Single-agent immune checkpoint inhibitor therapy in advanced non-small cell lung cancer can significantly prolong progression-free and overall survival when compared with cytotoxic chemotherapy. Here, we report a case of newly diagnosed adenocarcinoma of the lung with a solitary brain metastasis and a biopsy confirmed adenocarcinoma in the tail of the pancreas. Cytomorphology and immunohistochemistry suggested the lung and pancreas tumors were distinct primaries. However, molecular analysis of the lung primary and tumor in the pancreas revealed the same mutations of functional significance in PIK3CA, NF1 and TP53, suggesting the tumors were clonal. A total of three cycles of single-agent pembrolizumab, and radiation to the lung and brain administered between cycles 1 and 2, resulted in marked responses in lung, brain and pancreatic tumors. Despite the discontinuation of the pembrolizumab after three cycles due to severe immune-mediated toxicities, the patient has had no progression 11 months after stopping all active treatment. Results of a novel 27-gene immuno-oncology (IO) expression assay revealed strong IO scores for the lung and pancreatic tumors, indicating a favorable tumor immune-microenvironment and possibly explaining the significant response.