Can manual gemcitabine instillation or tumor microenvironment-based selection enhance the efficacy of TAR-200 in bladder cancer?

TAR-200, a novel intravesical drug delivery system, has demonstrated remarkable efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer, achieving a complete response rate of 82.4% in the phase IIb SunRISe-1 study. In this letter, we propose two strategies to further optimize treatment outcomes. First, we suggest that a single manual gemcitabine instillation given concurrently with TAR-200 placement-without adding an extra procedure - could combine the high peak concentration of manual instillation with the sustained release profile of TAR-200, potentially enhancing antitumor activity. Second, we discuss the immunological mechanisms underlying BCG failure, particularly the development of an immunosuppressive tumor microenvironment characterized by upregulation of PD-L1 on tumor and immune cells. We hypothesize that assessing baseline or BCG-induced immunosuppressive status may help identify patients who would derive greater benefit from the addition of the PD-1 inhibitor cetrelimab to TAR-200. These considerations warrant further investigation to maximize therapeutic efficacy in this challenging patient population.