An Overview of Emerging Agents for Non-Muscle Invasive Bladder Cancer - Guru Sonpavde
October 13, 2023
During the State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC) multidisciplinary symposium held at the 2023 Meeting of the New England Section of the AUA Guru Sonpavde provides a comprehensive overview of emerging agents for non-muscle invasive bladder cancer, highlighting both successes and challenges. He discusses a small phase one trial of intravesical pembrolizumab, noting its biological activity but also raising concerns about systemic immune adverse events. Dr. Sonpavde also mentions the recently approved nadofaragene (Adstiladrin), an adenovirus delivering interferon alfa-2b, which showed promising results in a non-randomized study. He introduces other agents like CG0070, an oncolytic adenovirus, and N-803, an IL-15 superagonist, both of which are showing promise in ongoing trials. Additionally, he touches on chemotherapeutic toxins like Enfortumab Vedotin and TAR-200, as well as targeted therapies like erdafitinib. Dr. Sonpavde concludes by emphasizing the rapid pace of drug development in this area, advocating for clinical trials as a standard of care to address unmet needs.
This video is part of the State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer multidisciplinary symposium held at the 92nd Meeting of the New England Section of the AUA, organized in partnership with the Bladder Cancer Advocacy Network and supported by Pfizer, the event featured a panel of experts from various institutions.
Biographies:
Guru Sonpavde, MD, AdventHealth
This video is part of the State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer multidisciplinary symposium held at the 92nd Meeting of the New England Section of the AUA, organized in partnership with the Bladder Cancer Advocacy Network and supported by Pfizer, the event featured a panel of experts from various institutions.
Biographies:
Guru Sonpavde, MD, AdventHealth
Related Content:
View the Symposium Video Channel: State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer
A Comprehensive Guide to Managing Immune-Related Adverse Events in Checkpoint Inhibitor Therapy - Laura Wood
The Future of Radiation and Anti-PD-1 Agents in Non-Muscle Invasive Bladder Cancer: An In-Depth Look at Ongoing Trials - Kent Mouw
In the Wake of BCG Shortages: A Look at Ongoing Clinical Trials and Future Therapies for Bladder Cancer - Jennifer Yates, Lydia Saravis, & Matthew Mossanen
View the Symposium Video Channel: State-of-the-Art Management of High-Risk Non-Muscle Invasive Bladder Cancer
A Comprehensive Guide to Managing Immune-Related Adverse Events in Checkpoint Inhibitor Therapy - Laura Wood
The Future of Radiation and Anti-PD-1 Agents in Non-Muscle Invasive Bladder Cancer: An In-Depth Look at Ongoing Trials - Kent Mouw
In the Wake of BCG Shortages: A Look at Ongoing Clinical Trials and Future Therapies for Bladder Cancer - Jennifer Yates, Lydia Saravis, & Matthew Mossanen
Read the Full Video Transcript
Guru Sonpavde: Thank you for the opportunity to discuss these novel emerging agents for non-muscle invasive bladder cancer. So since intravenous pembrolizumab is approved, there was interest in looking at this agent intravesically. And the only message I'm want to leave with you, based on this study, is that a small study, a nine patient phase one trial, essentially the drug given intravesically had biologic activity. It activated the immune system, but the worrisome thing here is that a couple of patients had systemic immune adverse events. So although the drug does not get into the blood, there seems to be systemic toxicity probably from the activation of the immune system within the bladder itself. So I'm not sure about the further development of intravesical PD-1 inhibition based on this, we need to wait and see.
Now this is a drug nadofaragene, also called Adstiladrin, which is approved. It got approved in December 2022. This is a replication deficient adenovirus that delivers the interferon alfa-2b gene. And as you can see in this non-randomized study of around 100 patients, around half of the patients, there are BCG-unresponsive patients, around half the patients had a CR and about half of the CRs were sustained up to 12 months. So this agent also is conveniently given once every three months, so very convenient, not a weekly instillation. And so this was approved and is ramping up to become more and more available in the clinic at this time as we speak.
Now, the other agent we want to discuss here is the drug called CG0070. This is also intravesically given. What this is is it's a cancer-selective oncolytic adenovirus. And so this is engineered to grow and replicate in Rb deficient cells and these patients have Rb deficiencies almost universally, high grade, non-muscle invasive bladder cancer. So really when you look at the early data that have come out in patients as monotherapy or in combination with systemic pembrolizumab, there is promising activity with this agent, both as monotherapy as well as in combination with pembrolizumab. So phase three trials are ongoing and are eagerly awaited.
And this is a drug that was in the news recently and this is N-803, an IL-15 superagonist, which essentially revs up NK cells and T-cells, given intravesically and in this trial, the QUILT trial, the combination of BCG and this IL-15 superagonist looked promising. As you see here, at 12 months there was a 45% durable CR rate, and the FDA is now, I believe, reviewing the data. This is BCG-unresponsive disease where this activity was seen.
Switching gears from immuno-therapeutic agents to chemotherapeutic toxins, so Enfortumab Vedotin is an antibody drug conjugate targeting Nectin-4, bearing the payload tubulin toxin. This, as you know, is approved in various settings of advanced urothelial carcinoma. So this drug was of huge interest to look at intravesically and in early data coming out, there is promising activity. It is still very early, but three out of five patients in this intravesical EV study achieved CR.
And now there's a new way of giving these toxins. Coming out, this is the TAR-200 agent, which gives intravesical slow-release gemcitabine looking promising in this small randomized study. As you can see, comparing the TAR agent with Cetrelimab. And as you can see, the CR rate is high in the 70% range with this slow-release gemcitabine using this pretzel, which is depicted in the figure on the right.
And then switching gears again to targeted therapy, the third class of agents I wanted to bring up is this trial which looked at erdafitinib given orally. This agent is approved in advanced disease with FGFR3, FGFR2 activating mutations, effusions. And as you can see here, this agent given in a small number of patients here, in BCG-unresponsive disease, achieved a promising CR rate. Again, this is very, very early, but this agent does have toxicities given orally, therefore, can we give this agent intravesically? So this is being looked at in this trial, looking at this agent TAR-210, which is essentially the same pretzel intravesically delivered. It's once every three weeks delivery into the bladder using a device and so this delivers the FGFR inhibitor slowly intravesically. So this is of huge interest in patients with non-muscle invasive bladder cancer because FGFR3, 2 alterations are more common in earlier disease.
And just an honorable mention to Vicinium. This agent is essentially an agent that targets the EpCAM surface molecule and was bearing the Pseudomonas toxin and had some activity. As you can see here, CR rate of around 40% and around half of them were sustained to 12 months, but this agent has not been approved and unfortunately, further development has been paused.
So really to conclude quickly, non-muscle invasive bladder cancer is undergoing vigorous drug development, approvals of intravenous pembrolizumab and intravesical nadofaragene for BCG-unresponsive disease. Multiple other new agents are in development. And precision medicine, I think, needs more work along with assessment of MRD, and also I think the message going out is we should consider trials as a standard of care and maybe even the preferred standard of care so we make advances quickly in this unmet need setting.
Thank you.
Guru Sonpavde: Thank you for the opportunity to discuss these novel emerging agents for non-muscle invasive bladder cancer. So since intravenous pembrolizumab is approved, there was interest in looking at this agent intravesically. And the only message I'm want to leave with you, based on this study, is that a small study, a nine patient phase one trial, essentially the drug given intravesically had biologic activity. It activated the immune system, but the worrisome thing here is that a couple of patients had systemic immune adverse events. So although the drug does not get into the blood, there seems to be systemic toxicity probably from the activation of the immune system within the bladder itself. So I'm not sure about the further development of intravesical PD-1 inhibition based on this, we need to wait and see.
Now this is a drug nadofaragene, also called Adstiladrin, which is approved. It got approved in December 2022. This is a replication deficient adenovirus that delivers the interferon alfa-2b gene. And as you can see in this non-randomized study of around 100 patients, around half of the patients, there are BCG-unresponsive patients, around half the patients had a CR and about half of the CRs were sustained up to 12 months. So this agent also is conveniently given once every three months, so very convenient, not a weekly instillation. And so this was approved and is ramping up to become more and more available in the clinic at this time as we speak.
Now, the other agent we want to discuss here is the drug called CG0070. This is also intravesically given. What this is is it's a cancer-selective oncolytic adenovirus. And so this is engineered to grow and replicate in Rb deficient cells and these patients have Rb deficiencies almost universally, high grade, non-muscle invasive bladder cancer. So really when you look at the early data that have come out in patients as monotherapy or in combination with systemic pembrolizumab, there is promising activity with this agent, both as monotherapy as well as in combination with pembrolizumab. So phase three trials are ongoing and are eagerly awaited.
And this is a drug that was in the news recently and this is N-803, an IL-15 superagonist, which essentially revs up NK cells and T-cells, given intravesically and in this trial, the QUILT trial, the combination of BCG and this IL-15 superagonist looked promising. As you see here, at 12 months there was a 45% durable CR rate, and the FDA is now, I believe, reviewing the data. This is BCG-unresponsive disease where this activity was seen.
Switching gears from immuno-therapeutic agents to chemotherapeutic toxins, so Enfortumab Vedotin is an antibody drug conjugate targeting Nectin-4, bearing the payload tubulin toxin. This, as you know, is approved in various settings of advanced urothelial carcinoma. So this drug was of huge interest to look at intravesically and in early data coming out, there is promising activity. It is still very early, but three out of five patients in this intravesical EV study achieved CR.
And now there's a new way of giving these toxins. Coming out, this is the TAR-200 agent, which gives intravesical slow-release gemcitabine looking promising in this small randomized study. As you can see, comparing the TAR agent with Cetrelimab. And as you can see, the CR rate is high in the 70% range with this slow-release gemcitabine using this pretzel, which is depicted in the figure on the right.
And then switching gears again to targeted therapy, the third class of agents I wanted to bring up is this trial which looked at erdafitinib given orally. This agent is approved in advanced disease with FGFR3, FGFR2 activating mutations, effusions. And as you can see here, this agent given in a small number of patients here, in BCG-unresponsive disease, achieved a promising CR rate. Again, this is very, very early, but this agent does have toxicities given orally, therefore, can we give this agent intravesically? So this is being looked at in this trial, looking at this agent TAR-210, which is essentially the same pretzel intravesically delivered. It's once every three weeks delivery into the bladder using a device and so this delivers the FGFR inhibitor slowly intravesically. So this is of huge interest in patients with non-muscle invasive bladder cancer because FGFR3, 2 alterations are more common in earlier disease.
And just an honorable mention to Vicinium. This agent is essentially an agent that targets the EpCAM surface molecule and was bearing the Pseudomonas toxin and had some activity. As you can see here, CR rate of around 40% and around half of them were sustained to 12 months, but this agent has not been approved and unfortunately, further development has been paused.
So really to conclude quickly, non-muscle invasive bladder cancer is undergoing vigorous drug development, approvals of intravenous pembrolizumab and intravesical nadofaragene for BCG-unresponsive disease. Multiple other new agents are in development. And precision medicine, I think, needs more work along with assessment of MRD, and also I think the message going out is we should consider trials as a standard of care and maybe even the preferred standard of care so we make advances quickly in this unmet need setting.
Thank you.