Introduction:

Standard-of-care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) with neoadjuvant chemotherapy or chemoradiotherapy. However, due to a variety of factors, as many as 50% of patients with MIBC worldwide may not receive curative intent therapy (Westergren D-O. J Urol. 2019; John JB. Eur Urol Focus. 2021; Patel VG. CA Cancer J Clin. 2020). This gap represents a considerable unmet need, most critically for those patients who are elderly or frail. TAR-200 (Figure 1) is a novel intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. Preclinical data demonstrate that TAR-200 achieves therapeutic gemcitabine levels across the thickness of the bladder with no evidence of systemic absorption. This single-arm, open-label, global phase 1 study (NCT03404791) aimed to evaluate safety, tolerability, and preliminary efficacy of TAR-200 in patients with MIBC who were unfit for or refused curative intent therapy.

Methods:

Eligible patients had urothelial carcinoma of the bladder (cT2-cT3b, N0, M0) and underwent complete resection via transurethral resection of bladder tumor (TURBT). Patients were deemed unfit for RC and refused or were unfit for chemoradiotherapy. TAR-200 was inserted for 4 consecutive 21-day dosing cycles during an 84-day induction period. Patients were eligible for up to 3 additional maintenance cycles every 3 months starting on Day 180. Patients underwent efficacy assessments via TURBT and imaging at Day 84. Clinical response was evaluated by cytology, cystoscopy, imaging every 3 months, and pathologic staging of biopsy tissue, if clinically indicated. The primary end points were safety and tolerability at 84 days. Key secondary end points were rates of clinical complete and partial response (cCR and cPR, respectively) and stable and progressive disease (SD and PD, respectively), as well as Kaplan-Meier estimates of duration of response (DOR) and overall survival (OS).

Results:

A total of 35 participants were enrolled, with median age of 84 years. 45.7% had an ECOG performance status of ≥ 3. 68.6% were male. TAR-200 was well tolerated with a favorable safety profile in this elderly and frail cohort. Treatment-emergent adverse events (TEAEs) (defined as new from baseline or worsening after first TAR-200 insertion) related to TAR-200 occurred in 15 patients (42.9%), with dysuria (20.0%) and urinary frequency (14.3%) the most common. Two patients (5.7%) experienced TEAEs leading to removal of TAR-200. None of the TEAEs leading to study discontinuation were treatment related. Clot evacuation and blood transfusion were required in 1 patient each. At 3 months, cCR was 31.4%, with an additional 8.6% of participants achieving a cPR. Median DOR was 12.7 months (95% CI, 10.6-NE). The progression-free rate at 12 months was 67.7% in responders. Median OS was 20.1 months (95% CI, 10.1-NE) (Figure 2).

Conclusion:

The TAR-200 system was generally safe and well tolerated in this elderly and frail cohort of patients with MIBC. TEAEs observed during the study were consistent with what would be expected in this patient population with lethal bladder cancer, with no unanticipated safety issues attributed to treatment with TAR-200. Procedural interventions in this high-risk cohort were modest. Clinical response was robust and durable in a cohort with very limited treatment options. TAR-200 is currently under investigation in combination with the systemic inhibitor of programmed cell death protein-1 cetrelimab in the SunRISe clinical trials program (NCT04640623, NCT04658862, NCT04919512). Enrollment in these clinical trials is ongoing in over 25 countries and 450 sites.

Funding: Janssen Research & Development