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Objectives: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort., Materials and Methods: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022., Results: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported., Conclusion: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Byoung Chul Cho: Received research funding from MOGAM, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer-Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Eli Lilly, MSD, Novartis, Nuvalent, Oncternal Therapeutics, Ono Pharmaceutical, Dong-A ST, Bridge Biotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS Bio, Hanmi Pharm, and CHA Bundang Medical Center. Royalties from Champions Oncology, Crown Bioscience, and Imagen. Consulting role for Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CJ, Celogen, Cyrus, Ono Pharmaceutical, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI Cell, Guardant Health, HK inno.N, Imnewrun, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines, RandBio, and Hanmi Pharm. Invited speaker for ASCO, AstraZeneca, Guardant Health, F. Hoffmann-La Roche Ltd, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer. Advisory role for Kanaph Therapeutics, Bridge Biotherapeutics, Cyrus, Guardant Health, and Oscotec. Member of the board of directors for Interpark Bio Convergence Corp and J INTS Bio. Stock ownership for TheraCanVac, Gencurix, Bridge Biotherapeutics, Kanaph Therapeutics, Cyrus, Interpark Bio Convergence Corp, and J INTS Bio. Employment with Yonsei University Health System. Founder of DAAN Biotherapeutics. Chao-Hua Chiu: Received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen, Merck KGaA, MSD, Novartis, Ono Pharmaceutical, Pfizer, F. Hoffmann-La Roche Ltd, and Takeda. Erminia Massarelli: Advisory board for Janssen, Eli Lilly, Bristol Myers Squibb, Sanofi, and Merck. Speaker’s bureau for Eli Lilly, Merck, and AstraZeneca. Gary L. Buchschacher Jr: Institutional research support from F. Hoffmann-La Roche Ltd/Genentech. Koichi Goto: Received research grants from Amgen, Astellas, AstraZeneca, Bayer Yakuhin Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Craif, Daiichi Sankyo, Eisai, Eli Lilly, Haihe Biopharma, Ignyta, Janssen Pharmaceutical, Kissei Pharmaceutical, Kyowa Kirin, Life Technologies, Loxo Oncology, LSI Medience Corporation, Medical & Biological Laboratories, Merck, Merus, MSD, Novartis, Ono Pharmaceutical Co, Pfizer, Precision Medicine, Riken Genesis Co, Sumitomo Pharma, Spectrum Pharmaceuticals, Sysmex Corporation, Taiho Pharmaceutical, Takeda, Xcoo, and Turning Point Therapeutics. Invited speaker for Amgen, Amoy Diagnostics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Bayer Yakuhin, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Guardant Health, Janssen, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Riken Genesis Co, Taiho Pharmaceutical, and Takeda. Advisory board for Amgen, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Janssen, and Syneos Health. Tobias R. Overbeck: Received payment or honoraria for lectures/presentations, speakers bureau, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche Pharma, Merck Sharp and Dohme, Novartis, and Takeda Oncology; support for attending meetings and/or travel from AstraZeneca and Janssen-Cilag; participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche Pharma, Merck Sharp and Dohme, Novartis, and Takeda Oncology. Herbert H.F. Loong: Received research grants from MSD, Mundipharma, and Novartis. Invited speaker for AbbVie, Bayer, Eisai, Eli Lilly, Guardant Health, and Novartis. Travel support from Bayer and Boehringer Ingelheim. Advisory role for Boehringer Ingelheim, Celgene, Eli Lilly, Illumina, Novartis, Merck, EMD Serono, Takeda, and George Clinical. Member, Pharmacy and Poisons (Registration of Pharmaceutical products and substances: Certification of clinical trial/medicinal test) Committee, Pharmacy & Poisons Board of Hong Kong. Cheng E. Chee: Received honoraria fees from AstraZeneca and has participated on a Data Safety Monitoring Board or Advisory Board for Guardant Health AMEA, Merck, and Roche/Genentech. Pilar Garrido: Invited speaker for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, MSD, Medscape, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Takeda, and TouchIME. Advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Eli Lilly, MSD, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, and Takeda. Xiaorong Dong: no disclosures. Yun Fan: no disclosures. Shun Lu: Research grants from AstraZeneca, Hutchinson, Bristol Myers Squibb, Hengrui Medicine, BeiGene, F. Hoffmann-La Roche Ltd, and Hansoh Pharmaceutical. Speaker fees from AstraZeneca, F. Hoffmann-La Roche Ltd, and Hansoh Pharmaceutical. Advisory and consulting fees from AstraZeneca, Pfizer, Hutchinson, Zai Lab, GenomiCare, Novartis, Yuhan, Menarini, Mirati Therapeutics, Inc, Daiichi Sankyo, D3 Bio, Simcere, Takeda, and F. Hoffmann-La Roche Ltd. Sven Schwemmers: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Owns stocks/share with F. Hoffmann-La Roche Ltd. Walter Bordogna: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Owns stocks/share with F. Hoffmann-La Roche Ltd. Harald Zeuner: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Stuart Osborne: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Owns stocks/share with F. Hoffmann-La Roche Ltd. Thomas John: Invited speaker for F. Hoffmann-La Roche Ltd and AstraZeneca. Advisory role for Bristol Myers Squibb, AstraZeneca, Amgen, F. Hoffmann-La Roche Ltd, Pfizer, Takeda, Boehringer Ingelheim, MSD, Merck, Puma, Specialised Therapeutics, Gilead, and Seagen., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of ∼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)