UGN-102 May Provide Alternative to Repetitive Surgery in Low-Grade Intermediate-Risk NMIBC

Mark Schoenberg, MD

Non-surgical primary chemoablation using mitomycin-containing reverse thermal gel UGN-102 produced significant, durable responses in those with low-grade intermediate-risk non–muscle invasive bladder cancer (NMIBC), according to data from the phase 2b OPTIMA II trial (NCT03558503) published in The Journal of Urology.¹

Results showed that among 63 patients who received 1 or more installation of UGN-102, 65% (n = 41; 95% CI, 52.0%-76.7%) achieved a complete response (CR) at 3 months. Of these patients, 95.1% (n = 39) remained disease free at 6 months; at 9 months and 12 months, 73.2% (n = 30) and 61.0% (n = 25) of patients, respectively, continued to be free of disease.

Although the median duration of CR was not estimable, the probability of experiencing a durable response 9 months after CR was estimated to be 72.5% (95% CI, 54.4%-84.3%) per Kaplan-Meier analysis.

“The data from the OPTIMA II trial represent a significant advancement in the development of UGN-102 for the treatment of low-grade intermediate-risk NMIBC and further support the contention that non-surgical therapy for this disease is both technically feasible and clinically meaningful,” Mark Schoenberg, MD, chief medical officer at UroGen, stated in a press release.² “With UGN-102, our goal is to change the treatment paradigm in [this population] by enabling non-surgical chemoablation. These results provide an important validation of our approach to treating low-grade disease, and our rationale for the continued evaluation of UGN-102 in the ongoing phase 3 ATLAS study.”

For patients with low-grade intermediate-risk NMIBC, the standard-of-care treatment is transurethral resection of bladder tumors (TURBTs). Adjuvant chemotherapy is recommended per US guidelines; however, peer-reviewed literature suggests this is not frequently utilized in clinical practice due to fear of permanent damage to the bladder, inconvenience, and lack of confirmation of malignancy.

Adjuvant intravesical immunotherapy is also recommended, although national shortages of Bacillus Calmette–Guérin (BCG) have complicated this approach for those with low-grade disease. Because of these factors, patients with low-grade intermediate-risk NMIBC frequently undergo repetitive TURBTs, which exposes them to the risks that come with general anesthesia.

UGN-102 is an investigational drug that was developed for primary nonsurgical treatment in this patient population. The agent is comprised of mitomycin, and a proprietary reverse thermal hydrogel that is utilized to reconstitute mitomycin prior to instillation. Moreover, the reverse thermal properties of UGN-102 allow for local administration of mitomycin as a liquid in a cooled state; after instillation, this converts to a semi-solid gel depot at body temperature.

Additionally, prolonged exposure of tumor cells to mitomycin is hypothesized to improve chemoablation vs aqueous preparations of the drug, and the mechanism of tumor cell destruction by mitomycin is largely attributed to DNA alkylation and resulting inhibition of DNA synthesis.

For the open-label, single-arm, phase 2 OPTIMA II trial, investigators sought to evaluate the safety and efficacy of UGN-102 in patients with low-grade intermediate-risk NMIBC. The trial was conducted from October 2018 to October 2020 at 20 sites throughout the United States and Israel.

To be eligible for enrollment, patients needed to be 18 years or age or older, have low-grade intermediate-risk NMIBC that was diagnosed via a cold cup biopsy, and negative voiding cytology for high-grade disease within 6 weeks prior to screening. Patients also had to have acceptable organ and bone marrow function.

Those with past or present muscle-invasive or metastatic urothelial carcinoma, concurrent upper tract urothelial carcinoma, a history of carcinoma in situ within the past 5 years, high-grade papillary urothelial carcinoma within the prior 2 years, or previous treatment with BCG for urothelial carcinoma within the prior 2 years were excluded.

Study participants received 6 weekly intravesical instillations of UGN-102, which was comprised of mitomycin at 75 mg in 56 mL admixture with reverse thermal hydrogel to equal 1.33 mg/mL. Treatment could be postponed for up to 4 weeks in the event of a urinary tract infection (UTI) or other adverse effects (AEs).

The ablative effect of the agent was evaluated at a 3-month visit, 4 to 6 weeks after the last weekly instillation, as well as 3 months after treatment initiation, and response was determined through visual assessment, biopsy of remaining lesions, and voided urine cytology. A complete response was defined as a cystoscopy that indicated no remaining tumors, negative urine cytology, and no detectable disease.

Patients who achieved a CR participated in monthly check-ins to report any AEs and were assessed for evidence of disease recurrence at 6, 9, and 12 months following the first instillation of UGN-102.

The primary end point of the study was the percentage of patients with a CR at the 3-month visit. The secondary end point was durable CR in patients who achieved CR at the 3-month visit, defined as the percentage of patients with no detectable disease at 6, 9, and 12 months following treatment initiation.

The median age in all treated participants (n = 63) was 68.0 years (range, 33.0-96.0), and 90% completed all 6 protocol-specified instillations of UGN-102. Additionally, 57.2% of patients were older than 65 years, 39.7% were older than 75 years, and most were male (60.3%) and White (87.3%). Additionally, 77.8% of patients had recurrent low-grade NMIBC, and 44.4% had had

previous episode within 1 year of the current diagnosis. Moreover, 82.0% of patients had multiple visible tumors, and 27.9% had tumors that were larger than 3 cm in size.

Patients with recurrent disease underwent a median of 3.0 (range, 0.0-13.0) prior TURBTs, with 75.5% having undergone more than 2 prior TURBTs, and 57.1% having undergone more than 3 prior TURBTs.

Additional data showed that 13 patients reported disease recurrence, and 3 patients ended the study early due to AEs (n = 1), death (n = 1), or concerns regarding COVID-19 (n = 1).

In terms of safety, 90.5% of patients experienced treatment-emergent AEs (TEAEs), and 63% were considered to be related to study treatment. Additionally, 8% of patients reported more than 1 serious TEAE, although none of these effects were related to the study treatment.

One patient experienced 4 serious TEAEs, which included cardiac disorder, hematuria, pneumonia, and klebsiella pneumonia. Moreover, 1 patient reported 2 serious TEAEs in the form of chronic obstructive pulmonary disease and stress cardiomyopathy. Three patients each experienced 1 serious TEAE, which included acute myeloid leukemia, gastroenteropancreatic neuroendocrine tumor disease, and metastatic urothelial carcinoma.

Six patients reported at least 1 TEAE that resulted in treatment discontinuation. One patient reported the following 3 TEAEs: dysuria, micturition urgency, and penile erythema. Five patients experienced 1 of the following TEAEs: lower urinary tract symptoms (n = 2), hand dermatitis, rash generalized, and urinary retention.

The most frequently reported TEAEs were dysuria (41%), urinary frequency (21%), hematuria (16%), micturition urgency and UTI (14%), and fatigue (11%).

“The significant treatment response and sustained durability observed in this trial indicate that UGN-102 has the potential to become a non-surgical alternative for these chronically relapsing patients who typically undergo repetitive surgeries,” William C. Huang, MD, FACS, professor of urology and radiology and vice chair of Urology at NYU Langone Health and principal investigator of the OPTIMA II trial, stated in a press release. “Even more encouraging is that 12 months after treatment was initiated, approximately 73% achieved durable response.”

References

1. Chevli KK, Shore ND, Trainer A, et al. Primary chemoablation of low-grade intermediate-risk non-muscle-invasive bladder cancer using UGN-102, a mitomycin-containing reverse thermal gel (Optima II): A phase 2b, open-label, single-arm trial. J Urol. Published online August 26, 2021. doi:10.1097/JU.0000000000002186
2. The Journal of Urology publishes results of UroGen Pharma’s phase 2b study of UGN-102 in patients with low-grade intermediate risk non-muscle invasive bladder cancer (LG IR-NMIBC). News release. UroGen Pharma Ltd. October 5, 2021. Accessed October 7, 2021. https://bit.ly/2Z8vgoY