This study aimed to evaluate a novel methodology to identify subjects that could derive benefit from Buparlisib treatment in metastatic SCCHN patients. The analysis was focused on image analysis of H&E images to select features associated with improved clinical benefit from paclitaxel+buparlisib. BERIL-1 (NCT01852292) was a multicenter, randomized, double-blind, placebo-controlled phase II study evaluating treatment with either buparlisib + paclitaxel or placebo + paclitaxel in adult patients with histologically or cytologically confirmed recurrent or metastatic SCCHN. H&E stained whole slide images (WSI) were scanned at 40x and a model was developed to identify features of the tumor and the tumor immune microenvironment through digital pathology. We then evaluated spatial histological biomarkers from 145 subjects (73 in treatment & 72 in placebo arms) associated with improvement in efficacy endpoints of Progression Free Survival (PFS) and Overall Survival (OS) within and between the treatment and control arms. A deep learning model was developed that can accurately identify and classify tumor, necrotic and stromal areas as well as fibroblast, endothelial and immune cells (plasma, lymphocyte, granulocyte), from H&E images. The accuracy of this model was developed against the ground truth of human pathology analysis of the same images. This analysis demonstrated that a >10% infiltration of TILs (p=0.00058, HR=0.195) as well the heterogeneity of cells in the TME (p=0.015, HR=0.53) are both associated with a survival advantage in patients receiving the combination treatment when compared to placebo. Moreover, we discovered that the proximity of granulocytes to tumor cells (p=0.00006, HR=0.32) is associated with improved survival in patients treated with buparlisib + paclitaxel combination therapy. This analysis highlights a novel approach, utilizing the common and cost-effective biomarker of H&E to identify metastatic SCCHN subjects that could derive therapeutic benefit from the combination of Buparlisib + paclitaxel. Further analysis will be conducted to determine if this method provides a better prediction of clinical benefit than regular pathology evaluation. This approach also highlights interesting and novel biological observations that underscore the mechanisms of this therapeutic combination that could lead to studies evaluating novel therapeutic combinations. The results of this analysis can be expanded to the ongoing Phase III BURAN study to further optimize and validate this method of identifying subjects for therapeutic intervention; providing a fast and cost effective method for clinicians to understand which subject would benefit from treatment with Buparlisib.