Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer Journal Article

Authors: Farago, A. F.; Le, L. P.; Zheng, Z.; Muzikansky, A.; Drilon, A.; Patel, M.; Bauer, T. M.; Liu, S. V.; Ou, S. H. I.; Jackman, D.; Costa, D. B.; Multani, P. S.; Li, G. G.; Hornby, Z.; Chow-Maneval, E.; Luo, D.; Lim, J. E.; Iafrate, A. J.; Shaw, A. T.
Article Title: Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer
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. © 2015 by the International Association for the Study of Lung Cancer.
Keywords: adult; treatment response; middle aged; unclassified drug; major clinical study; exon; drug tolerability; fatigue; paresthesia; advanced cancer; drug safety; cancer staging; carboplatin; computer assisted tomography; tumor volume; cohort analysis; gene frequency; cancer pain; protein tyrosine kinase; docetaxel; drug dose escalation; dyspnea; lung adenocarcinoma; brain metastasis; chromosome rearrangement; pleura effusion; navelbine; pemetrexed; brain derived neurotrophic factor receptor; non small cell lung cancer; phase 2 clinical trial (topic); phase 1 clinical trial (topic); multiplex polymerase chain reaction; human; male; priority journal; article; pembrolizumab; entrectinib; neurotrophic tyrosine kinase 1
Journal Title: Journal of Thoracic Oncology
Volume: 10
Issue: 12
ISSN: 1556-0864
Publisher: Elsevier Inc.  
Date Published: 2015-12-01
Start Page: 1670
End Page: 1674
Language: English
DOI: 10.1097/01.JTO.0000473485.38553.f0
PROVIDER: scopus
PMCID: PMC4643748
PUBMED: 26565381
Notes: Article -- Export Date: 7 January 2016 -- 1670 -- Source: Scopus
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MSK Authors
  1. Alexander Edward Drilon
    198 Drilon