TRK inhibitor activity and resistance in TRK fusion-positive cancers in adults.

NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.

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Copyright © 2022. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of Competing Interests G.H. declares no competing interests. A.D. declares: HONORARIA/ADVISORY BOARDS: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX; ASSOCIATED RESEARCH PAID TO INSTITUTION: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; ROYALTIES: Wolters Kluwer; OTHER: Merck, Puma, Merus, Boehringer Ingelheim; CME HONORARIA: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis,Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences.