PIVOT-006: Phase III Trial of Creto vs Surveillance in Intermediate-Risk Bladder Cancer - Mark Tyson
December 6, 2024
A discussion between Zachary Klaassen and Mark Tyson explores the PIVOT-006 trial examining cretostimogene versus surveillance for intermediate-risk non-muscle invasive bladder cancer. The study evaluates this oncolytic immunotherapy in a new patient population, focusing on both low-grade and high-grade disease that meets specific AUA criteria for intermediate risk. The trial design includes an induction phase followed by maintenance therapy, with a surveillance arm that allows crossover upon recurrence. Dr. Tyson highlights the importance of investigating treatment options for this patient group, particularly given the burden of recurring tumors and potential BCG shortages. The discussion emphasizes strong enrollment progress and the vital role of partnerships with organizations like SUO-CTC and BCAN in supporting patient-centered research, while noting the potential value of this therapy for patients seeking alternatives to frequent surgical interventions.
Biographies:
Mark Tyson II, MD, MPH, Urologic Oncologist, Associate Professor of Urology, Mayo Clinic, Scottsdale, AZ
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Mark Tyson II, MD, MPH, Urologic Oncologist, Associate Professor of Urology, Mayo Clinic, Scottsdale, AZ
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zachary Klaassen: Hello! My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined on UroToday for an SUO discussion with Dr. Mark Tyson, urologic oncologist at Mayo Clinic, Arizona. Mark's going to be discussing data presented at SUO 2024, looking at PIVOT-006: a phase three, randomized study of adjuvant intravesical cretostimogene versus surveillance for the treatment of intermediate-risk non-muscle invasive bladder cancer. Mark, always good having you on your UroToday. Looking forward to updates on PIVOT-006.
Mark Tyson: Thank you, Zach. I'm delighted to be here, and thanks for including us. I thought it might be nice to just start with the mechanism of action for cretostimogene, just to remind the viewers of how it works. Cretostimogene is a conditionally replicating oncolytic adenovirus that selectively targets and kills cancer cells. The E2F1 promoter restricts the replication to Rb pathway-deficient tumor cells, and theoretically that's what spares normal tissue. And it also encodes GM-CSF, which is a cytokine that primes a tumor-specific immunity following cancer cell lysis.
So, kind of has this one-two punch mechanism of action, so-called oncolytic immunotherapy, very promising response rates, as well as tolerability seen in the BCG-unresponsive non-muscle invasive bladder cancer disease state. That brings us to PIVOT-006, which is a randomized phase three study involving cretostimogene versus surveillance for patients with intermediate-risk non-muscle invasive bladder cancer.
As you can see here, this includes all the classic definitions for intermediate risk that the AUA outlines for current low-grade disease: high-volume, low-grade Ta; low-volume, high-grade Ta; multifocal low-grade Ta; and low-grade T1. And it does require complete resection at baseline. And you can see there we are stratifying by receipt of intravesical chemotherapy and low-grade versus high-grade.
The classic design of this trial is cretostimogene versus surveillance. Patients who get randomized to cretostimogene get weekly induction times six, and then maintenance at three months, six months, and then nine and 12 months as well. And patients who are on surveillance will be able to cross over if they recur and still have a tumor that's appropriate to treat with cretostimogene at the physician's discretion. The primary endpoint is recurrence-free survival at 12 months and 24 months, and progression-free survival, as you can see there.
So this is a very exciting concept. I give CG Oncology a lot of credit here. I think from this trial, we're going to know average treatment effects of cretostimogene in this population of patients. It is an adjuvant therapy trial, so I think the role for cretostimogene could be seen. Obviously, we're all excited about the data in the BCG-unresponsive setting, but this could be Creto's entry into the intermediate risk pending the results of this trial.
We are—in terms of enrollment—we are doing quite well, maybe even a little ahead of schedule. But we are still actively recruiting sites and would encourage any of your listeners or viewers who are interested in participating to reach out to CG Oncology.
Zachary Klaassen: Mark, thanks so much for the update on PIVOT-006. I'm not surprised that it is enrolling quickly. I think there's a paucity of trials in that intermediate-risk disease space. It's interesting when we're about to launch this trial at our site too. And I think at a tertiary center like ours and also like yours, we see a lot of that high-grade Ta, less than 3 centimeters. And I think that's going to be the majority of patients that we enroll. When we look at the stratification, high-grade versus low-grade, and we'll see that data when the trial reports.
What are your thoughts on how well there's going to be activity for Creto in those low-grade intermediate-risk patients specifically?
Mark Tyson: Yeah, it's a fantastic question. I think when this trial first rolled out, there were a lot of investigators who were concerned about using it in the high-grade histology because obviously the standard of care there is BCG. But without BCG, as many centers are experiencing right now, their patients are going to get observation anyway. So getting randomized to observation isn't a huge drawback. And if they have a 50% chance of getting Creto, and then the opportunity to cross over upon recurrence, that's a pretty good bet for a patient, and also pretty easy to sign up for.
How well this works in low-grade relative to high-grade histology, I don't think we can say at the moment what the activity is going to be by disease state. We obviously have seen quite a bit of promising response rates presented at the SUO for BOND-003 in a very difficult-to-treat, unresponsive patient, but that's a different disease state altogether than a naive high-grade patient. So, I'm not sure.
But I think if there is activity, as you know, these tumors are often recurrent—not all that threatening to their long-term health or their bladder, but they're multiply recurrent, and they can be quite onerous, especially for the older population who doesn't want to go back to surgery every 6 to 12 months to remove a low-grade tumor or come off anticoagulation, those kinds of things. So I think there could be value here if there is demonstrated efficacy.
Zachary Klaassen: Yeah, great answer. I think it's important work, as urologists partnering with SUO-CTC and support groups like BCAN to support these trials because I think that all of that helps with enrollment. It certainly helps with availability. Can you speak to the importance of these partnerships for a trial like PIVOT-006?
Mark Tyson: Yes! SUO-CTC and BCAN support have been pivotal in driving the success of these trials. I think their advocacy for patient-centered research is important, and their ability to get everybody to collaborate—from research clinicians to patients—is impressive. And so I think SUO-CTC has a long history of supporting CG Oncology research. And so I think their efforts in education, and in patient engagement, and all that are really quite vital to the success of these trials.
Zachary Klaassen: Absolutely! Mark, thanks, as always, for your time on UroToday and great updates on PIVOT-006. I know as enrollment continues, we'll have more updates and hopefully some data in a future meeting down the road. Thanks, as always, for your time, Mark.
Mark Tyson: No, not a problem, Zach. Thanks for having me.
Zachary Klaassen: Hello! My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined on UroToday for an SUO discussion with Dr. Mark Tyson, urologic oncologist at Mayo Clinic, Arizona. Mark's going to be discussing data presented at SUO 2024, looking at PIVOT-006: a phase three, randomized study of adjuvant intravesical cretostimogene versus surveillance for the treatment of intermediate-risk non-muscle invasive bladder cancer. Mark, always good having you on your UroToday. Looking forward to updates on PIVOT-006.
Mark Tyson: Thank you, Zach. I'm delighted to be here, and thanks for including us. I thought it might be nice to just start with the mechanism of action for cretostimogene, just to remind the viewers of how it works. Cretostimogene is a conditionally replicating oncolytic adenovirus that selectively targets and kills cancer cells. The E2F1 promoter restricts the replication to Rb pathway-deficient tumor cells, and theoretically that's what spares normal tissue. And it also encodes GM-CSF, which is a cytokine that primes a tumor-specific immunity following cancer cell lysis.
So, kind of has this one-two punch mechanism of action, so-called oncolytic immunotherapy, very promising response rates, as well as tolerability seen in the BCG-unresponsive non-muscle invasive bladder cancer disease state. That brings us to PIVOT-006, which is a randomized phase three study involving cretostimogene versus surveillance for patients with intermediate-risk non-muscle invasive bladder cancer.
As you can see here, this includes all the classic definitions for intermediate risk that the AUA outlines for current low-grade disease: high-volume, low-grade Ta; low-volume, high-grade Ta; multifocal low-grade Ta; and low-grade T1. And it does require complete resection at baseline. And you can see there we are stratifying by receipt of intravesical chemotherapy and low-grade versus high-grade.
The classic design of this trial is cretostimogene versus surveillance. Patients who get randomized to cretostimogene get weekly induction times six, and then maintenance at three months, six months, and then nine and 12 months as well. And patients who are on surveillance will be able to cross over if they recur and still have a tumor that's appropriate to treat with cretostimogene at the physician's discretion. The primary endpoint is recurrence-free survival at 12 months and 24 months, and progression-free survival, as you can see there.
So this is a very exciting concept. I give CG Oncology a lot of credit here. I think from this trial, we're going to know average treatment effects of cretostimogene in this population of patients. It is an adjuvant therapy trial, so I think the role for cretostimogene could be seen. Obviously, we're all excited about the data in the BCG-unresponsive setting, but this could be Creto's entry into the intermediate risk pending the results of this trial.
We are—in terms of enrollment—we are doing quite well, maybe even a little ahead of schedule. But we are still actively recruiting sites and would encourage any of your listeners or viewers who are interested in participating to reach out to CG Oncology.
Zachary Klaassen: Mark, thanks so much for the update on PIVOT-006. I'm not surprised that it is enrolling quickly. I think there's a paucity of trials in that intermediate-risk disease space. It's interesting when we're about to launch this trial at our site too. And I think at a tertiary center like ours and also like yours, we see a lot of that high-grade Ta, less than 3 centimeters. And I think that's going to be the majority of patients that we enroll. When we look at the stratification, high-grade versus low-grade, and we'll see that data when the trial reports.
What are your thoughts on how well there's going to be activity for Creto in those low-grade intermediate-risk patients specifically?
Mark Tyson: Yeah, it's a fantastic question. I think when this trial first rolled out, there were a lot of investigators who were concerned about using it in the high-grade histology because obviously the standard of care there is BCG. But without BCG, as many centers are experiencing right now, their patients are going to get observation anyway. So getting randomized to observation isn't a huge drawback. And if they have a 50% chance of getting Creto, and then the opportunity to cross over upon recurrence, that's a pretty good bet for a patient, and also pretty easy to sign up for.
How well this works in low-grade relative to high-grade histology, I don't think we can say at the moment what the activity is going to be by disease state. We obviously have seen quite a bit of promising response rates presented at the SUO for BOND-003 in a very difficult-to-treat, unresponsive patient, but that's a different disease state altogether than a naive high-grade patient. So, I'm not sure.
But I think if there is activity, as you know, these tumors are often recurrent—not all that threatening to their long-term health or their bladder, but they're multiply recurrent, and they can be quite onerous, especially for the older population who doesn't want to go back to surgery every 6 to 12 months to remove a low-grade tumor or come off anticoagulation, those kinds of things. So I think there could be value here if there is demonstrated efficacy.
Zachary Klaassen: Yeah, great answer. I think it's important work, as urologists partnering with SUO-CTC and support groups like BCAN to support these trials because I think that all of that helps with enrollment. It certainly helps with availability. Can you speak to the importance of these partnerships for a trial like PIVOT-006?
Mark Tyson: Yes! SUO-CTC and BCAN support have been pivotal in driving the success of these trials. I think their advocacy for patient-centered research is important, and their ability to get everybody to collaborate—from research clinicians to patients—is impressive. And so I think SUO-CTC has a long history of supporting CG Oncology research. And so I think their efforts in education, and in patient engagement, and all that are really quite vital to the success of these trials.
Zachary Klaassen: Absolutely! Mark, thanks, as always, for your time on UroToday and great updates on PIVOT-006. I know as enrollment continues, we'll have more updates and hopefully some data in a future meeting down the road. Thanks, as always, for your time, Mark.
Mark Tyson: No, not a problem, Zach. Thanks for having me.