Background: The phase 3 JAVELIN Renal 101 trial in previously untreated patients (pts) with aRCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate with A+Ax vs S (Motzer, ESMO 2018; LBA6_PR). Here, we report outcomes from biomarker analyses of baseline tumor samples. Methods: We correlated efficacy with the results of molecular analyses of tissue samples from all 886 pts enrolled in JAVELIN Renal 101. Nephrectomy or tumor samples were characterized by immunohistochemistry (CD8 and PD-L1), whole-exome sequencing (WES), and RNAseq. WES and RNAseq were used to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcomes. GES analyses included published and de novo signatures: effector T cell (T_eff), angiogenesis (angio),T cell-inflamed (T_inf), and a novel immune-related signature incorporating pathway indicators for T- and NK-cell activation and IFNγ signaling, among others. Results: PD-L1 expression (≥1% immune cells) was associated with the longest PFS in the A+Ax arm and the shortest in the S arm (HR, 0.63; 95% CI, 0.49, 0.81). Significant treatment arm–specific differences in PFS were observed relative to wildtype when mutations in genes such as CD1631L, PTEN, or DNMT1 were present. Tumor mutational burden did not distinguish pts with respect to PFS. High-angio GES was associated with significantly improved PFS in the S arm but did not differentiate PFS in the A+Ax arm. In the low-angio subset, A+Ax improved PFS vs S. Pts with high T_eff and T_inf in the A+Ax arm had longer PFS vs the S arm. In the A+Ax arm, PFS was enhanced in patients with immune GES–positive tumors vs those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p = 0.004), as well as in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p = 0.064). Updated efficacy, including overall survival, will be presented. Conclusions: These findings define molecular features that differentiate therapy-specific outcomes in first-line aRCC and may inform personalized therapy strategies for pts with aRCC. Funding: Pfizer and Merck KGaA. Clinical trial information: NCT02684006