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Substantial developments are under way in the treatment of upper tract urothelial cancer (UTUC). Seth P. Lerner, MD, FACS, recently spoke with i3 Health about mitomycin gel (JelmytoTM, UroGen Pharma), now FDA approved as the first agent specifically indicated for the treatment of low-grade UTUC. In this second installment of his interview, Dr. Lerner, principal investigator of the OLYMPUS study, on which the mitomycin gel approval was based, discusses research advances in the treatment of both low-grade and high-grade UTUC and shares advice for urologists treating patients with this disease.
Is further research being done on mitomycin gel?
Seth P. Lerner, MD, FACS: A phase 2 trial has been completed with the same mitomycin gel for the treatment of low-grade bladder tumors. They are getting ready to launch a phase 3 trial, taking the same approach. I'm not aware of next steps regarding the upper urinary tract, but clearly there will be interest in further studies as the community gains experience with this new treatment approach for upper urinary tract low-grade disease.
The real opportunities lie in what still, quite frankly, constitutes an area of unmet need: patients with high-grade disease where, for instance, removing a kidney might put them on dialysis. We face many of the same geographic logistical issues with treating high-grade disease of the upper urinary tract as we face in low-grade disease, although the standard of care currently for those patients with high-risk disease would be kidney removal. Are there other drugs that can be combined with the thermo-reversible mitomycin gel, for example? That remains to be seen.
Are there any additional treatment options in development for UTUC?
Dr. Lerner: Well, the exciting thing is that there are drugs that target the fibroblast growth factor receptor (FGFR) family, specifically FGFR3, which is altered in a high percentage of patients with both low-grade and high-grade disease of the upper urinary tract. One of those drugs, erdafitinib, has been approved in a different disease state, metastatic urothelial carcinoma. Because of the frequency of alterations in this receptor family in upper urinary tract tumors, a trial has been launched testing an FGFR inhibitor in patients, usually with high-grade disease, who have had their kidney removed and have an FGFR alteration.
There is a lot of interest in this topic. For instance, an investigator-initiated phase 1/2 trial has been launched at MD Anderson under the direction of Surena Matin. That is just one example of the ongoing trials. Suffice it to say there is an intense amount of interest in studying FGFR-targeted agents in upper urinary tract disease, and it makes a lot of sense because of the frequency of the alterations.
What advice can you share as a result of the OLYMPUS trial that could help urologists who are treating patients with UTUC?
Dr. Lerner: I think the exciting thing is that through running this trial, all of us who treated patients have worked through the learning curve of delivering drugs, mitomycin gel in this particular case, to the upper urinary tract.
In my own experience, for instance, and I think for most people, the default would be to insert a nephrostomy tube. This is a tube that goes from the flank or the side into the kidney, and we've learned how to deliver both chemotherapy and immunotherapy with bacillus Calmette-Guerin (BCG), a vaccine that we use for high-grade disease, into the kidney through a nephrostomy tube.
In contrast, through the course of this trial, most of the patients had a ureteral catheter placed from the bladder. This is standard procedure for all urologists, where like in my case, because we have fluoroscopy in our outpatient clinic, I would bring a patient in, I'd do a cystoscopy, look inside the bladder, put a catheter up to the kidney, move the patient over to the fluoroscopy unit, verify the position of catheter, put the drug in and take the catheter out, and do that weekly for six weeks.
So I would have never really considered doing that before I gained the experience with mitomycin gel, both in the compassionate use study that we first published and then in the trial that followed. Now, I have used that technique in other situations. For instance, I used it for a patient who had a carcinoma in situ of the upper urinary tract, and it was very easy to do this. I adopted this for BCG administration up in the kidney, and I followed the same treatment pattern that I do in the bladder. She's been out of treatment for over a year now, and her carcinoma in situ is completely gone. Otherwise, I may very well have had to remove the kidney.
So I think that's really been gaining experience with a new way––not a way that we invented, but a new way––to deliver these drugs.
The other insight that I gained from this experience is the importance of learning from your peers. In this trial, the multicenter investigator group was very forthright in making suggestions regarding how to solve little problems regarding everything, ranging from access, to size of catheters, to ways to get biopsies––everyone just problem-solved little tricks to do all the things that we needed to do in this study, and that information was very liberally shared with everybody. We had a number of investigator meetings, and at each one we deliberately left time for people to bring up problems in need of troubleshooting and to make recommendations to the rest of the study team regarding what might work here or what might work there.
All of that has been just a body of knowledge that gets absorbed by the investigator group, and ultimately, that group will serve as guides for urologists who are going to do this for the first time. There is a very meticulous plan by UroGen, the pharmaceutical company that developed this drug, to provide support for urologists who are seeing these patients and who know how to get access to the upper urinary tract but don't have experience with the drug. There has been a fantastic knowledge transfer, and I can just tell you that for me, I've been doing this for 28 years, but I've learned a lot from this amazing group of experts.
About Dr. Lerner
Seth P. Lerner, MD, FACS, is Professor of Urology, Beth and Dave Swalm Chair of Urologic Oncology, and Vice Chair for Faculty Affairs in the Scott Department of Urology of Baylor College of Medicine, where he is also Director of Urologic Oncology and of the Multidisciplinary Bladder Cancer Program. Dr. Lerner established and directs the multi-disciplinary Bladder Cancer Research Program at Baylor. His research interests include the use of selective estrogen receptor modulators for treatment of bladder cancer, gene therapy, integrated genomic analysis of bladder and upper urinary tract cancers, and outcomes of radical cystectomy and pelvic lymphadenectomy. He is the Chair of the Local Bladder Cancer Committee of the Southwest Oncology Group (SWOG), the founding and former Cochair of the NCI Bladder Cancer Task Force, and the current Cochair of the NCI Cancer Therapy Evaluation Program (CTEP) Genitourinary Steering Committee. In addition, he cochaired the Analysis Working Group of The Cancer Genome Atlas Project for muscle-invasive bladder cancer. He is a member of the Board of Directors and past Chair of the Bladder Cancer Think Tank of the Bladder Cancer Advocacy Network (BCAN), Cochair of the Management Committee of the Bladder Cancer Research Network, and a member of the American Association of Genitourinary Surgeons. Dr. Lerner has authored over 200 peer-reviewed articles and served as co-editor of a comprehensive Textbook of Bladder Cancer. He is a founding Coeditor-in-Chief of the journal Bladder Cancer.
For More Information
To learn more about the use of mitomycin gel for the treatment of low-grade UTUC, read the first installment of Dr. Lerner's interview.
Kleinmann N, Matin S, Pierorazio P, et al (2019). Nephron-sparing management of low grade (LG) UTUC with UGN-101 (mitomycin gel) for instillation: the OLYMPUS trial experience. J Urol (AUA Annual Meeting Abstracts), 201(suppl_4). Abstract LBA-16. DOI:10.1097/01.JU.0000557508.23335.0a
Huang W, Chevli K, Trainer A, et al (2020). Can TURBT be avoided? Primary chemoablation with a reverse thermal gel containing mitomycin (UGN-102) in patients with low grade intermediate risk non-muscle invasive bladder cancer. J Urol (AUA Annual Meeting Abstracts), 203(suppl_4). Abstract LBA02-03. DOI:10.1097/JU.0000000000000958.03
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.