53 patients that were treated with TAR-200, which is an intravesical special delivery system of gemcitabine in combination with cetrelimab, a PD-1 antibody. And in the 53 patients that were treated with the combination, the pathologic complete response rate was 42%. About 13% of patients had to discontinue due to treatment-related adverse events, and immune-related adverse events that were greater than or equal to grade 3 were seen in 6% of patients.
Another intravesical combination looked at cretostimogene, which is an oncolytic viral immunotherapy. And this study looked at the combination of cretostimogene intravesically with two doses of nivolumab. And this was done by Dr. Lee's group at Mayo. And what we saw here is in 21 patients, there was a pathologic complete response rate of 42% and a 1-year relapse-free survival of 70%.
And there were no grade 3 treatment-related adverse events or immune-related adverse events reported in this study. So in summary, for cisplatin-eligible patients, we do believe that NIAGARA may be practice-changing. The contribution of neoadjuvant-adjuvant treatment still remains in question, and more studies are likely required to evaluate that question.
There are also more studies in cisplatin-eligible patients that are likely to result soon that may further change our practice. And then in cisplatin-ineligible patients, there's a lot of work being done. There are a number of immune checkpoint inhibitor plus antibody-drug conjugate combinations under study. There are studies looking at targeted therapy plus checkpoint inhibitors, which brings to mind the practicality of doing this kind of immunohistochemical staining or next-generation sequencing prior to starting neoadjuvant therapy.
And then finally, the combination of checkpoint inhibitors and intravesical therapy is very interesting, but it must be noted that the SunRISe-2 study that is looking at intravesical TAR-200 plus cetrelimab versus chemoradiation for patients appropriate for trimodal therapy was halted early for lack of efficacy. So it's unclear if we will be moving forward with intravesical plus checkpoint inhibitor combinations. But nevertheless, there's a lot of excitement in this space. Thank you.
Sam Chang: That was just a wonderful summary, Dr. Parikh, of a constantly evolving field. As a urologic surgeon—well, actually, you've got really smart urologic surgeons at Davis. As a more standard urologic surgeon, the wealth of studies of combination therapies can be overwhelming for us, especially as we garner data from the metastatic setting that looks so exciting.
I think the first message that we may want to emphasize is, look, we've got neoadjuvant studies going on. We can't immediately extrapolate in the metastatic setting to the neoadjuvant setting. Would you agree with that?
Mamta Parikh: I do agree with that. I think that we are seeing some of the same trends. As you probably know, the CheckMate 901 study that looked at gemcitabine plus cisplatin plus nivolumab also was superior to gemcitabine plus cisplatin in the metastatic setting. But it's a very different patient population.
And so it is very important that these studies are being conducted in patients with muscle-invasive disease. And the real question will be whether cisplatin eligibility remains a true split point for patients with muscle-invasive disease, because the combination of enfortumab vedotin plus pembrolizumab, if positive, may change that paradigm altogether.
Sam Chang: Yeah. You basically answered that question I was going to follow up with. Is that really going to be a fork in the road? We've, as a field, hung our hats on the importance of cisplatin eligibility in terms of benefit and response. And then we've shifted to a platinum eligibility. And now, does it make any difference at all with these possible combinations being superior to any chemotherapy that we had?
So as we look at these different trials with combination therapies, and clearly, it seems that a combination is going to be important. Could it be a combination of an ADC plus a checkpoint plus perhaps a TKI?
These different combinations. Intravesical treatment, all these combinations. As you look at these data in a neoadjuvant setting or perhaps even in a curative setting for non-metastatic disease, tell me, in these studies, what you think will be the most important primary endpoint.
Is it this pathologic CR? Is it going to be overall survival? Clearly, it's a tough target for us because we know that a pathologic CR really requires a cystectomy. Otherwise, we're getting clinical CRs and we have some concerns. So tell me what your thoughts are about endpoints and how we are going to determine what's going to win out.
Mamta Parikh: Yeah. I think that is probably the most important question facing us as a community in this muscle-invasive space. What we saw in the NIAGARA study is the pathologic complete response rate actually did not meet statistically significant superiority, and yet overall survival was extended in this study. Event-free survival was extended.
There is the reality of doing phase II studies and needing an endpoint that can allow us to move forward into larger phase IIIs because I think everybody agrees that in phase III studies, we should be having at least one endpoint that involves survival. I think that's very important. But I think the role of pathologic complete response is really in question right now.
And I would like to see more rigorous standards for what defines pathologic complete response and its association with overall survival in our new era of all these new treatments that are emerging. We know that checkpoint inhibitors work very differently than chemotherapy in terms of durability of response. And so I think that these more long-term endpoints are going to become more important.
Sam Chang: And basically may help us then truly decide what our initial treatment should be. And obviously, important for all of us then will be, like everything is sequencing then afterwards, and timing of any type of local consolidation therapy, be it radiation, be it cystectomy, et cetera. So no. Dr. Parikh, the presentation at the SUO was obviously very well received as this field continues to evolve over time. So we want to thank you very much for your presentation. And we look forward to, in a year or two, as some of these studies mature, where we're going next in this field.
Mamta Parikh: Yes. I think the only other thing I wanted to mention is I think we have to be on the lookout in all of these phase III studies on the rate of patients actually getting to radical cystectomy. We are starting to see patients declining radical cystectomy, and we don't know yet truly if that is a safe approach. And so I think that's going to affect the survival endpoints but also may affect how we design trials moving forward.
Sam Chang: I think that's really a key point. And in all honesty, it is becoming increasingly more difficult as, honestly, the treatments get better, to persuade patients that—and even for us to really have that clinical equipoise—that it really is better to remove your bladder. It really is when there have been some dramatic responses with some of these regimens. So I think that improvement in evaluation of really what that pathologic CR will translate into.
So hopefully, we'll have long-term follow-up of those patients in some of these studies to give us an idea that, hey, it is safe prior to bladder removal or radiation that these patients have truly responded and that they do OK for years. So that will be, I think, increasingly important for sure as these treatments become more effective. So thank you once again, Dr. Parikh. And we hope that we can do this again, seriously, in a year or two, because I know there'll be more and more data regarding the impact and change in our therapies.
Mamta Parikh: Agreed. Thank you, Dr. Chang.