Introduction:

Neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) are underutilized standards of care for muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicity and postoperative complications. Many patients are either ineligible for treatment or unwilling to undergo RC. Therefore, between 25% to 57% of patients receive no definitive therapy for MIBC (Gray et al. Eur Urol 2013, Westergren et al. J Urol 2019, John et al. Eur Urol Focus 2020, Patel et al. J Cancer Immunol 2021). TAR-200 (Figure 1) is a novel intravesical drug delivery system that provides continuous local delivery of gemcitabine, which results in saturation of drug into the stromal layers of the bladder (unpublished data). The TAR-200-101 study (NCT02722538) evaluated the safety and tolerability of TAR-200 when used as neoadjuvant treatment prior to RC in patients with MIBC.

Methods:

This phase 1, open-label study was conducted across 6 US/European sites. Eligible patients were aged ≥18 years with histologically confirmed T_2a-T_3b N_0-1 M₀ urothelial bladder cancer, had refused/were ineligible for NAC, and were candidates for RC. Patients in Arm 1 had, at minimum, residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); Arm 2 had maximal TURBT (residual tumor <3 cm). Patients received two 7-day cycles of intravesical gemcitabine via TAR-200 prior to RC (Figure 2). The primary endpoint was safety, assessed via treatment-emergent adverse events (TEAEs) per NCI CTCAE v4.0. Secondary endpoints included tolerability (including % patients not requiring unscheduled removal of TAR-200), pharmacokinetics of gemcitabine and its metabolite, 2',2'-difluorodeoxyuridine (dFdU), and preliminary efficacy (proportion of patients with pathological complete [pCR; T₀ disease] or partial [pPR; <T₂ disease] response at RC). All endpoints were assessed in the intention-to-treat (ITT) population.

Results:

Of the 23 patients in the ITT population (20 men; median age 70 [53-88] years; 11 in Arm 1, 12 in Arm 2), 22 completed Cycle 1 and 20 completed both cycles. No patients were classified as intolerant to TAR-200. Ten patients (4 in Arm 1; 6 in Arm 2) experienced ≥1 TEAEs; 4 and 5 patients had TAR-200-related and procedure-related TEAEs, respectively. All TEAEs prior to RC were grade ≤2, except for 1 in Arm 2 (grade 3 abdominal pain with disease progression). Pollakiuria (4/23 patients) was the most common TAR-200-related TEAE. Plasma concentrations of gemcitabine were undetectable and plasma concentrations of dFdU did not exceed 0.332 μg/mL. For Arm 1 patients at RC, 4 out of 10 patients exhibited pathologic downstaging; 1 demonstrated a pCR and 3 a pPR. In Arm 2, 6 out of 10 patients exhibited downstaging, 3 experienced a pCR and 3 a pPR.

Conclusion:

TAR-200 was shown to be safe and well-tolerated in patients with MIBC prior to RC. Observed adverse events were consistent with those commonly seen in patients with MIBC. Results from this phase 1 study provide preliminary evidence of the antitumor response of neoadjuvant TAR-200 prior to RC. The safety and efficacy of TAR-200 is under further investigation, in combination with the anti–programmed cell death protein-1 antibody cetrelimab, in several phase 2b and phase 3 clinical trials 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