ATLAS: Analyzing UGN-102, TURBT for Intermediate-Risk NMIBC

Is there a better way to manage low-grade (LG) non-muscle invasive bladder cancer (NMIBC)? Adding UGN-102 to the current standard of care shows a potential therapeutic benefit.¹ LG NMIBC is typically managed with endoscopic resection and has a high likelihood of recurrence, especially for patients with intermediate-risk (IR) disease. Multiple factors lead to recurrence, including a lack of complete surgical resection of tumor.² To reduce the risk of recurrence, adjuvant immunotherapy or chemotherapy is recommended for patients with IR disease, but there is room for improvement in both obtaining complete disease clearance and reducing the risk of recurrence to minimize the need for repeat transurethral resection of bladder tumor (TURBT).

According to the authors, “a phase 2b trial (OPTIMA II; NCT03558503) of primary chemoablation using UGN-102 (an investigational mitomycin-containing reverse thermal gel) in patients with new or recurrent LG IR NMIBC suggested favorable rates of complete response (CR) and durability of response.”³ These findings led the authors to describe the efficacy and safety of primary chemoablation using UGN-102 with or without subsequent TURBT compared with TURBT alone in the management of patients with LG IR NMIBC.

The authors recruited patients over an approximately 2-year period from 72 international sites. LG NMIBC (Ta) was diagnosed on cold cup biopsy and negative cytology. IR disease was defined as having 1 or 2 of the following: multifocal tumor burden, solitary tumor >3 cm, or recurrence of LG NMIBC within 1 year of current diagnosis. Patients were randomized to 6 weekly intravesical instillations of UGN-102 with or without TURBT or TURBT alone. Patients were followed 3 months after treatment. If patients had a CR, they went into the follow-up period. Those who did not have a CR in either treatment arm were managed with TURBT and then entered the follow-up arm. Patients in the follow-up arm were surveilled quarterly and, if disease-free, remained in the study until completion of all follow-up visits, disease recurrence, progression, or death. Patients who had a recurrence or progression during the follow-up period were released to the care of their treating physicians and were considered to have “completed the study.”

The study’s primary end point was disease-free survival (DFS). Of note, residual LG disease at 3-month assessment for patients with UGN-102 +/- TURBT was not counted as a DFS event. Secondary end points included CR and durability of response. The authors noted that “study enrollment was stopped early by the sponsor to pursue an alternative development strategy for UGN-102 in the treatment of bladder cancer. Patients who had consented at the time the trial terminated were permitted to continue, but follow-up was terminated once the last patient had been followed for 15 months after start of treatment. No intermit efficacy analyses were performed, and early termination rendered the trial underpowered to perform hypothesis testing. Thus, all analyses are descriptive.”

A total of 142 patients were randomized to the UGN-102 +/- TURBT cohort, while 140 were randomized to the TURBT alone cohort. Most patients were older than 65 years and male. Of the patients included, 38% in the UGN-102 +/- TURBT cohort and 46% in the TURBT alone cohort had a history of LG NMIBC. In both cohorts, 29% of patients had received the diagnosis within the past year. A total of 37% and 46% of patients had undergone prior TURBT in the UGN-102 +/- TURBT and TURBT alone cohorts, respectively; 58% and 67% had multifocal disease in the UGN-102 +/- TURBT and TURBT alone cohorts, respectively; and 47% and 42% had tumor burden >3 cm in the UGN-102 +/- TURBT and TURBT alone cohorts, respectively.

At 3 months, a CR was seen in 65% (95% CI, 56.3-72.6) of UGN-102 +/- TURBT patients and 64% (95% CI, 55.0-71.5) of TURBT alone patients. Disease progression was seen in 8.5% and 6.4% of patients in the UGN-102 +/- TURBT and TURBT alone cohorts, respectively. For patients with residual disease at first assessment, 24 of 26 and 18 of 22 patients underwent TURBT in the UGN-102 +/- TURBT and TURBT alone cohorts, respectively.

Median follow-up time for DFS was similar for both cohorts (slightly longer than 15 months in 72% of patients in the UGN-102 +/- TURBT cohort compared with 50% in the TURBT alone cohort). Of the patients who had a CR at first assessment, the estimated durability of response at 1 year was 80% in the UGN-102 +/- TURBT cohort compared with 68% in the TURBT alone cohort. The authors noted that of the patients who had a CR at initial assessment, by the end of the study period, 67 of 92 (73.0%) patients in the UGN-102 +/- TURBT cohort and 49 of 89 (55.1%) in the TURBT alone cohort were still disease free.

Regarding safety and tolerability, 96% of patients in the UGN-102 +/- TURBT cohort received 6 instillations of UGN-102. There were more treatment-emergent adverse events (TEAEs) in the UGN-102 +/- TURBT (75%) cohort compared with the TRUBT alone cohort (48%). TEAEs were seen in 39% and 11% of patients, respectively. A total of 8.7% of patients in the UGN-102 +/- TURBT cohort and 5.3% in the TURBT alone cohort experienced serious AEs; however, the investigators did not consider these events to be related to treatment. Treatment and study discontinuation was 3.6% and 2.9% for the UGN-102 +/- TURBT and TURBT alone cohorts, respectively. Common AEs seen in the UGN-102 +/- TURBT cohort included dysuria (30%), micturition urgency (18%), nocturia (18%), and pollakiuria (16%). One patient in the TURBT alone cohort died secondary to COVID-19 infection. Quality of life questionnaire results were similar or better in the UGN-102 +/- TURBT cohort.

For a disease with a high rate of recurrence, it is necessary to reduce the rate of recurrence to avoid the need for repetitive resections, which are associated with risk (eg, anesthesia). Intravesical chemotherapy has been investigated, and studies have shown that drug concentration and dwell time are important factors contributing to the efficacy of chemotherapy. Reverse thermal gels can play an important role in the genitourinary setting. The authors noted that UGN-101 is a reverse thermal gel containing mitomycin that has US Food and Drug Administration approval for LG upper tract urothelial carcinoma,⁴ and its use is guideline based.⁵ UGN-102 has a similar chemical structure, although it does have lower concentrations of mitomycin and is administered via a urethral catheter in an ambulatory setting. The drug is administered in 60-cc doses and offers twice the dose of mitomycin in an aqueous solution. It disintegrates over a period of 6 to 8 hours with gel fragments and is excreted during normal voiding.

This study showed that the use of UGN-102 when added to TURBT had similar CR rates and a greater probability of DFS compared with TURBT alone. These results should be interpreted cautiously, the authors noted, given that “residual LG disease at the 3-month assessment was counted as a disease-free survival event in the TURBT monotherapy arm but not in the UGN-102 +/- TURBT arm.” The authors also found that the patients who achieved a CR at the initial 3-month assessment maintained that response over time.

Study limitations included an inability to reach the study enrollment numbers needed to illustrate UGN-102 +/- TURBT superiority over TURBT alone. Also, the TURBT cohort did not receive adjuvant intravesical therapy, and the study population may be different from study populations that investigated intravesical chemotherapy in an aqueous solution, making it difficult to compare.

These findings are a good indication that “further study of primary chemoablation with UGN-102 for initial treatment of patients with new or recurrent LG IR NMIBC is warranted,” the authors concluded.

David Ambinder, MD is a urology resident at New York Medical College/Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. Prasad SM, Huang WC, Shore ND, et al. Treatment of low-grade intermediate-risk nonmuscle-invasive bladder cancer with UGN-102 ± transurethral resection of bladder tumor compared to transurethral resection of bladder tumor monotherapy: a randomized, controlled, phase 3 trial (ATLAS). J Urol. 2023;210(4):619-629. doi:10.1097/JU.0000000000003645
2. Tan WS, Steinberg G, Witjes JA, et al. Intermediate-risk non-muscle-invasive bladder cancer: updated consensus definition and management recommendations from the International Bladder Cancer Group. Eur Urol Oncol. 2022;5(5):505-516. doi:10.1016/j.euo.2022.05.005
3. Chevli KK, Shore ND, Trainer A, et al. Primary chemoablation of low-grade intermediate-risk nonmuscle-invasive bladder cancer using UGN-102, a mitomycin-containing reverse thermal gel (Optima II): a phase 2b, open-label, single-arm trial. J Urol. 2022;207(1):61-69. doi:10.1097/JU.0000000000002186
4. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9
5. Coleman JA, Clark PE, Bixler BR, et al. Diagnosis and management of non-metastatic upper tract urothelial carcinoma: AUA/SUO Guideline. J Urol. 2023;209(6):1071-1081. doi:10.1097/JU.0000000000003480