Atezolizumab and BCG in High Risk BCG naïve Non-muscle Invasive Bladder Cancer (NMIBC) Patients (BladderGATE)
Status:
Recruiting
Trial end date:
2023-02-01
Target enrollment:
Participant gender:
Summary
Patients with high-risk non-muscle invasive bladder cancer (NMIBC) are usually managed by
transurethral resection of their bladder tumor (TURBT) alone plus additional intravesical
therapy to deliver high local concentrations of a therapeutic agent within the bladder,
potentially destroying viable tumor cells that remain following TURBT. Although the exact
mechanism of bacillus Calmette-Guerin (BCG) antitumor action is unknown, its intravesical
instillation triggers a variety of local immune responses, which appear to correlate with
antitumor activity. BCG induction plus maintenance is the current, guideline-recommended
standard of care for high-risk NMIBC. Both recent evidence and guidelines suggest that
full-dose BCG maintenance after the first BCG dose of induction course as used in the SWOG
8507 and European Organization for Research and Treatment of Cancer (EORTC) 30911 and 30962
trials, is the most appropriate maintenance schedule. High-risk NMIBC patients following
adequate treatment have a recurrence rate at 1 and 2 years of 25 and 30% respectively after
treatment with the current standard (BCG), which is clearly unsatisfactory. Programmed death
ligand 1 (PD-L1) is a surface glycoprotein that functions as an inhibitor of T-cells and
plays a crucial role in suppression of cellular immune response. It is implicated in tumor
immune escape by inducing apoptosis of activated antigen-specific CD8 T-cells, impairing
cytokine production and diminishing the toxicity of activated T-cells. PD-L1 expression by
immunohistochemistry using the Ventana SP142 assay on tumor-infiltrating immune cell (IC)
status defined by the percentage of PD-L1 positive ICs: IC0 (<1%); IC1 (≥1% but<5%); and
IC2/3 (≥5%PD-L1) has been demonstrated to be higher (IC2/3) in resection and TURBT specimens
versus biopsies from primary lesions or metastatic sites. In patients with metastatic bladder
cancer, treatment with the PD-L1 inhibitor atezolizumab (1200 mg, every 3 weeks) resulted in
objective response rates of 26% in the IC2/3 group, 18% in the IC1/2/3 group and 15% in all
patients. The median overall survival was 11.4 months in the IC2/3 group, 8.8 months in the
IC1/2/3, and 7.9 months in all patients. Grade 3-4 related treatment-related adverse events
occurred in 16% and grade 3-4 immune-mediated adverse events occurred in 5% of treated
patients. In murine models with invasive bladder cancer, anti-PD-1 plus CpG has shown to
increase survival in mice, with anti-PD-1 plus CpG being superior to either agent alone.
Taken together, these results confirmed the clinical activity of atezolizumab in metastatic
bladder cancer, which could be beneficial in patients with NMIBC in combination with standard
approaches such as BCG.