Novel Mitomycin-Based Therapy Shows Promise As “Game-Changing” Option for UTUC

By Yair Lotan, MD, Zachary Bessette - Last Updated: February 10, 2023

UGN-101, also known as Jelmyto, is a novel delivery system for intracavitary treatment of upper tract urothelial cancer (UTUC) that has the potential to save patients from lifelong dialysis. Its US Food and Drug Administration (FDA) approval was based on the results of a small study, and a recent post-market analysis is the first to highlight how UGN-101 is being used in practice as well as patient outcomes.

GU Oncology Now spoke with Yair Lotan, MD, co-leader of the post-market analysis and a professor of urology at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, about the real-world use and effectiveness of UGN-101, as well as how soon UGN-101 may be considered standard-of-care for certain patients with UTUC.

Your study was the first post-market analysis of UGN-101 for upper tract urothelial carcinoma, and you saw that practice patterns were considerably varied with the drug. What are some of the ways the drug was used?

Dr. Lotan: For context, it’s worth noting the FDA approval indication of UGN-101. The Olympus trial was designed to treat small low-grade cancers of the renal pelvis and as a marker lesion trial. Patients had to have a tumor between 5 millimeters and 1.5 centimeters in diameter. They received 6 treatments, with the goal of seeing if the tumor went away. Ultimately, this led to approval [of UGN-101] as a chemo-ablative therapy. There aren’t many instances where we purposefully leave tumors after ureteroscopy. Typically, when we find a tumor in a kidney, we biopsy it, and then we burn it with a laser or with cautery. It’s unusual to find a tumor and forego either of these options for chemo-ablative therapy. Even with complete ablation there is a high risk of recurrence, and so we studied the efficacy of UGN-101 in the adjuvant setting, which has a goal of decreasing that risk of recurrence. This is a similar approach to treating many bladder cancers.

There were also patients in our study who had multiple low-grade tumors that were not completely ablated due to size or multiplicity, but we also included tumors much larger than the 1.5-centimeter limit in the Olympus trial.

We documented yet another use of UGN-101. Some patients had several small ureteral tumors with or without renal pelvis involvement and were treated with Jelmyto. Furthermore, there were patients with high-grade disease—even though the FDA only approved it for low-grade disease—in solitary kidneys or very poor kidney function.

What did your findings suggest about the effectiveness of UGN-101, as it is being administered in the real-world?

Dr. Lotan: Our study was a multicenter study and included 5 different types of analyses. Thus far, we’ve only published the overall analysis; there will be reports in the Journal of Urology addressing adjuvant use specifically. When used as an adjuvant therapy, there was no evidence of disease in about 70% of patients at first evaluation. When used as a chemo-ablative therapy, there was no evidence of disease in close to 40% of patients. Thus, this initial evaluation suggests that UGN-101 is more effective when the tumor has been removed.

We also saw that using UGN-101 as a chemo-ablative therapy for tumors less than 1 centimeter in diameter provided disease-free responses closer to 70% – similar to adjuvant use in larger tumors.

In some of patients, investigators noted a partial response with chemo-ablative therapy. There may be a benefit to a strategy of using UGN-101 to shrink larger low-grade tumors first and then ablate them, rather than removing the kidneys altogether.

UGN-101 is being heralded as a true “game-changing” therapy. Do you believe this to be the case? How does UGN-101 figure to impact the treatment paradigm for patients with UTUC?

Dr. Lotan: Generally speaking, intracavitary therapies have been used before for upper tract disease, but the challenge has always been that when it comes in a completely liquid form, how do you keep it in the renal pelvis? These therapies tend to wash down to the bladder in patients with unobstructed kidneys. You could put it in a nephrostomy tube and drip it in very slowly. You could also put a stent in and try to insert a large volume of the drug in the bladder and hope that some will reflux up to the kidney. However, neither of these methods have been effective, and removing the kidney is a fairly morbid approach for patients with low-grade disease that is unlikely to spread.

Thus, there has long been a need for more effective treatment for recurrent low-grade tumors in the upper tract. It’s a niche that UGN-101 fills; it’s a novel and quite effective agent.

There is an ongoing study of UGN-101 for bladder cancer as a potential chemo-ablative agent, but for now, it is safe to say that UGN-101 offers a novel approach in UTUC, with biologic activity and a proven track record of reducing both disease burden and likelihood of disease recurrence.

Can you speak to the impact on quality of life that patients with UTUC may experience after receiving UGN-101?

Dr. Lotan: The largest risk associated with UGN-101 is issues related to ureteral narrowing, stenosis, and scarring. It’s a little problematic to know how to attribute the problem, because anytime you perform a ureteroscopy, you might cause damage. Regardless, repeated instillation of UGN-101 was associated with ureteral narrowing in approximately 23% of patients in our study. As a consequence, if you have scar tissue in your ureter and have to live with a long-term stent, you’re likely to need repeated procedures, which increases risks of infection and further discomfort. The risk of scar tissue forming in the ureter has to be balanced out by the fact that UGN-101 treatment can potentially allow the patient to keep his or her kidney and not undergo a nephroureterectomy. The quality-of-life implications of kidney removal in someone with poor kidney function can be profound and include dialysis or at least significant dietary changes.

There is some investigation into putting in nephrostomy tubes and administering UGN-101 that way, which could result in less manipulation of the ureter and subsequently less toxicity in the ureter itself. However, asking a patient to walk around with a nephrostomy tube, even if it’s capped, for 6 weeks has its own risks.

We all know stents and nephrostomy tubes can cause discomfort. But overall, UGN-101 is well-tolerated with not much association with systemic risk of absorption and associated myelosuppression or fatigue.

Is there anything else patients should be aware of before undergoing UGN-101 therapy?

Dr. Lotan: All of these considerations need to be discussed with the patient before a decision is made on how to manage the upper tract cancer. There has to be transparency. They not only need to be made aware of the benefits and potential side effects of UGN-101, but they should also be privy to the alternatives of treating low-grade disease, such as removing the kidney, with the potential risk of losing kidney function and developing recurrences in other parts of the urinary tract. These are legitimate concerns, but I imagine many patients will embrace an approach that will spare them a major surgery. After all, the UTUC population is largely older, and they often have other comorbidities. If we have an effective tool to avoid major surgery, I’d like to think patients with low-risk disease will be on board.