Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma.
Materials and methods
In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored.
Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs.
Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease.
Despite the indications from European and American Association of Urology Guidelines (EAU, AUA) on conservative management which include kidney-sparing options such as endoscopic ablation, radical nephroureterectomy is still one of the most common treatments for low-grade upper tract urothelial carcinoma (UTUC).
In the OLYMPUS, a phase 3 clinical trial, Kleinmann and colleagues  aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel which is instilled via ureteral catheter or nephrostomy tube and becomes a semisolid gel at body temperature that dissolves during urine production over 4-6 hours resulting in increased dwell time at the tumour site.
The authors already reported interim results from OLYMPUS on its primary endpoint which was complete eradication of disease in the ipsilateral pyelocalyceal system (defined as negative ureteroscopic evaluation, negative cytology, and negative for-cause biopsy) 4-6 weeks following 6-weekly induction instillations of UGN-101. In their original work, complete response was observed in 59% of treated patients independently from baseline demographic and clinical characteristics. The scheme of UGN-101 administration was with 6 once-weekly instillations and patients who demonstrated complete response were offered maintenance treatment of up to 11 once-monthly instillations. Follow-up visits for evaluation of response durability were at 3, 6, 9 and 12 months.
In their novel publication, Kleinmann and colleagues  address on their key secondary outcome on the long-term durability of response, focusing on their cohort of n=71 patients with low-grade UTUC where all patients with complete response at the primary disease evaluation had been followed for at least 12 additional months.
The population followed for evaluation of response durability comprised of 41 out of 71 patients (58%). Among the 29 patients who received any maintenance treatment, the median number of maintenance instillations was six (range 1-11). Of 41 patients who achieved complete response at primary disease evaluation, 23 (56%) remained in complete response after 12 months (95% CI 40, 72), eight experienced disease recurrence, and ten were unable to be evaluated. Durability of response was estimated as 82% (95% CI 66 – 91) 12 months after the primary disease evaluation visit.
Ureteric stenosis was the most frequently reported treatment-emergent adverse event (31/71, 44%) followed by urinary tract infection and haematuria (23/71, 32.4% and 22/71, 31%). An increasing number of instillations appeared to be associated with increased incidence of urinary treatment emergent adverse events. Of note, regarding the 23 urinary obstructions adverse events that occurred in 19 patients and did not resolve or resolved with sequelae (including ureteric stenosis, hydronephrosis, urinary tract obstruction, pelvi-ureteric obstruction, obstructive uropathy and ureteric obstruction), 21 events occurred after more than six instillations of UGN-101 suggesting the actual role of the ideal schedule and/or the maintenance therapy should be further explored as future perspectives.
In conclusion, the results from the final analysis of the OLYMPUS trial suggest durability of response in most patients for up to 12 months following induction therapy, with or without maintenance treatment. The safety profile for UGN-101 at this moment appears to be consistent with the known safety profile of endoscopic administration of intravesical mitomycin. Nevertheless, with more than 40% of ureteral stenosis, concerns regarding the optimal perioperative management should be raised to reduce this important limitation. While benefit-risk profile of UGN-101 for induction treatment of low-grade UTUC appears favourable, no specific clinical, patient or tumour related characteristics seemed to influence both the efficacy and safety profile, if not the number of UGN-101 administered itself. For these reasons, future investigations regarding the role of the number of inductions and maintenance scheduled will need to be further investigated along with the possibility to whether further instillations and surveillance would be well tolerated in clinic under local anaesthesia to potentially reduce total cost of therapy.