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Detecting and Targeting NTRK Fusions in Cancer in the Era of Tumor Agnostic Oncology

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Abstract

Gene rearrangements involving the neurotrophic receptor kinase genes NTRK1, NTRK2, and NTRK3 (referred to as TRK, encoding TRKA, TRKB, and TRKC, respectively) result in highly oncogenic fusions. TRK fusions are rare, with a prevalence of < 1% in solid tumors. Detection of TRK fusions can be based on fluorescence in-situ hybridization (FISH), immunohistochemistry (IHC), and next-generation sequencing (NGS), where RNA sequencing is the most sensitive method. Inhibition of TRK fusions with highly selective small-molecule TRK inhibitors (TRKi) such as entrectinib and larotrectinib, results in profound responses in most cancer patients, regardless of cancer histology. Even response in CNS metastases is relatively common. Although responses are often durable, many patients develop resistance to TRKi due to mutations in one of the TRK genes, or due to genetic alterations conferring activation of alternative oncogenic signaling pathways. Second-generation TRKi have been developed, which can overcome some of the TRK resistance mutations. TRKi are well tolerated, with most common adverse events being related to on-target/off-tumor inhibition of TRKs.

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Authors and Affiliations

  1. Department of Oncology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark

    Kristoffer S. Rohrberg & Ulrik Lassen

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  1. Kristoffer S. Rohrberg
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  2. Ulrik Lassen
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Correspondence to Ulrik Lassen.

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Dr. Rohrberg reports grants, non-financial support, and other support from Roche, grants and non-financial support from Loxo Oncology, Bayer, Orion Pharma, Pfizer, PUMA, Cantargia, Genmab, Novartis, Incyte, Symphogen, Astra-Zeneca, Alligator, Merck, Pierre Fabre, and BMS, outside the submitted work. Dr. Lassen reports Advisory Board and honorarium from Bayer, Pfizer, and Novartis Research, and funding from BMS, Roche, Pfizer, and GSK, outside the submitted work.

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KSR and UL contributed equally to this manuscript.

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Rohrberg, K.S., Lassen, U. Detecting and Targeting NTRK Fusions in Cancer in the Era of Tumor Agnostic Oncology. Drugs 81, 445–452 (2021). https://doi.org/10.1007/s40265-020-01459-w

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