Background
Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel.
Methods
In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5–15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient’s renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4–6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128.
Findings
Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47–71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1–12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment.
Interpretation
Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients.
Funding
UroGen Pharma.
This prospective open-label single-arm phase 3 study is the first to assess the activity of topical chemoablation (mitomycin containing thermal gel) for the primary treatment of low-grade upper tract urothelial carcinoma (UTUC). The treatment called UGN-101 is a formulation of mitomycin with mixture of polygel designed to provide extended contact time with tissue surface. Non-clinical studies and early human experience suggested that UGN-101 was well tolerated and feasible for delivery to the upper urothelial tract using a retrograde ureteral catheter with a low level of systemic absorption of mitomycin
The study enrolling 74 patients in 24 academic sites in USA, who had biopsy proven primary or recurrent low grade UTUC involving the renal pelvis or calyces and a size between 5 and 15 mm (an endoscopic debulking was allowed before initiation of the treatment). The protocol was based on 6 weekly instillations of UGN-101 (max 15mL) via a retrograde catheter.
The primary endpoint used was a complete response (CR) defined as a negative endoscopic examination and negative cytology at the primary disease evaluation (PDE) which were performed 4 to 6 weeks after completion of initial treatment. The secondary endpoint was the assessment of durable response at 12 months for those who had a CR at PDE. Patients who had a CR at PDE underwent monthly maintenance and quarterly surveillance.
Of the 71 patients finally treated, most of them had same baseline characteristics as in the literature for this disease. 75% were over 65 years old, and 52% had a past history of UTUC. Interestingly tumors measurements at baseline were close to the maximal size accepted with a mean of 14.8mm. 86% received the 6 instillations, and 59% had a complete response at PDE. At the time of the data cutoff, 26 (63%) of 41 patients in follow-up had reached the 12-month timepoint. 20 (77%) of these 26 patients had a 12-month assessment, 14 (70%) of whom showed durability of their complete response. There was no progression to high grade or invasive cancer. Durability of response was estimated at 84·2% at 12 months after the primary disease evaluation, and the median time to recurrence was estimated as 13 months. Adverts events occurred for 94% of the 71 patients with 37% of serious adverse events. The most frequent adverse event was the ureteral stricture which was described in 44% of the patients with 8% considered as grade 3 AE. Also, impairment of renal function was found in 20% of patients from who 7% did not recovered.
The FDA has already approved UGN-101 (mitomycin gel; Jelmyto) for the treatment of patients with low-grade upper tract urothelial cancer (LG UTUC). We definitely have to compliment all the investigators of this first study who clearly opens the way for more conservative management of UTUC using chemoablation. The high CR rate at PDE is really promising but further evaluations and long-term follow-up are still required.
Despite these promising results, we would have to take into consideration the related cost of this treatment which was launched at $21,376/dose i.e a total amount of $128,256 for only the 6 firsts instillations without maintenance therapy.
Moreover, ureteral stricture is definitely a major concern in the treatment of low-grade tumors. As endoscopic treatment is the first line option for these low risk tumors, the risk of ureteral strictures could lead to a difficult access to the renal pelvis on a long-term period, or even worth require a chronic double J stent. Therefore, long term outcomes from an endoscopic aspect, renal access with the endoscope, and double J stent requirements need to be assessed.
Finally, it would be really interesting to assess this treatment in an RCT comparing endoscopic treatment alone vs. Chemoablation + laser treatment. In order to assess the real benefit of chemoablation compared to laser treatment. Another indication where there is still an unmet need is for patients contraindicated to radical nephroureterectomy (ie. Imperative indications of conservative management).