Acquired resistance to entrectinib, an orally available tyrosine kinase inhibitor (TKI) targeting NTRK-fusion-positive and ROS1-positive tumors, appeared to be largely characterized by mutations in the kinase domain of the oncogenic driver, according to a results of a study comparing plasma-based next-generation sequencing (NGS) performed at baseline and following disease progression that were presented at the European Society for Medical Oncology Congress 2019 held in Barcelona, Spain. 

Entrectinib has recently received approval from the US Food and Drug Administration (FDA) for the treatment of adults with ROS1-positive metastatic non-small cell lung cancer (NSCLC), as well as for the treatment of selected patients 12 years of age or older with solid tumors characterized by an NTRK gene fusion.2 

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Despite the broad and substantial clinical activity of this targeted therapy, disease progression will still eventually occur in all patients treated with entrectinib. Hence, an increased understanding of the mechanisms through which disease becomes resistant to entrectinib may improve the clinical management of patients undergoing treatment with this targeted therapy.

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In this study, blood specimens were collected at baseline (ie, pretreatment) and following disease progression on entrectinib (ie, posttreatment) for most patients enrolled in the phase 2, nonrandomized STARTRK-2 clinical trial ( Identifier: NCT02568267), a basket study of patients with solid tumors characterized by gene fusions in NTRK 1/2/3, ROS1, or ALK. Plasma-based NGS was performed on these samples using a 324-gene NGS assay (Foundation Medicine FoundationOne Liquid NGS-based test) of tumor circulating cell-free DNA. 

Matched pretreatment and posttreatment plasma specimens were available for 29 and 18 patients with NTRK-positive and ROS1-positive disease, respectively. 

In the subgroup of patients with disease characterized by an NTRK gene fusion, new mutations affecting the binding of a chemical group on the NTRK TKI to the solvent-exposed area of the NTRK kinase were found in the posttreatment plasma samples of 10 patients (NTRK1 [5 patients]; NTRK3 [5 patients]; 34% of patients). 

In addition, emergence of a BRAF V600E mutation and a KRAS G12D mutation was detected in the posttreatment sample of a patient with NTRK-positive pancreatic cancer who had a partial response to entrectinib. 

For patients with NSCLC characterized by a ROS1 gene fusion (18 patients), acquired ROS1 resistance mutations (G2032R and F2004C/I) were found on posttreatment sequencing, at disease progression. 

Specifically, the following ROS1-based mutations occurred in 5 patients (28%): 4 patients had a CD74-ROS1 fusion and 1 patient had a SLC34A2-ROS1 fusion. Importantly, these mutations were not detected prior to treatment with entrectinib. 

In addition, a new NRAS Q16K mutation was observed in 1 patient who had a partial response to entrectinib. 

In their concluding remarks in the abstract, the study authors wrote that “resistance to entrectinib can occur by multiple mechanisms, which should be studied in larger cohorts.”

Disclosure: F. Hoffman-La Roche funded this study. For a full list if author disclosures, please refer to the original abstract.


  1. Doebele RC, Dziadziusko R, Drilon A, et al. Genomic landscape of entrectinib resistance from ctDNA analysis in STARTRK-2. Presented at: European Society for Medical Oncology (ESMO) Congress 2019; September 27-October 1, 2019: Barcelona, Spain. Abstract LBA28.
  2. Entrectinib (Rozlytrek®) [package insert]. South San Francisco, CA: Genentech, Inc.; 2019.