Discussion
MIBC, tumor necrosis
RECURRENCES, TUMOR NECROSIS, METASTATIC BLADDER CANCER
To our knowledge, this is among the first prospective trials to test TURBT plus cisplatin-based chemotherapy as definitive bladder-sparing treatment for MIBC; the first to define the performance characteristics of uniformly assessed and defined cCR as a tool for patient selection for this strategy; and the first to integrate immune checkpoint blockade into this approach. Our study demonstrates that stringently defined cCR is associated with favorable survival outcomes and that prolonged bladder-intact survival is achievable in a large subset of patients with MIBC and a cCR to TURBT and gemcitabine, cisplatin, plus nivolumab.Radical cystectomy or radiation therapy are mainstays of local treatment for MIBC. However, despite such treatments, more than 50% of patients experience metastatic recurrenceAlthough the IMvigor 130 and Keynote 361 studies exploring concurrent administration of platinum-based chemotherapy and PD-1/PD-L1 blockade in patients with metastatic bladder cancer did not demonstrate improvements in survival, those studies pooled patients treated with cisplatin-based and carboplatin-based chemotherapyOur study has potential limitations. The median follow-up of patients achieving a cCR was 30 months at the time of the data lock. The vast majority of local and distant recurrences occur within 2 years of treatment in previous bladder-sparing studies of MIBC, although whether the same pattern and timing holds true for patients not undergoing cystectomy or receiving radiation is not well establishedA disconnect between clinical and pathological staging has often been cited as a barrier to TURBT plus systemic therapy as definitive treatment for MIBC, although many analyses highlighting such a disconnect have been retrospective and without uniform approaches to clinical response assessmentIntegrating pre-treatment and on-treatment biomarkers could potentially refine selection of patients achieving a cCR after TURBT plus systemic therapy for omission of additional local therapy. Mutations in a pre-specified set of genes selected based on previous workAnalysis of circulating immune parameters may facilitate biomarker discovery and insights related to the immunomodulatory effects of treatment. Mass cytometry analysis of PBMCs revealed that a higher abundance of pre-treatment naive CD4 T cells and on-treatment naive CD8 T cells was associated with longer metastasis-free and overall survival. Multiplex proteomic analysis of plasma revealed that increased on-treatment levels of cytotoxicity-related markers TRAIL, FasL and CD244 were associated with a higher likelihood of achieving a cCR. TRAIL and FasL are members of the tumor necrosis factor (TNF) superfamily and are expressed by immune effector cells, whereas CD244 is a surface receptor on natural killer (NK) cells and a subset of CD8 T cellsIn our study, neoadjuvant gemcitabine, cisplatin, plus nivolumab after TURBT was associated with a cCR rate of 43%, and clinical response assessment identified patients with particularly favorable outcomes and facilitated bladder sparing. Genomic, imaging and immunological biomarkers have the potential to refine this treatment paradigm, but they require further investigation. These findings may help advance a more personalized approach to the management of MIBC.