1. Academic Validation
  2. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101

An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101

  • Cancer Discov. 2015 Oct;5(10):1049-57. doi: 10.1158/2159-8290.CD-15-0443.
Robert C Doebele 1 Lara E Davis 2 Aria Vaishnavi 3 Anh T Le 3 Adriana Estrada-Bernal 3 Stephen Keysar 3 Antonio Jimeno 3 Marileila Varella-Garcia 3 Dara L Aisner 3 Yali Li 4 Philip J Stephens 4 Deborah Morosini 4 Brian B Tuch 5 Michele Fernandes 5 Nisha Nanda 5 Jennifer A Low 5
Affiliations

Affiliations

  • 1 University of Colorado Cancer Center, Aurora, Colorado. robert.doebele@ucdenver.edu.
  • 2 Oregon Health and Science University Knight Cancer Institute, Portland, Oregon.
  • 3 University of Colorado Cancer Center, Aurora, Colorado.
  • 4 Foundation Medicine, Cambridge, Massachusetts.
  • 5 Loxo Oncology, South San Francisco, California.
Abstract

Oncogenic Trk fusions induce Cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These Trk fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the Trk kinase and is highly selective only for the Trk family of receptors. Preclinical models of LOXO-101 using TRK-fusion-bearing human-derived Cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers.

Significance: Trk fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective Trk Inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting Trk fusions.

Figures
Products