Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer

• DOI: 10.6004/jnccn.2017.7029
• Publication Date: 2017-11-08T12:15:20Z
• Authors: Darren Sigal; Marie Tartar; Marin Xavier; Fei Bao; Patrick Foley; David Luo; Jason Christiansen; Zachary Hornby; Edna Chow Maneval; Pratik Multani
• Keywords: Adult; Male; 0301 basic medicine; Clinical Trials as Topic; Indazoles; Oncogene Proteins, Fusion; Biopsy; Palliative Care; High-Throughput Nucleotide Sequencing; Drugs, Investigational; Exons; 3. Good health; Neuroendocrine Tumors; 03 medical and health sciences; Chemotherapy, Adjuvant; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Intestinal Neoplasms; Intestine, Small; Disease Progression; Humans; Neoplasm Grading; Low Back Pain

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.