Background: Tumor mutational burden (TMB), PD-L1 expression, T-effector gene expression (GE) and a fibroblast TGF-β–response signature (F-TBRS) are associated with clinical outcomes with atezo mono in mUC (Mariathasan, Nature, 2018). Here we explore the potential predictive role of these biomarkers and APOBEC mutagenesis in IMvigor130. Methods: Pts receiving first-line (1L) mUC treatment (tx) were randomized 1:1:1 to atezo + PBC, atezo mono, or placebo + PBC. Coprimary efficacy endpoints were PFS and OS. Planned exploratory biomarker analyses included PD-L1 expression, TMB (FoundationOne), and T-effector GE (RNA-seq). Results: The 851 biomarker-evaluable pts (BEP) were representative of the 1200 ITT pts. Biomarker results are shown in Table. PD-L1 IC2/3 was associated with significantly longer OS for atezo mono vs placebo + PBC and a combination of PD-L1 IC2/3, and high TMB (> 10 muts/Mb) identified a pt subset (≈ 14% of BEP) with particularly favorable outcomes with atezo mono vs placebo + PBC; similar results for PD-L1 and TMB were not seen with atezo + PBC vs placebo + PBC. APOBEC mutagenesis was associated with improved OS with atezo-containing regimens whereas high F-TBRS was associated with inferior OS with atezo mono. Conclusions: These results reinforce the potential predictive nature of biomarkers associated with response/resistance to atezo and highlight potentially distinct biology driving benefit with atezo and atezo + PBC. These findings suggest a possible biomarker-directed approach to 1L mUC tx that warrants mechanistic interrogation and prospective validation. Clinical trial information: NCT02807636.

^aHRs for the BEP are for descriptive purposes only. ^b PD-L1 expression on immune cells (IC; VENTANA SP142 IHC assay) ≥ 5%.