Gene fusions involving neuregulin 1 ( ) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of fusion-positive pancreatic ductal adenocarcinoma is not fully understood. Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as wild type by whole-genome sequencing. All wild-type tumors were positive for gene fusions involving the ERBB3 ligand . Two of 3 patients with fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. This work adds to a growing body of evidence that gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with wild-type tumors harboring gene fusions may benefit from treatment with afatinib. .