Axitinib plus Avelumab in Recurrent/Metastatic Adenoid Cystic Carcinoma: Biomarker Analysis and Updated Results of the Phase II Trial

PURPOSE: The phase II axitinib plus avelumab trial in recurrent/metastatic adenoid cystic carcinoma (ACC) demonstrated favorable response rates and progression-free survival (PFS), leading to its inclusion in NCCN guidelines as the first immunotherapy-based option for ACC. We sought to identify biomarkers predictive of clinical benefit from axitinib plus avelumab. EXPERIMENTAL METHODS: Twenty-eight patients with ACC enrolled. Pre-treatment tumors underwent whole exome sequencing, transcriptome profiling, imaging mass cytometry, and tumor, oral rinse and stool microbiome characterization using 16s rRNA gene sequencing. Associations with PFS were assessed using Cox proportional hazards model, incorporating ACC subtype (ACC-I vs. ACC-II) as a covariate. RESULTS: ACC comprises two proteogenomically distinct subtypes: aggressive, NOTCH1-activated ACC-I and more indolent ACC-II. Here, median PFS was 1.8 months for ACC-I versus 11.4 months for ACC-II (HR, 0.14; P<0.0001), representing the first demonstration of subtype-specific clinical trial outcomes in ACC. Clinical benefit was not associated with PD-L1 expression, tumor mutational burden, or recurrent genomic mutations. Instead, improved PFS correlated with the presence of intratumoral Escherichia and gut Bifidobacterium and Akkermansia. Transcriptomic profiling identified a 167-gene immune-enriched signature predictive of PFS benefit with axitinib plus avelumab. This signature also predicted benefit from ipilimumab plus nivolumab, but not from regorafenib monotherapy, suggesting its specificity for immunotherapy-based combinations. CONCLUSIONS: Clinical trial outcomes with axitinib plus avelumab differ significantly by ACC subtype. Furthermore, the identified 167-gene immune-related signature predicts clinical benefit to immunotherapy-based combinations in ACC. These findings provide a framework for future biomarker-driven trial design and patient stratification strategies for this rare malignancy.