Adenoid Cystic Carcinoma (ACC), the 2nd most common salivary gland tumor, is chemotherapy-refractory and there is no standard of care treatment for patients with recurrent/metastatic (R/M) disease, highlighting a major clinical unmet need. Vascular endothelial growth factor receptor (VEGFR) inhibitors are frequently used to treat ACC, but render mostly disease stabilization. ACC is also resistant to single agent immune checkpoint inhibitors (ICI), consistent with its low tumor mutational burden (TMB) and overall uninflamed tumor immune microenvironment (TIME). To test if the immunomodulatory role of anti-VEGFR therapy can enhance ICI efficacy and overcome resistance to VEGFR inhibitor monotherapy, we are conducting an investigator-initiated phase II trial, where progressing R/M ACC patients receive axitinib (a VEGFR tyrosine kinase inhibitor) and avelumab (anti-PD-L1 antibody). Study accrual has recently completed with 28 patients evaluable for the efficacy analysis. Interim results revealed an overall response rate of 18% (5/28) per RECIST 1.1, which is superior over VEGFR or ICI monotherapy, and a clinical benefit rate, defined as objective response or disease stability > 6 months, of 50%. Recently, we have conducted a comprehensive proteogenomic analysis of 54 ACC which revealed two distinct subtypes ACC-I and ACC-II. ACC-I is enriched with NOTCH1 activating mutations and MYC overexpression and is associated with poor prognosis while ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases and longer patient survival. Thus far, IHC tumor staining for P63/MYC is available for 22 of 28 trial patients; 12 are ACC-I and 10 are ACC-II demonstrating significant representation of both ACC molecular subtypes. Computational analysis of RNA-seq data of our published cohort with 54 ACC suggested that the ACC-I subtype has a distinct TIME with increased CD8 T cells, along with upregulation of immune suppressive markers. On the basis of our intriguing data, we hypothesize 1) genomic heterogeneity is associated with differential responses to axitinib/avelumab in R/M ACC, and 2) distinct ACC immune landscape and T cell attributes are associated with the clinical outcomes of patients treated with axitinib/avelumab. We will test these hypotheses leveraging the unique tumor tissue and blood from our trial with two aims: 1) Identify genetic determinants of clinical benefit to axitinib and avelumab in ACC. Using the baseline tumors (n=28), we will conduct whole exome sequencing (seq) and RNA-seq and assess if any specific gene alterations, TMB or gene expression profile are associated with benefit. 2) Assess stroma and immunologic determinants of clinical benefit to axitinib and avelumab in ACC. We will examine ACC TIME composition using imaging mass cytometry and determine if the composition of the TIME correlates with clinical benefit. We will also assess tumor-associated T-cell attributes via baseline tumors TCR-seq and circulated T-cell attributes ...