UGN-102 Active in Non-Muscle Invasive Bladder Cancer

Mark P. Schoenberg, MD

UGN-102 (mitomycin) for intravesical solution induced a 65% complete response (CR) rate in patients with low-grade intermediate-risk non-muscle invasive bladder cancer (NMIBC), according to interim data from the phase IIb OPTIMA II trial published in The Journal of Urology.¹

Among patients who achieved a CR, 97% remained disease free at 6 months and 85% remained disease free at 9 months. UroGen, the manufacturer of UGN-102, reported in a press release that the complete data from the study will be available online in mid-May 2020 via the American Urological Association. The company plans to launch a pivotal trial to continue evaluating UGN-102 in this setting.

“The responses we have seen demonstrate that nonsurgical primary chemoablation of low-grade intermediate risk non-muscle invasive bladder cancer using UGN-102 results in a considerable treatment response with encouraging durability,” said Mark Schoenberg, MD, chief medical officer at UroGen, said in the press release. “There are approximately 80,000 treatable patients annually in the US, but this remains a very challenging disease with high rates of recurrence associated with currently available therapies and a need for lifelong active surveillance and repetitive surgical intervention.”

In the press release, UroGen explained that UGN-102 (mitomycin) for intravesical uses “the RTGel^™ Technology Platform, UroGen’s proprietary sustained release, hydrogel-based formulation, to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using standard intravesical catheters.”

The multicenter, single-arm, open-label phase IIb OPTIMA II trial (NCT03558503) accrued 63 patients with low-grade NMIBC at intermediate risk of recurrence. Enrollment on the trial was completed in September 2019. Overall, 41 of the 63 patients achieved a CR.

The majority of adverse events (AEs) were considered to be mild to moderate. The most frequently occurring AEs across all grades included dysuria, hematuria, urinary frequency, fatigue, urgency, and urinary tract infection.

UGN’s lead investigational candidates is UGN-101 (mitomycin gel) for pyelocalyceal solution. The FDA granted a priority review designation in December 2019 to a new drug application for UGN-101 for the treatment of patients with low-grade, upper tract urothelial cancer (UTUC).²

The designation was based on results from the pivotal phase III OLYMPUS trial, in which a final analysis showed that UGN-101 elicited a CR rate of 59% in this patient population. Under the Prescription Drug User Fee Act, the FDA must make a decision on the application by April 18, 2020.

UGN-101 uses the RTGel^™ technology platform and is designed to permit longer exposure of mitomycin to urinary tract tissue, which allows for the nonsurgical treatment of these tumors. The therapy is administered to patients using standard ureteral catheters.

The prospective, international, multicenter, open-label, single-arm OLYMPUS trial was designed to evaluate the efficacy, safety, and tolerability of UGN-101 in patients with low-grade UTUC. To be eligible for enrollment, adult patients had to have treatment-naïve or recurrent disease, ≥1 measurable papillary low-grade tumor ≤15 mm, and a wash urine cytology sampled from the pyelocaliceal system showing the absence of high-grade disease.

Those who previously received Bacillus Calmette-Guérin within the past 6 months, had untreated concurrent urothelial cancer in other sites aside from the target area, prior carcinoma in situ in the urinary tract, prior 5-year history of invasive urothelial carcinoma in the urinary tract, prior 2-year history of high-grade papillary urothelial carcinoma in the urinary tract, or is actively being treated or intends to be treated with chemotherapy are excluded.

Investigators enrolled 71 patients with low-grade UTUC who received 4 mg mitomycin C (MMC) concentration per 1 mL of TC-3 gel, with a maximum dose of 15 ml for 6 once-weekly intravesical instillations. The co-primary endpoints were CR, which was defined as a negative ureteroscopic evaluation and negative wash cytology and adverse events rate.

Moreover, patients in CR will receive UGN-101 once monthly as maintenance treatment for 11 instillations or the first recurrence, whichever comes first.

Secondary endpoints included long-term durability of CR, CR rate at 3, 6, and 9 months after evaluation, partial response, MMC level in the plasma for select patients.

Sixty-one patients were evaluated for CR; primary disease evaluation is awaited in the remaining 10 patients. Previously announced results also showed that 45% of tumors were found to be unresectable by surgery at baseline.³

The results of the final analysis also showed that, by Kaplan Meier analysis, the durability of response was approximately 89% at 6 months and 84% at 12 months; the median time to recurrence was estimated to be 13 months.

Regarding safety, the most commonly reported treatment-emergent AEs were ureteric stenosis (43.7%), urinary tract infection (32.4%), hematuria (31.0%), flank pain (29.6%), nausea (23.9%), dysuria (21.1%), renal impairment (19.7%), and vomiting (19.7%). A total 8.5% of patients reported severe events of ureteric stenosis.

In an interim analysis of the OLYMPUS study of 28 evaluable patients, the CR rate in the intent-to-treat (ITT) cohort was 57%, with 5 patients who had not undergone their assessment.⁴  At the time 6 patients underwent 3-month follow-up and remained in CR.

Previously, the FDA granted UGN-101 orphan drug designation, fast track designation, and, in October 2018, a breakthrough therapy designation for UGN-101 in this setting.

References

1. UroGen Announces Positive Interim Data from Phase 2b Study of UGN-102 in Patients with Low-Grade Intermediate Risk Non-Muscle Invasive Bladder Cancer. Published April 3, 2020. https://bwnews.pr/345Mguk. Accessed April 3, 2020.
2. UroGen Pharma Announces FDA Filing Acceptance and Priority Review of U.S. New Drug Application (NDA) for UGN-101 [news release]. UroGen Pharma. Published December 19, 2019. https://bwnews.pr/2Q1cYxx. Accessed December 19, 2019.
3. UroGen Pharma Announces Positive Results of UGN-101 from Pivotal Phase 3 OLYMPUS Trial for the Non-Surgical Treatment of Patients with Low-Grade Upper Tract Urothelial Cancer (LG UTUC). UroGen Pharma Ltd. Published January 8, 2019. https://bit.ly/2LX0ogq?rel=0". Accessed January 8, 2019.
4. Kleinmann N, Pierorazio P, Matin S, et al. Non-surgical management of low grade upper tract urothelial cancer: an interim analysis of the international multicenter OLYMPUS trial (NCT02793128). J Urol. 2018;199(4S):e1166. doi: 10.1016/j.juro.2018.03.097