Background: ACC is a heterogeneous malignancy with no standard treatment for patients (pts) with R/M disease. Two distinct ACC subtypes have been identified proteogenomically, which contribute to ACC’s biological variability. ACC-I is enriched with NOTCH activating mutations and MYC overexpression and has a poor prognosis (median survival [mOS] = 3.4 years). ACC-II has upregulation of TP63 and presents with an indolent disease course (mOS = 23.2 years). In a phase II trial of axitinib (VEGFR inhibitor) plus avelumab (PD-L1 inhibitor) in R/M ACC, clinical benefit was heterogenous. We hypothesized that ACC subtype and gene expression profile are associated with benefit to axitinib plus avelumab. Methods: Cohort of 28 R/M ACC pts with radiological or clinical progression within 6 months (mos) of enrollment in the axitinib plus avelumab trial (NCT03990571). Target transcriptome profile including 19,616 probes was generated using HTG Transcriptome Panel [HTP]. Gene expression was used to identify ACC subtypes (ACC-I vs. ACC-II). Confirmed overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1 was assessed for each ACC subtype. An analysis of genes associated with benefit vs. no benefit from axitinib plus avelumab was conducted for the overall population and per ACC subtype. Benefit was defined as disease control (partial response [PR] or stable disease [SD]) and PFS longer than the median PFS. PFS > 6 mos was not used to define benefit due to the significant differences in PFS between ACC subtypes. Results: Out of 28 pts, 14 (50%) were classified as ACC-I and 14 (50%) were ACC-II. For ACC-I, ORR was 14.3% (2/14; 95%CI: 1.8-42.8%), DCR was 35.7% (2 PR + 3 SD; 95%CI: 12.8-64.9%) and median PFS was 1.86 mos (95%CI: 1.81-8.61 mos). For ACC-II, ORR was 21.4% (3/14; 95%CI: 4.7-50.8%), DCR was 100% (3 PR + 11 SD; 95%CI: 76.8-100%) and median PFS was 10.5 mos (95%CI: 7.40-NA). PFS was significantly longer for ACC-II vs. ACC-I (HR 0.19 [95%CI: 0.08 – 0.49], p = 0.0002). Through the previously defined benefit vs. no benefit cutoff, ACC-I had a 42.9% (6/14) and ACC-II had a 50.0% (7/14) benefit rate. Benefit in all ACC pts, ACC-I and ACC-II was associated with high expression of immune-related genes, especially B and T-lymphocyte function. Angiogenesis-related genes were not significantly upregulated in the benefit group as previously reported in renal cell carcinoma pts treated with the same combination. Conclusions: Clinical outcomes to axitinib plus avelumab were distinct between ACC-I and ACC-II subtypes, with ACC-II pts demonstrating an improved DCR and significantly longer PFS. Gene expression analysis revealed high expression of immune function-related genes in patients who benefited from axitinib plus avelumab in both ACC subtypes, indicating possible biomarkers predictive of benefit from the combination in ACC. Clinical trial information: NCT03990571.