UGN-301 Shows Early Tolerability in Recurrent Non–Muscle-Invasive Bladder Cancer

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UGN-301, an intravesical formulation of zalifrelimab, proved to be well tolerated with an acceptable toxicity profile at all dose levels evaluated in patients with recurrent non–muscle-invasive bladder cancer (NMIBC) enrolled in a phase 1 study (NCT05375903) shared during the 2025 American Urological Association Annual Meeting.1

Of the 20 patients who received at least 1 dose of UGN-301, 3 received the agent at 100 mg, 6 received it at 300 mg, 8 received it at 500 mg, and 3 received it at 700 mg. Treatment-emergent adverse effects (TEAEs) were mild or moderate with the exception of 1 severe event in the form of a urinary tract infection (UTI), which was thought to be related to the procedure rather than the treatment.

The most common TEAEs experienced with UGN-301 comprised dysuria, urinary retention, headache, hematuria, nausea, and UTI. One patient experienced two serious AEs, UTIs requiring hospitalization; these effects were not determined to be related to the study treatment. No dose-limiting toxicities (DLTs) were reported, and no TEAEs resulted in discontinuation of the agent.

Of the efficacy evaluable patients with Ta/T1 disease (n = 13), 46% had a complete response (CR) at week 12 or were recurrence free; of those with carcinoma in situ (CIS) ± Ta/T1 disease (n = 6), 33% had a CR at week 12 or were free of recurrence. Specifically, 1 patient who received UGN-301 at 100 mg and had high-grade Ta disease continued to be free of recurrence through 9 months. Of 5 patients who received 300 mg of the drug and had Ta/T1 disease, 3 continued to be free of recurrence at the time of the 15-month disease assessment. Of those who received UGN-301 at 500 mg who had CIS disease (n = 4) or Ta/T1 disease (n = 3), one patient each were free of disease at 6 months, and both are still on study.

“Local delivery of UGN-301, formulated in a RTgel, allowed sustained exposure of zalifrelimab in the bladder while limiting systemic exposure and thus mitigating the risk of systemic immune-related toxicities associated with CTLA-4 inhibition,” Marco Maruzzo, MD, PhD, of the Oncology, Unit 3, Istituto Oncologico Veneto IOV – IRCCS, in Padua, Italy, and colleagues, wrote in a poster.

The phase 1 study was launched to examine the safety and identify the recommended phase 2 dose of UGN-301 as a single agent (arm A) or as part of a combination regimen in patients with NMIBC.1,2 Those included in arm A had recurrent NMIBC with intermediate-risk low-grade Ta/T1 disease or HG Ta/T1 disease and/or CIS who have progressed on 1 or more prior courses of intravesical therapy. All patients had papillary tumors that were detectable via white light resected and evident areas of CIS cauterized with electricity during screening or within 6 weeks of screening.

In the induction period, UGN-301 was administered once weekly for 6 weeks. A disease assessment was performed at week 12. This was followed by an optional maintenance period in which the product was administered once every 3 months—at 6, 9, and 12 months—following treatment initiation. Investigators utilized a Bayesian logistic regression model to identify the biologically effective dose and maximum feasible dose of UGN-301.

Primary end points included incidence of TEAEs and DLTs, 3-month CR rate/recurrence-free survival, and pharmacokinetics (PK).

In the 20 total patients, the median age was 71 years (range, 57-89). Seventy-five percent of patients were male. Patients had 1 (15%), 2 (25%), 3 (25%), or more than 3 (35%) prior occurrences of urothelial carcinoma. The current urothelial carcinoma stage for patients were LG Ta (25%), HG Ta (35%), HG T1 (5%), CIS alone (20%), and CIS + Ta (15%). Moreover, 65% of patients were BCG unresponsive, 5% were BCG intolerant, 20% experienced BCG failure, and 10% were BCG experienced.

A total of 19 patients received all 6 doses of UGN-301. Six patients received at least 1 dose of maintenance treatment at the following doses: 100 mg (n = 1), 300 mg (n = 2), and 500 mg (n = 3). The data cutoff date for the data shared during the meeting was September 30, 2024.

In terms of PK, the median duration of detectable UGN-301 was at least 9.7 hours at weeks 1 and 6. Moreover, maximal concentration in urine (Cmax) plateaus was observed at 500 mg, and there was no or limited systemic exposure.

Regarding safety in the 100-mg cohort, 66.7% of patients experienced any TEAEs. Any treatment- or procedure-related TEAEs occurred in 33.3% of patients, treatment-related TEAEs were reported in 33.3% of patients, and any procedure-related TEAEs were experienced by 33.3% of patients. In the 300-mg cohort, all patients experienced TEAEs. Any treatment- or procedure-related TEAEs were observed in 50% of patients, treatment-related TEAEs were reported in 16.7% of patients, and any procedure-related TEAEs were experienced by 33.3% of patients.

In the 500-mg cohort, 50% of patients experienced any TEAEs, 12.5% had serious AEs, 37.5% had any treatment- or procedure-related TEAEs, 25% had any treatment-related TEAEs, and 12.5% experienced any procedure-related TEAEs. Moreover, any serious TEAEs were experienced by 12.5% of patients, any treatment- or procedure-related serious TEAEs were observed in 12.5% of patients, and any procedure-related serious TEAEs were reported in 12.5% of patients. In the 700-mg cohort, 33.3% experienced any TEAEs, 33.3% had any treatment- or procedure-related TEAEs, and 33.3% experienced any procedure-related TEAEs.

“Continued evaluation of UGN-301 for the treatment of NMIBC is warranted, and this study is ongoing with patients receiving a combination therapy of UGN-301 with UGN-201 (arm B) and gemcitabine (arm C),” the study authors concluded.

Disclosures: Dr Maruzzo serves as an advisor for BMS, IPSEN, AstraZeneca, Johnson & Johnson, Recoardati, MSD, and Merck-Serono.

References

1. Maruzzo M, Padron O, Ribal MJ, et al. Treatment of recurrent non-muscle invasive bladder cancer with UGN-301 (zalifrelimab): Results of a phase 1 dose-escalation study. Presented at: American Urological Association Annual Congress; April 26-29, 2025; Las Vegas, NV. IP02-34.
2. A phase 1 dose-escalation study of UGN-301 in patients with recurrent non-muscle invasive bladder cancer (NMIBC). ClinicalTrials.gov. Updated February 14, 2025. Accessed April 26, 2025. https://clinicaltrials.gov/study/NCT05375903