Summary Background Patients with metastatic urothelial carcinoma have limited treatment options after failure of platinum-based chemotherapy. This multicenter, single-arm phase 2 trial evaluated atezolizumab, an engineered humanized IgG1 monoclonal antibody that binds selectively to programmed death–ligand 1 (PD-L1), in this population. Methods Three hundred and ten patients received atezolizumab (1200 mg, every 3 weeks). PD-L1 expression on tumor-infiltrating immune cells (IC) was prospectively assessed by immunohistochemistry. The co-primary endpoints were the objective response rate by RECIST v1.1 and immune modified RECIST. A hierarchical testing procedure was used to test whether the objective response rate was significantly higher than the historical control of 10% at alpha level of 0·05. Exploratory analyses included assessing the association between The Cancer Genome Atlas (TCGA) molecular subtypes, CD8+ T cell infiltration, mutation load, and clinical outcomes. Findings By independent review, objective response rates were 26% (95% CI 18 to 36) in the IC2/3 group, 18% (95% CI 13 to 24) in the IC1/2/3 group and 15% (95% CI 11 to 19) in all patients. With a median follow-up of 11·7 months, ongoing responses were observed in 84% of responders. The median duration of response was not reached (range 2·0*, 13·7* months, *censored). The median overall survival was 11·4 months (95% CI 9·0 to not estimable) in the IC2/3 group, 8·8 months (95% CI 7·1 to 10·6) in the IC1/2/3, and 7·9 months (95% CI 6·6 to 9·3) 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. Exploratory analyses showed TCGA subtypes and mutation load to be independently predictive for response to atezolizumab. Interpretation Atezolizumab demonstrated durable activity and good tolerability in this population. PD-L1 expression on immune cells was associated with response. This is the first report to show the association of TCGA subtypes with response to immune checkpoint inhibition and demonstrate the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. Funding F. Hoffmann-La Roche Ltd.

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