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NTRK gene fusions are rare oncogenic driver mutations that can be found in a broad range of neoplasms. In secretory carcinoma (SC), ETV6-NTRK3 gene fusion is seen in a majority of the cases and represents a druggable target for patients with advanced disease in the absence of a currently accepted standard of care. In our case, we describe a patient with recurrent, metastatic SC treated with first line entrectinib with clinically meaningful, durable ongoing response after 49 months. The patient experienced grade 1 fatigue, dysgeusia, skin sensitivity, arthralgias, an increase in serum creatinine, and weight-gain as well as grade 2 hypotension which resolved after a dose reduction. Entrectinib is a well-tolerated treatment with the potential for durable responses and TRK inhibition should be considered the standard of care in SC and other NTRK gene fusion-positive advanced neoplasms without acceptable alternative treatment options. [ABSTRACT FROM AUTHOR]