Background
In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1 IgG1 antibody) 1L maintenance + BSC significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC without disease progression with 1L induction chemotherapy in all randomized pts and pts with PD-L1+ tumors. We report exploratory biomarker analyses.
Methods
Tumor biopsies were collected prior to randomization. Tumor analyses included PD-L1 (Ventana SP263 assay) and CD8 immunohistochemistry, whole-exome sequencing (including FCGR2A and FCGR3A genotypes), whole-transcriptome sequencing, and T-cell receptor (TCR) sequencing. Analyses of peripheral blood included baseline C-reactive protein (CRP) level and neutrophil:lymphocyte ratio (NLR) as well as TCR sequencing before and on treatment. Associations between OS or progression-free survival and biomarkers were evaluated using the Cox proportional hazards model. Hazard ratios and nominal p values were reported, and no multiplicity adjustments were made (5% level for statistical significance).
Results
Increased OS benefit with avelumab 1L maintenance + BSC vs BSC alone was positively associated with CD8+ T cells in the invasive margin or tumor center, high tumor mutation burden, and tumor gene expression signatures of innate and adaptive immune response. Increased OS benefit was also positively associated with the number of FCGR2A/FCGR3A alleles encoding high-affinity Fcγ receptors for IgG1. OS benefit with avelumab was negatively associated with tumor epithelial cell gene signatures, mutations affecting fibroblast growth factor receptor signaling, CRP, and NLR. In pts with elevated immune gene expression signatures, lower TGFb expression was associated with greater OS benefit with avelumab. Further analyses will be presented, including outcomes by exploratory PD-L1 cutoffs in tumor vs immune cells.
Conclusions
OS benefits of avelumab 1L maintenance in pts with advanced UC are positively associated with biomarkers of immune activity and negatively associated with biomarkers of tumor homeostasis and chronic inflammation.