Low-grade upper tract urothelial carcinoma is a rare disease with limited treatment options. The available treatment options today include:
- Kidney sparing endoscopic resection or ablation, requiring repetitive interventions and are at times, limited due to the fact that the disease is often multifocal with high rates of local recurrence. Intracavitary therapy can be added for the frequent, recurrent, or multifocal disease.
- Radical nephroureterectomy is required for difficult to access tumors or unrespectable tumor volume. It is ultimately used for many patients who are originally treated with kidney sparing treatments.
UGN-101 is a poloxamer 407 based inverse thermo-sensitivity factor that blocks co-polymer PEO-PPO-PEO. It is instilled as a liquid and converts to semisolid gel. It consists of Mitomycin 4mg/1 ml gel, and It releases the mitomycin for a duration of 4-6 hours inside the body (Figure 1). It remains in liquid form at low temperatures and solidifies at body temperature.
Figure 1: UGN-101 chemistry:
UGN-101 is supplied with two vials of sterile lyophilized mitomycin and one vial of a sterile hydrogel. For its use, it also requires flexible rigid cystoscopy, guidewire, a syringe with contrast, and ice to chill the UGN-101.
Dr. Lerner moved on to discuss the study design for the OLYMPUS trial, which was a prospective phase three, open-label, single-arm trial, in patients with low-grade upper tract urothelial carcinoma. The primary endpoint was the complete response at primary disease evaluation. The key secondary endpoints included durability of response at 12 months and safety (Figure 2).
Figure 2 – OLYMPUS study design:
Patients were treated with six once-weekly instillations of UGN-101. The dose was individualized based on renal pelvis and calyx volume. 1.3 gr of Sodium bicarbonate was given one day prior, on the morning of, and 30 minutes before treatment with no diuretics.
Patients who achieved complete response were eligible to receive up to 11 additional monthly maintenance instillations.
Overall, 74 patients with pathologically confirmed low grade non-invasive upper tract urothelial carcinoma were enrolled. The study had a 90% power to demonstrate that the observed complete response rate is superior to the rate of 15%
Inclusion criteria consisted of new or recurrent patients with low-grade upper tract urothelial carcinoma in the pyelocaliceal system, diagnosed less than two months before screening. A biopsy had to be done to confirm low-grade disease and cytology had to be negative for high-grade disease. There had to be at least one measurable papillary low-grade tumor with the size being 0.5 to 1.5 centimeters in diameter. Partial resection was permitted if the tumor was over 1.5 centimeters, at least one remaining papillary tumor of at least 0.5 millimeters. The tumor had to be located superior to the ureteropelvic junction.
Exclusion criteria consisted of any Bacillus Calmette-Guerin (BCG) treatments within the last six months, history of carcinoma in situ (CIS), invasive urothelial carcinoma in the last five years, and high grade papillary urothelial carcinoma in the last two years. Additional exclusion criteria consisted of current treatment with systemic chemotherapy, concurrent untreated urothelial carcinoma outside the target area, and the inability to instill medications into the upper tract system. Patient Disposition in depicted in Figure 3 and data of the maintenance period are shown in Figure 4.
Figure 3 – Patient disposition:
Figure 4 – Maintenance period data:
The final cohort is shown in Table 1, with a total of 71 patients. The final primary endpoint results are shown in Table 2, showing a complete response of 59%. Lastly, the estimated durability of response at 12 months is shown in Figure 5, demonstrating a median time to recurrence of 13 months with 84% durability of response. A total of 3 patients died due to failure to thrive, natural causes, and cerebrovascular accidents. All deaths were unrelated to the use of UGN-101. A total of 42.3% reported at least one grade 1 adverse event.
Table 1 – Final cohort:
Table 2 – Primary endpoint results:
Figure 5 – Estimated Durability of response at 12 months:
Dr. Lerner concluded that the OLYMPUS trial tested a strategy of chemoablation for low-grade upper tract urothelial carcinoma and met its primary endpoint with a complete response rate of 59% (leading to FDA approval on the 04/15/2020). This high rate of complete response obviated the need for kidney removal in 48% of patients deemed to have unresectable disease. The durability of response at 12 months was seen in most patients (interim analysis). Most adverse events were mild to moderate, with ureteral stenosis occurring in 8.5% of patients.
Presented by: Seth P. Lerner, MD, FACS, Vice Chair for Faculty Affairs, Baylor College of Medicine, Houston, TX, USA
Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, @GoldbergHanan, at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020.
References:
- Kleinmann N, Wirth G, Lin JS, Matin SF, Nativ O, Mayer G, et al. Thermo Reversible Hydrogel Based Delivery of Mitomycin C (UGN-101) for Treatment of Upper Tract Urothelial Carcinoma (UTUC). Bladder Cancer. 2019;5:21-9.