SunRISe-1 Trial Advances Bladder Cancer Treatment with TAR-200 - Michiel Van der Heijden
September 27, 2024
Zach Klaassen interviews Michiel Van der Heijden about the SunRISe-1 trial, which evaluates TAR-200 with or without cetrelimab in BCG-unresponsive high-risk non-muscle-invasive bladder cancer. Dr. Van der Heijden discusses the trial design and results, highlighting TAR-200 monotherapy's impressive complete response rate of 83.5% and 12-month complete response rate of 57%. He emphasizes the favorable tolerability profile of TAR-200 monotherapy compared to combination therapy or cetrelimab alone. The discussion covers the potential mechanisms behind TAR-200's efficacy, the future of cetrelimab in this setting, and the next steps for TAR-200 development. Dr. Van der Heijden outlines the broader SunRISe program, including potential applications in muscle-invasive bladder cancer and as a bladder-sparing option. He concludes by emphasizing TAR-200 monotherapy's promising efficacy and tolerability profile, positioning it as a potential new standard in this challenging patient population.
Biographies:
Michiel Van der Heijden, MD, PhD, Trial Group Leader, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Michiel Van der Heijden, MD, PhD, Trial Group Leader, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Professor Michiel Van der Heijden, who is a medical oncologist at the Netherlands Cancer Institute in Amsterdam. Michiel, thanks so much for joining us today.
Michiel Van der Heijden: Yeah, thanks for having me.
Zach Klaassen: So we're going to discuss the ESMO data you presented looking at the SunRISe-1 trial. This is an exciting platform really looking at several indications for TAR-200. Maybe walk us through your slides and discuss the SunRISe-1 trial for ESMO.
Michiel Van der Heijden: Yeah. At ESMO I presented updated results from SunRISe-1, which is a study of TAR-200 with or without cetrelimab or cetrelimab alone in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer. This was, of course, a huge team effort with a lot of people involved, including the authors that are shown here on this slide. These are my disclosures.
The standard of care for BCG-unresponsive high-risk non-muscle-invasive bladder cancer is radical cystectomy. However, radical cystectomy is a life-changing operation, which is associated with considerable morbidity and mortality and has a significant impact on the quality of life of patients. For these reasons, many patients are unable or unwilling to undergo cystectomy. Several agents have been approved in recent years in this setting with 12-month CR rates that are shown here, which is a key metric of efficacy in this setting.
TAR-200 is a novel gemcitabine intravesical sustained-release device that can be brought into the bladder in a short office visit. Cetrelimab is an anti-PD-1 agent with an efficacy and safety profile which is consistent with other approved checkpoint inhibitors.
In SunRISe-1, patients having histologically confirmed high-risk non-muscle-invasive bladder cancer, which was in this case always CIS with or without papillary disease which was recurrent within 12 months of completion of BCG, were randomized to receive either TAR-200 plus cetrelimab in cohort one, TAR-200 monotherapy in cohort two, or cetrelimab monotherapy in cohort three. There was also a cohort four, which included patients who had papillary-only high-risk non-muscle-invasive bladder cancer, which I will not discuss today.
The primary endpoint of the trial was overall complete response rate, which was rigorously assessed, including with central pathology review and imaging. In June 2023, because of the observed risk-benefit ratio, cohort one and three were discontinued, whereas TAR-200 alone, so cohort two, continued to enroll to a total of 85 patients.
These are the baseline characteristics of our patients, which were well-balanced between the cohorts. Of note, about two-thirds of patients had CIS only, whereas one-third of patients had CIS plus papillary disease. The vast majority of patients declined cystectomy, whereas some were ineligible to receive a cystectomy.
This is the primary endpoint of the trial, which is centrally assessed complete response rate at any time. We observed a CR in 83.5% of patients receiving TAR-200 monotherapy, whereas this number was 67.9% in patients receiving the combination, so TAR-200 plus cetrelimab, and 46.4% in patients receiving cetrelimab monotherapy. The 12-month complete response rate was 57% in both cohort one and cohort two, whereas it was close to 23% in the cetrelimab monotherapy cohort three. Note that in the TAR-200 monotherapy, as this cohort continued to enroll for a longer period of time, the median duration of follow-up is lower, with 9.2 months.
Overall, TAR-200 was tolerated well, with most AEs being of low-grade urinary tract symptoms. Higher rates of grade three or higher treatment-related adverse events were observed with the combination regimen both for TAR-200 and for cetrelimab monotherapy. Discontinuation was also higher in this cohort for both agents, whereas discontinuation for monotherapy TAR-200 was only 5.9%.
In conclusion, TAR-200 monotherapy provides the highest single-agent complete response rate in patients with BCG-unresponsive CIS based on published data, and responses in TAR-200 monotherapy seem durable with 82% of patients remaining in response after a median follow-up of 9.2 months. TAR-200 monotherapy was well-tolerated with few grade three or higher treatment-related adverse events or discontinuations.
Cetrelimab monotherapy provided a complete response rate which was comparable to other checkpoint inhibitors in this setting. The SunRISe-1 results indicate a more favorable risk-benefit profile for TAR-200 monotherapy compared with TAR-200 plus cetrelimab or cetrelimab alone in BCG-unresponsive CIS. These results support the prioritized development of TAR-200 monotherapy in patients with BCG-unresponsive high-risk, non-muscle-invasive bladder cancer.
Zach Klaassen: Professor van der Heijden, thanks so much for sharing those results. Certainly some exciting data for the TAR-200 monotherapy specifically. In your opinion, from a mechanistic standpoint, we're seeing excellent complete response rates. Is this due to just longer drug interaction with the urothelium, or what's your hypothesis why we're seeing these outstanding results?
Michiel van der Heijden: Yeah, so I think it is, Zach, because gemcitabine has been used intravesically, of course, but that's always a dose that just stays in the bladder for as long as the patient can keep it in, and this is a sustained release over a few weeks. So I think that apparently makes all the difference here.
Zach Klaassen: Yeah, absolutely. I think you showed cohort one and cohort three with cetrelimab. In your opinion, because the monotherapy is so well-tolerated and the efficacy results are excellent, is this the end for cetrelimab in this population, or where do you see it going from the I-O therapy standpoint?
Michiel Van der Heijden: From the results that we have now... So this trial was started actually with a higher randomization towards the combination arm, so we were really thinking that that would be the more active combination. But what we're seeing is that the combination, and maybe it's especially in this setting, can lead to more urinary tract irritation, more problems. Of course, with I-O, even though it's generally well-tolerated, there are the occasional patients who have really serious toxicity.
From what we've observed here and what I've shown today, the added efficacy maybe in durability that we could potentially still see with longer follow-up probably doesn't weigh up to the toxicity that we're observing. Actually, from what we've seen now, there's no indication that durability of response is more in the combination arm, but this might still change a little bit in the future.
Zach Klaassen: Sure. Your final point on the conclusion slide was important, really prioritizing the TAR-200 monotherapy moving forward. What's the next steps for TAR-200 monotherapy in this high-risk BCG-unresponsive cohort?
Michiel Van der Heijden: This was not the final analysis. So there will be more analyses, and I think based on FDA guidance and what we've seen with other agents, I think there is a chance that this drug will be registered for this indication, which I think would make it really an attractive new therapy in this setting.
The SunRISe program covers a lot of studies. So at this point, there's SunRISe-1, 2, 3, 4, and 5. Some of these are large randomized studies. One of the things that we will see still in the future is from SunRISe-1, the papillary-only situation, which is a bit of a smaller cohort and may have a slightly more difficult path to registration, but we'll see. There will also be randomized studies, and I think with the results we've seen today, it might even be possible for TAR-200 to compete against BCG, so that's something that will be tested.
We've also seen at ESMO the combination with cetrelimab in another setting, so in the muscle-invasive setting, and I think that will be also a very interesting one, maybe not as a neoadjuvant treatment, but maybe as a bladder-sparing option. So there are several areas in bladder cancer where this device will move forward and I think has good chances of eventually entering clinical care.
Zach Klaassen: Yeah. The SunRISe platform certainly is taking almost after the STAMPEDE in prostate cancer. We're seeing it in a lot of different aspects, and certainly SunRISe when we need options in this population. So maybe just a couple of take-home points for our listeners today.
Michiel Van der Heijden: Well, so I think that the take-home point is that the TAR-200 monotherapy has very good efficacy, both in complete response rate and in 12-month complete response rate, which I think is the most important metric. Also, importantly, is that TAR-200 seems in most patients, in the vast majority of patients, actually well-tolerated with few adverse events and few discontinuations.
Zach Klaassen: That's great. Thanks so much for joining us again on UroToday and for your time and expertise discussing the SunRISe-1 trial.
Michiel Van der Heijden: Thanks, Zach.
Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Professor Michiel Van der Heijden, who is a medical oncologist at the Netherlands Cancer Institute in Amsterdam. Michiel, thanks so much for joining us today.
Michiel Van der Heijden: Yeah, thanks for having me.
Zach Klaassen: So we're going to discuss the ESMO data you presented looking at the SunRISe-1 trial. This is an exciting platform really looking at several indications for TAR-200. Maybe walk us through your slides and discuss the SunRISe-1 trial for ESMO.
Michiel Van der Heijden: Yeah. At ESMO I presented updated results from SunRISe-1, which is a study of TAR-200 with or without cetrelimab or cetrelimab alone in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer. This was, of course, a huge team effort with a lot of people involved, including the authors that are shown here on this slide. These are my disclosures.
The standard of care for BCG-unresponsive high-risk non-muscle-invasive bladder cancer is radical cystectomy. However, radical cystectomy is a life-changing operation, which is associated with considerable morbidity and mortality and has a significant impact on the quality of life of patients. For these reasons, many patients are unable or unwilling to undergo cystectomy. Several agents have been approved in recent years in this setting with 12-month CR rates that are shown here, which is a key metric of efficacy in this setting.
TAR-200 is a novel gemcitabine intravesical sustained-release device that can be brought into the bladder in a short office visit. Cetrelimab is an anti-PD-1 agent with an efficacy and safety profile which is consistent with other approved checkpoint inhibitors.
In SunRISe-1, patients having histologically confirmed high-risk non-muscle-invasive bladder cancer, which was in this case always CIS with or without papillary disease which was recurrent within 12 months of completion of BCG, were randomized to receive either TAR-200 plus cetrelimab in cohort one, TAR-200 monotherapy in cohort two, or cetrelimab monotherapy in cohort three. There was also a cohort four, which included patients who had papillary-only high-risk non-muscle-invasive bladder cancer, which I will not discuss today.
The primary endpoint of the trial was overall complete response rate, which was rigorously assessed, including with central pathology review and imaging. In June 2023, because of the observed risk-benefit ratio, cohort one and three were discontinued, whereas TAR-200 alone, so cohort two, continued to enroll to a total of 85 patients.
These are the baseline characteristics of our patients, which were well-balanced between the cohorts. Of note, about two-thirds of patients had CIS only, whereas one-third of patients had CIS plus papillary disease. The vast majority of patients declined cystectomy, whereas some were ineligible to receive a cystectomy.
This is the primary endpoint of the trial, which is centrally assessed complete response rate at any time. We observed a CR in 83.5% of patients receiving TAR-200 monotherapy, whereas this number was 67.9% in patients receiving the combination, so TAR-200 plus cetrelimab, and 46.4% in patients receiving cetrelimab monotherapy. The 12-month complete response rate was 57% in both cohort one and cohort two, whereas it was close to 23% in the cetrelimab monotherapy cohort three. Note that in the TAR-200 monotherapy, as this cohort continued to enroll for a longer period of time, the median duration of follow-up is lower, with 9.2 months.
Overall, TAR-200 was tolerated well, with most AEs being of low-grade urinary tract symptoms. Higher rates of grade three or higher treatment-related adverse events were observed with the combination regimen both for TAR-200 and for cetrelimab monotherapy. Discontinuation was also higher in this cohort for both agents, whereas discontinuation for monotherapy TAR-200 was only 5.9%.
In conclusion, TAR-200 monotherapy provides the highest single-agent complete response rate in patients with BCG-unresponsive CIS based on published data, and responses in TAR-200 monotherapy seem durable with 82% of patients remaining in response after a median follow-up of 9.2 months. TAR-200 monotherapy was well-tolerated with few grade three or higher treatment-related adverse events or discontinuations.
Cetrelimab monotherapy provided a complete response rate which was comparable to other checkpoint inhibitors in this setting. The SunRISe-1 results indicate a more favorable risk-benefit profile for TAR-200 monotherapy compared with TAR-200 plus cetrelimab or cetrelimab alone in BCG-unresponsive CIS. These results support the prioritized development of TAR-200 monotherapy in patients with BCG-unresponsive high-risk, non-muscle-invasive bladder cancer.
Zach Klaassen: Professor van der Heijden, thanks so much for sharing those results. Certainly some exciting data for the TAR-200 monotherapy specifically. In your opinion, from a mechanistic standpoint, we're seeing excellent complete response rates. Is this due to just longer drug interaction with the urothelium, or what's your hypothesis why we're seeing these outstanding results?
Michiel van der Heijden: Yeah, so I think it is, Zach, because gemcitabine has been used intravesically, of course, but that's always a dose that just stays in the bladder for as long as the patient can keep it in, and this is a sustained release over a few weeks. So I think that apparently makes all the difference here.
Zach Klaassen: Yeah, absolutely. I think you showed cohort one and cohort three with cetrelimab. In your opinion, because the monotherapy is so well-tolerated and the efficacy results are excellent, is this the end for cetrelimab in this population, or where do you see it going from the I-O therapy standpoint?
Michiel Van der Heijden: From the results that we have now... So this trial was started actually with a higher randomization towards the combination arm, so we were really thinking that that would be the more active combination. But what we're seeing is that the combination, and maybe it's especially in this setting, can lead to more urinary tract irritation, more problems. Of course, with I-O, even though it's generally well-tolerated, there are the occasional patients who have really serious toxicity.
From what we've observed here and what I've shown today, the added efficacy maybe in durability that we could potentially still see with longer follow-up probably doesn't weigh up to the toxicity that we're observing. Actually, from what we've seen now, there's no indication that durability of response is more in the combination arm, but this might still change a little bit in the future.
Zach Klaassen: Sure. Your final point on the conclusion slide was important, really prioritizing the TAR-200 monotherapy moving forward. What's the next steps for TAR-200 monotherapy in this high-risk BCG-unresponsive cohort?
Michiel Van der Heijden: This was not the final analysis. So there will be more analyses, and I think based on FDA guidance and what we've seen with other agents, I think there is a chance that this drug will be registered for this indication, which I think would make it really an attractive new therapy in this setting.
The SunRISe program covers a lot of studies. So at this point, there's SunRISe-1, 2, 3, 4, and 5. Some of these are large randomized studies. One of the things that we will see still in the future is from SunRISe-1, the papillary-only situation, which is a bit of a smaller cohort and may have a slightly more difficult path to registration, but we'll see. There will also be randomized studies, and I think with the results we've seen today, it might even be possible for TAR-200 to compete against BCG, so that's something that will be tested.
We've also seen at ESMO the combination with cetrelimab in another setting, so in the muscle-invasive setting, and I think that will be also a very interesting one, maybe not as a neoadjuvant treatment, but maybe as a bladder-sparing option. So there are several areas in bladder cancer where this device will move forward and I think has good chances of eventually entering clinical care.
Zach Klaassen: Yeah. The SunRISe platform certainly is taking almost after the STAMPEDE in prostate cancer. We're seeing it in a lot of different aspects, and certainly SunRISe when we need options in this population. So maybe just a couple of take-home points for our listeners today.
Michiel Van der Heijden: Well, so I think that the take-home point is that the TAR-200 monotherapy has very good efficacy, both in complete response rate and in 12-month complete response rate, which I think is the most important metric. Also, importantly, is that TAR-200 seems in most patients, in the vast majority of patients, actually well-tolerated with few adverse events and few discontinuations.
Zach Klaassen: That's great. Thanks so much for joining us again on UroToday and for your time and expertise discussing the SunRISe-1 trial.
Michiel Van der Heijden: Thanks, Zach.