Christopher Wallis: Hello, thank you for joining us for this UroToday Journal Club. Today we're discussing a recently published trial, the OLYMPUS study, looking at primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomcyin-containing reverse thermal gel. This is really interesting and exciting data looking at a novel way to treat patients with upper tract disease. And so I'm Chris Wallis. I'm a Fellow in Urologic Oncology at Vanderbilt, and joining me is Zach Klaassen, an Assistant Professor at the Medical College of Georgia. And together we'll go through a bit of the background and rationale for the present study and then review important details from the OLYMPUS trial.

By way of initial background, it's important to review the epidemiology of upper tract disease. This is a rare cancer and one of the more uncommon diseases that urologists treat. While everyone is familiar with urothelial carcinoma of the bladder, upper tract disease accounts for only 5% to 10% of all urothelial carcinomas with an annual incidence ranging around two diagnoses per 100,000 people in Western countries. As a result of differences in evaluation and presentation compared to bladder cancer, which is predominantly nonmuscle-invasive at diagnosis, nearly two-thirds of all upper tract diagnoses are invasive disease. And as with bladder cancer and other urothelial carcinomas, the peak incidence is towards the end of life in the 70 year and upward range and the disease is more common in men.

Now, upper track management, thus far, ranges across a wide [crosstalk] span of interventions and is driven predominantly by both the disease grade histologically and patient co-morbidity. It's important to know that, given limitations in our ability to stage upper tract disease, a grade is often used as a proxy for stage. In numerous observational studies, as well as the EAU guidelines that result from these studies have suggested that endoscopic management is a safe and reasonable option for patients with low-grade disease as it preserves nephron-sparing compared with radical surgery, such as a nephroureterectomy. And we know from the bladder cancer literature, the low-grade urothelial cancers are sensitive to chemotherapeutic agents, and both gemcitabine and mitomycin have been used quite frequently in the treatment of bladder cancers. However, there are logistic issues in the use of these topical agents in the upper tract, unlike bladder cancer, where we can instill into the bladder and then leave to sit, there's trouble with continuous drug dilution as a result of urine flow for topical agents in the upper tract.

And so over the course of the early 2000s, there was interest in administration of BCG in the upper tract. This was given through a variety of means, whether via percutaneous nephrostomy tube, via a retrograde ureteral catheter with a drip installation, or through a bladder instillation with reflux through a double-J stent. And in every case, the efficacy of adjuvant BCG really was failed to be established, and as a result, this review from 2009 set the stage that current therapy using BCG as adjuvant was not recommended. However, they did leave open the question of the role of mitomycin C. And that brings us towards the intervention used in the OLYMPUS trial.

And so UGN-101, which is also known as MitoGel™, and now trade named Jelmyto™, consists of a combination of MitoGel™ and a sterile RTGel™, which is a hydrogel allowing for the prolonged dwelling of the agent in the upper tract. The RTGel™ has interesting chemical properties allowing for it to be administered as a liquid with conversion to a semi-solid gel while in the upper track at body temperatures. And then over time, urine flow dissolves the gel, which allows for a slow release mitomycin into the upper tract over approximately a four to six-hour window. And mitomycin, just as a reminder, acts as a DNA alkylating agent leading to tumor cell destruction.

And so the first preclinical studies were published in 2017, and these started off with a swine model. And in these animals, bilateral percutaneous nephrostomy tubes were placed and MitoGel™ was instilled. And then using CT scanning, we were able to identify that the agent remained in the upper tract for four to six hours and plasma levels were not sufficiently elevated to raise concerns for significant systemic absorption.

Moving on, there was a second pre-clinical swine model. And in this case, rather than integrated instillation, this was a unilateral retrograde instillation in a dose-finding study. And at a variety of doses, the investigators were able to demonstrate that peak plasma levels were well below known toxicity thresholds. And so this allowed the transition to the first human studies. And in this small cohort of 22 patients, patients received six weekly installations of UGN-101 and then received a ureteroscopy for evaluation of the upper tract following treatment completion. And these early promising results suggested that over a third of patients had a complete response and an additional 23% had partial responses.

So that set the stage for the trial we're going to discuss today in detail, which is the OLYMPUS trial, an open-label, single-arm, Phase III trial.

Zachary Klaassen: Thanks, Chris. So as Chris mentioned, the OLYMPUS trial was published April 29th, 2020 in the Lancet Oncology. Senior author was Seth Lerner. And if we look at the baseline characteristics of these patients, there were 71 patients enrolled and they're pretty standard for patients that have urothelial carcinoma in that their median age was 71 years, predominantly male at 68%, 87% were Caucasian, and most patients did have two kidneys at enrollment at 89%. Fifty-two percent had a history of upper tract urothelial carcinoma, and 52% had previous renal ablative surgery.

Looking at the tumor characteristics, you can see that the median number of tumors was two and the median size of the tumors of the papular tumor was 14 millimeters. Interestingly, you can see that almost half of these patients had tumors that were not reachable by laser. So whether this was lower pole, inability to access the collecting system, these were not feasible for endoscopic approach.

So the primary outcome was basically a six-week evaluation of the upper tract with ureteroscopy and cytology and biopsies as needed. And you can see here among these 71 patients, 59% had a complete response at that evaluation and 11% had a partial response. So you can see that, in total, 70% had some degree of a response to this therapy.

Based on these results, the FDA approved mitomycin gel for urothelial cancer on April 15th, 2020 under the trade name of Jelmyto™.

So several discussion points based on this data. As I mentioned, 59% of patients had a complete response at their evaluation following the instillation. And at the time of the analysis, of the 41 for patients that had a complete response, 20 had the full 12-month evaluation. And among those 20 patients, 14 had a durable response. So there's a good signal that if you do have a response to a UGN-101 that you'll have a durable response at 12 months. And I think this is important. Low-grade upper tract with repeated treatments, difficulty accessing these tumors. Some of these patients will undergo an ipsilateral radical nephroureterectomy, so the utilization of UGN-101 may potentially delay or completely avoid the need for a radical nephroureterectomy in these patients.

Certainly, there's an adverse effect profile with the medication. Thirty-five percent had Grade 1-2 and 8% had Grade 3 ureteral stenosis. What the etiology of this is somewhat for conjecture, but it may be the result of recurrent instrumentation of the upper tract. Whether some of this is related to the UGN-101 treatment, certainly most patients did require temporary ureteral stenting, but this is relatively common with other nephron-sparing approaches such as laser ablation.

So in conclusion, the data from the OLYMPUS study suggests that primary chemoablation of low-grade upper tract urothelial carcinoma with UGN-101, there was a substantial number of patients that did have a complete response. And among those that did have a complete response at the first data analysis, there was durable control among these patients. As I mentioned, urethral stenosis was the most common adverse event, but serious adverse events were uncommon. And as we continue to navigate the low-grade upper tract urothelial carcinoma treatment, this adds another novel kidney sparing approach, which adds to our armamentarium for treatment of these patients.