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J Thorac Oncol. 2015 Dec;10(12):1670-4. doi: 10.1097/01.JTO.0000473485.38553.f0.

Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.

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1
*Department of Medicine, Massachusetts General Hospital, Boston, MA; †Department of Pathology, Massachusetts General Hospital, Boston, MA; ‡Memorial Sloan Kettering Cancer Center, New York, NY; ‖Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; §Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; ¶Department of Medicine, Georgetown University Medical Center, Washington, DC; #University of California Irving Health, Orange, CA; **Dana-Farber Cancer Institute, Boston, MA; ††Beth Israel Deaconess Medical Center, Boston, MA; and ‡‡Ignyta, Inc., San Diego, CA.

Abstract

INTRODUCTION:

Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.

METHODS:

We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.

RESULTS:

We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.

CONCLUSIONS:

Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

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