LEGEND Trial Investigates EG-70 in Bladder Cancer Patients - Gautier Marcq
October 18, 2024
Zachary Klaassen interviews Gautier Marcq about the LEGEND trial, a phase 1/2 study of detalimogene voraplasmid (EG-70) for BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ. Dr. Marcq discusses the trial design, which involves intravesical administration of EG-70, a non-viral gene medicine-based immunotherapy. The phase 2 study, which began in May 2023, aims to enroll 100 patients across multiple sites in the US and Europe. The primary endpoints are complete response at 48 weeks and safety. Dr. Marcq highlights the ease of administration for urologists and the potential to address an unmet need in bladder-sparing therapies. He notes the trial's expansion to include BCG-naive patients and those with papillary-only disease. The discussion covers the trial's progress, expected timeline for results (around 2026), and its importance in providing new treatment options for patients who currently have limited alternatives to radical cystectomy.
Biographies:
Gautier Marcq, MD, MSc, Assistant Professor, Onco-Urology, Centre Hospitalier Régional Universitaire de Lille, Lille, France
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:
Gautier Marcq, MD, MSc, Assistant Professor, Onco-Urology, Centre Hospitalier Régional Universitaire de Lille, Lille, France
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
Zachary 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 on UroToday for an ESMO 2024 discussion with Dr. Gautier Marcq, who is a urologic oncologist at Lille University in Lille, France. Gautier, thanks so much for joining us today.
Gautier Marcq: Thank you for having me.
Zachary Klaassen: Yeah, absolutely. We're excited to have you on to discuss a really exciting trial. This non-muscle invasive bladder cancer space has gotten really exciting. And at ESMO 2024, you guys presented an updated trial in progress for the LEGEND trial. So maybe just walk our listeners through those slides.
Gautier Marcq: Sure. Thank you, Zach, for this kind introduction. So yeah, we presented during ESMO 2024 a phase 1/2 study about detalimogene voraplasmid, or EG-70, intravesical monotherapy for patients with BCG-unresponsive NMIBC with CIS. So as our viewers today are well aware, bladder-sparing therapy for BCG-unresponsive NMIBC addresses an important unmet need, and EG-70, or detalimogene voraplasmid, is an investigational non-viral gene medicine-based immunotherapy carrying a plasmid that can target at the same time a recombinant single-chain interleukin-7 and two double-stranded RNA activators of the intracellular innate immunity regulator called RIG-I.
So detalimogene voraplasmid was actually specifically engineered for intravesical administration. So it was basically designed for urologists to use in clinical practice. It presents itself as a powder that you have to reconstitute and then instill in the bladder. This technology has been well known for many, many years now by urologists. And those nanoparticles that you have can be handled without any onerous administration or decontamination procedures for clinicians or patients.
So the current trial we're presenting, or the LEGEND trial, is an ongoing, registrational phase 1/2 study using detalimogene voraplasmid in patients with BCG-unresponsive NMIBC and CIS. So the phase one part of the study was done and we will report a 73% complete response rate at any time and a safe and durable profile. So here I'm going to walk you through the design of the phase two study, which opened in May 2023. So as you know, bladder cancer is a common cancer and actually BCG-unresponsive non-muscle invasive bladder cancer is a disease where urologists need new therapies. The gold standard treatment for those patients is radical cystectomy, which we all know is associated with an alteration of the quality of life in some patients, and some patients may actually not be eligible for radical cystectomy.
So here we're going to dive into the mechanism of action of detalimogene voraplasmid. As you can see, when you have the detalimogene voraplasmid in the bladder lumen, it goes intracellularly into the bladder wall, and the DNA plasmid will have a dual action and will activate the intracellular RIG-I receptor and locally stimulate incoming T cells.
So as I mentioned earlier, the detalimogene voraplasmid is designed to meet the practice needs for community urologists. And as I told you, this is a powder that you have to reconstitute and instill into the bladder with a 50 cc volume and a 60-minute dwelling time.
So here we go with the design of the study. So as I told you, the phase one was completed and we have the phase two ongoing. The cohort one is patients with NMIBC with CIS, and I'm not going to go again through the criteria of BCG-unresponsive, as we are all well aware of those. The one thing important is those patients need to have CIS for cohort one. And the cycles are 12-week cycles and there are four cycles. So basically those patients will undergo therapy for a year. And they have regular assessment by cystoscopy, urine cytology and, if needed, a biopsy.
So the primary endpoint of the trial will be efficacy, and efficacy will be measured as a complete response at 48 weeks, and of course, safety.
Secondary endpoints will be DFS, CR at the end of each cycle and the duration of CR, which is actually a very important, in my own opinion, secondary endpoint. And exploratory endpoints will be basically pharmacokinetics and biomarkers. So what is important to know is the sponsor is actually opening new cohorts for patients that are BCG-naive or have BCG-unresponsive disease, papillary only, meaning without CIS. So with that, I'm going to wrap up and thank all the participating sites in the US that have done the phase one study and all the investigators in Europe that will be participating in the LEGEND trial. So stay tuned for the results of that trial. Thank you.
Zachary Klaassen: Gautier, thanks so much for that great presentation of LEGEND. You mentioned that there are additional sites coming on. It's going to accrue, I would imagine, relatively quickly. You're going to be one of the first European sites to start that phase two trial. Maybe just tell us about your experience about getting this trial set up and what other sites can look to when they open the trial at their site as well.
Gautier Marcq: Yeah. Great question. Thanks. Yeah. So we are very excited to have that trial because actually in Europe, it's not the same as in the US. We don't have any drugs right now available for those patients that are experiencing BCG-unresponsive disease, so they don't have any option other than radical cystectomy. So we have been treating some patients with gem/doce, but it's very important to have trials in the BCG-unresponsive space for patients to get to those drugs. So we're eager to start. And all European centers will be starting very soon. So it's actually easy to set up in the urology department because the nurses—and this is the most important point when you talk about NMIBC and bladder instillation—have access and are well-trained to perform those instillations. So I do believe that this is one important point: the nurses will be ready to start very soon.
Zachary Klaassen: Excellent. And so you mentioned the ongoing accrual starting in May 2023. Any idea or can you give us an update on what the target accrual is, how quickly it's been accruing at the current sites and when maybe we will see some data? Obviously, it's going to take a little bit of time.
Gautier Marcq: Yeah. It's going to take a little bit of time. Obviously, you have the challenge of enrolling those patients also due to competitive exclusion criteria. But the target is not that big. It's a phase two study. The goal is 100 patients. So it's fair to say in a year or so we're going to have included those patients and we're going to, I hope, have the first results by 2026.
Zachary Klaassen: Yeah. That's great, because first results about that 48-week anytime CR, so it'll be hopefully in the next couple of years. Yeah. Excellent discussion. Maybe just a couple of take-home points from LEGEND and maybe the high-risk non-muscle invasive disease space in general.
Gautier Marcq: Yeah. For sure. So the LEGEND trial investigates the BCG-unresponsive patients with CIS. It's a powder that has to be reconstituted with a 50 cc volume and then instilled into the bladder. It's a 12-week cycle for a year. And we are excited to start.
Zachary Klaassen: That's great. Gautier, it's great to have you on UroToday. Thanks so much for your time and expertise. We look forward to hearing more about the LEGEND trial.
Gautier Marcq: Well, thanks for having me.
Zachary 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 on UroToday for an ESMO 2024 discussion with Dr. Gautier Marcq, who is a urologic oncologist at Lille University in Lille, France. Gautier, thanks so much for joining us today.
Gautier Marcq: Thank you for having me.
Zachary Klaassen: Yeah, absolutely. We're excited to have you on to discuss a really exciting trial. This non-muscle invasive bladder cancer space has gotten really exciting. And at ESMO 2024, you guys presented an updated trial in progress for the LEGEND trial. So maybe just walk our listeners through those slides.
Gautier Marcq: Sure. Thank you, Zach, for this kind introduction. So yeah, we presented during ESMO 2024 a phase 1/2 study about detalimogene voraplasmid, or EG-70, intravesical monotherapy for patients with BCG-unresponsive NMIBC with CIS. So as our viewers today are well aware, bladder-sparing therapy for BCG-unresponsive NMIBC addresses an important unmet need, and EG-70, or detalimogene voraplasmid, is an investigational non-viral gene medicine-based immunotherapy carrying a plasmid that can target at the same time a recombinant single-chain interleukin-7 and two double-stranded RNA activators of the intracellular innate immunity regulator called RIG-I.
So detalimogene voraplasmid was actually specifically engineered for intravesical administration. So it was basically designed for urologists to use in clinical practice. It presents itself as a powder that you have to reconstitute and then instill in the bladder. This technology has been well known for many, many years now by urologists. And those nanoparticles that you have can be handled without any onerous administration or decontamination procedures for clinicians or patients.
So the current trial we're presenting, or the LEGEND trial, is an ongoing, registrational phase 1/2 study using detalimogene voraplasmid in patients with BCG-unresponsive NMIBC and CIS. So the phase one part of the study was done and we will report a 73% complete response rate at any time and a safe and durable profile. So here I'm going to walk you through the design of the phase two study, which opened in May 2023. So as you know, bladder cancer is a common cancer and actually BCG-unresponsive non-muscle invasive bladder cancer is a disease where urologists need new therapies. The gold standard treatment for those patients is radical cystectomy, which we all know is associated with an alteration of the quality of life in some patients, and some patients may actually not be eligible for radical cystectomy.
So here we're going to dive into the mechanism of action of detalimogene voraplasmid. As you can see, when you have the detalimogene voraplasmid in the bladder lumen, it goes intracellularly into the bladder wall, and the DNA plasmid will have a dual action and will activate the intracellular RIG-I receptor and locally stimulate incoming T cells.
So as I mentioned earlier, the detalimogene voraplasmid is designed to meet the practice needs for community urologists. And as I told you, this is a powder that you have to reconstitute and instill into the bladder with a 50 cc volume and a 60-minute dwelling time.
So here we go with the design of the study. So as I told you, the phase one was completed and we have the phase two ongoing. The cohort one is patients with NMIBC with CIS, and I'm not going to go again through the criteria of BCG-unresponsive, as we are all well aware of those. The one thing important is those patients need to have CIS for cohort one. And the cycles are 12-week cycles and there are four cycles. So basically those patients will undergo therapy for a year. And they have regular assessment by cystoscopy, urine cytology and, if needed, a biopsy.
So the primary endpoint of the trial will be efficacy, and efficacy will be measured as a complete response at 48 weeks, and of course, safety.
Secondary endpoints will be DFS, CR at the end of each cycle and the duration of CR, which is actually a very important, in my own opinion, secondary endpoint. And exploratory endpoints will be basically pharmacokinetics and biomarkers. So what is important to know is the sponsor is actually opening new cohorts for patients that are BCG-naive or have BCG-unresponsive disease, papillary only, meaning without CIS. So with that, I'm going to wrap up and thank all the participating sites in the US that have done the phase one study and all the investigators in Europe that will be participating in the LEGEND trial. So stay tuned for the results of that trial. Thank you.
Zachary Klaassen: Gautier, thanks so much for that great presentation of LEGEND. You mentioned that there are additional sites coming on. It's going to accrue, I would imagine, relatively quickly. You're going to be one of the first European sites to start that phase two trial. Maybe just tell us about your experience about getting this trial set up and what other sites can look to when they open the trial at their site as well.
Gautier Marcq: Yeah. Great question. Thanks. Yeah. So we are very excited to have that trial because actually in Europe, it's not the same as in the US. We don't have any drugs right now available for those patients that are experiencing BCG-unresponsive disease, so they don't have any option other than radical cystectomy. So we have been treating some patients with gem/doce, but it's very important to have trials in the BCG-unresponsive space for patients to get to those drugs. So we're eager to start. And all European centers will be starting very soon. So it's actually easy to set up in the urology department because the nurses—and this is the most important point when you talk about NMIBC and bladder instillation—have access and are well-trained to perform those instillations. So I do believe that this is one important point: the nurses will be ready to start very soon.
Zachary Klaassen: Excellent. And so you mentioned the ongoing accrual starting in May 2023. Any idea or can you give us an update on what the target accrual is, how quickly it's been accruing at the current sites and when maybe we will see some data? Obviously, it's going to take a little bit of time.
Gautier Marcq: Yeah. It's going to take a little bit of time. Obviously, you have the challenge of enrolling those patients also due to competitive exclusion criteria. But the target is not that big. It's a phase two study. The goal is 100 patients. So it's fair to say in a year or so we're going to have included those patients and we're going to, I hope, have the first results by 2026.
Zachary Klaassen: Yeah. That's great, because first results about that 48-week anytime CR, so it'll be hopefully in the next couple of years. Yeah. Excellent discussion. Maybe just a couple of take-home points from LEGEND and maybe the high-risk non-muscle invasive disease space in general.
Gautier Marcq: Yeah. For sure. So the LEGEND trial investigates the BCG-unresponsive patients with CIS. It's a powder that has to be reconstituted with a 50 cc volume and then instilled into the bladder. It's a 12-week cycle for a year. And we are excited to start.
Zachary Klaassen: That's great. Gautier, it's great to have you on UroToday. Thanks so much for your time and expertise. We look forward to hearing more about the LEGEND trial.
Gautier Marcq: Well, thanks for having me.