Anna F. Farago, MD, PhD, Long P

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Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer Anna F. Farago, MD, PhD, Long P. Le, MD, PhD, Zongli Zheng, PhD, Alona Muzikansky, MA, Alexander Drilon, MD, Manish Patel, MD, Todd M. Bauer, MD, Stephen V. Liu, MD, Sai-Hong I. Ou, MD, PhD, David Jackman, MD, Daniel B. Costa, MD, PhD, Pratik S. Multani, MD, Gary G. Li, PhD, Zachary Hornby, MBA, Edna Chow-Maneval, PhD, David Luo, MPH, Jonathan E. Lim, MD, Anthony J. Iafrate, MD, PhD, Alice T. Shaw, MD, PhD Journal of Thoracic Oncology Volume 10, Issue 12, Pages 1670-1674 (December 2015) DOI: 10.1097/01.JTO.0000473485.38553.f0 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 SQSTM1-NTRK1 fusion transcripts detected by AMP in a NSCLC. (A) Contiguous reads from amplified transcripts mapped to the locations of SQSTM1 on chromosome 5 and NTRK1 on chromosome 1 (red arrowheads). (B) Visualization of subset of sequence read pileup showing fusion reads. The y axis represents read coverage. The x axis represents reference bases and their respective codons below. Shown in gray are read portions corresponding to the randomly ligated universal adapter end with staggered distribution of reads and differing start positions. Shown in blue are read portions corresponding to the anchored end targeted with GSP1 and GSP2. The fusion is in-frame with respect to both transcripts. (C) Schematic drawing of gene fusion involving SQSTM1 and NTRK1. TM, transmembrane domain. Not drawn to scale. (D) FISH confirmation SQSTM1-NTRK1 rearrangement showed individual 3' (red only) probe signals that represent a region downstream of the NTRK1 gene along with normal paired green and red signals that represent non-rearranged alleles. White arrows highlight representative red only signals. Journal of Thoracic Oncology 2015 10, 1670-1674DOI: (10.1097/01.JTO.0000473485.38553.f0) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Partial response to entrectinib. Horizontal (A) and coronal (B) images of the chest at day −7 (baseline scan), day 26 (C, D), and day 155 (E, F) on entrectinib. Journal of Thoracic Oncology 2015 10, 1670-1674DOI: (10.1097/01.JTO.0000473485.38553.f0) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Complete response of brain metastases to entrectinib. (A-C) Baseline head CT scan at day −7 demonstrating metastases (green arrows) in the right thalamus (A), left occipital lobe (B) and left cerebellum (C). (D-I) Restaging head CT scans at day 26 (D-F) and day 155 (G-I) on entrectinib. Journal of Thoracic Oncology 2015 10, 1670-1674DOI: (10.1097/01.JTO.0000473485.38553.f0) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Trk signaling. (A) Schematic diagrams showing wild-type TrkA, TrkB or TrkC protein, top, and showing an oncogenic fusion involving a partner gene that contains a dimerization domain and the kinase domain of TrkA, TrkB or TrkC, bottom. Of note, the fusion shown here includes the transmembrane (TM) domain, though Trk fusion proteins that lack the TM domain have also been described. (B) In the absence of ligand, left, Trk proteins do not dimerize or activate downstream signaling pathways. In the presence of ligand (red circle), Trk proteins dimerize, leading to downstream pathway activation. Double line represents the cell membrane. (C) Fusion oncogenes dimerize in a ligand-independent manner, leading to constituative activation and downstream signaling. Proteins and their domains are not draw to scale. Journal of Thoracic Oncology 2015 10, 1670-1674DOI: (10.1097/01.JTO.0000473485.38553.f0) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions