Long-term follow-up of OLYMPUS study shows promising results for patients with UTUC

Karim Chamie, MD

Patients with low-grade upper tract urothelial carcinoma (LG UTUC) usually receive treatment in the form of radical nephroureterectomy (RNU), an endoscopic procedure associated with high recurrence rates. Recent studies have found that UGN-101 (Jelmyto) is a new efficacious treatment for this condition that mitigates the risk of recurrence.

In a study presented at the 2021 American Urological Association Annual Meeting,¹ senior author Karim Chamie, MD, and coauthors further examine the long-term results of UGN-101 for patients with LG UTUC given the favorable outcomes of the initial OLYMPUS trial. Chamie is an associate professor of urology and director of the Urologic Oncology Fellowship and the Bladder Cancer Program at the University of California, Los Angeles.

Please discuss the background for this study.

The background of this study really hinges on the OLYMPUS trial, which was a registrational study conducted by UroGen to evaluate the efficacy and safety of UGN-101. It's a reverse hydrogel polymer which is liquid in cold temperatures and solid at body temperature. Essentially, you can mix it with mitomycin C at cold or room temperature and then inject it directly into the kidney, whereby the gel solidifies in the collecting system of the kidney. Over a period of 6 to 7 hours, it starts to dissolve. Meanwhile, the tumor that's located up in the renal pelvis is exposed to the chemotherapy for that period of time.

The purpose of doing this study, which was presented as a late-breaking abstract at the [2021] AUA, was to look at long-term follow-up. The reason that's important is because if you look at published data from the best of hands, the incidence of recurrence of upper tract urothelial carcinoma, even for low- and intermediate risk, is still very high. So, if you follow patients out for 3.5 years, you'll see that 65% of patients still recur despite endoscopic therapies like laser and fulgurations. These are authors who are proud of the results and published it. And what we found in this OLYMPUS trial was that the recurrence rate was significantly lower than what we would find with pooled analyses of standard endoscopic therapy. The OLYMPUS trial examined 1-year data. The purpose of this study was to quantify longer term follow-up, so 2 to 3 years.

What were some of the notable findings from this study? Were any of them surprising to you and your coauthors?

The fact that you're seeing durability of this agent speaks volumes. These patients have a high chance of recurrence. Remember that the cohort in the OLYMPUS trial was composed of nearly half of patients that had already recurred at least once. We have historically attributed the high recurrence rates to the concept of the entire urothelium being diseased—like a ticking time bomb. We are actively monitoring our patients, anxiously waiting for the next tumor to show up—at least that's what we used to think. It's entirely possible that the problem with what we've done in the past was that A; we didn't see all of the tumor, and those are the areas where tumors came back, or B; we were potentially seeding the urothelium with tumors. So you go up there with the laser fiber and you start ablating the tumor, and you end up seeding the cancer cell throughout the urothelial lining. To have the durability and efficacy rate that is seen with UGN-101 being that high is very surprising.

I was also a coauthor on a separate paper that examined the Mayo Clinic series of patients with upper tract urothelial carcinoma. What they found was that patients that had tumors in the upper urinary tract where the urologist ureteroscoped and lasered the tumor—versus upfront nephroureterectomy without manipulating the tumor—their recurrence rate was much higher. It's entirely possible that as urologists we may be seeding tumors when we start to laser the lesion. Maybe the less we manipulate the better.

How does this study build on previous research on UGN-101?

The prior study, which was published in Lancet Oncology, looked at the complete response rate and the durability up to a year.2 This [study] builds on that and shows that in patients that have a complete response, the chances of maintaining that complete response is really quite high—much higher than we'd anticipate with endoscopic therapies.

What is the significance of these findings for patients with low-grade UTUC?

I think this is very significant for patients who have low-grade upper tract urothelial carcinoma because this will eventually be the standard of care. I wouldn't be surprised to see urologists switching from endoscopic ablation to chemoablation of tumors. This may be a paradigm shift when you see that the recurrence rates are that low.

What is the take-home message for the practicing urologist?

The take-home message is that patients who have low-grade upper tract urothelial carcinoma develop a complete response to UGN-101, and the probability of maintaining that complete response is quite high. And it's durable; up to 2 years or even longer.

References

1. Kleinmann N, Pierorazio P, Raman J, et al. Long-term recurrence free survival following UGN-101 treatment for low-grade upper tract urothelial carcinoma. Paper presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-10.

2. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9