Drugs with companion diagnostics
Drugs relevant to surgical pathology
Larotrectinib (LOXO-101)


Topic Completed: 31 October 2019

Revised: 2 December 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Larotrectinib [title]

Y. Albert Yeh, M.D., Ph.D.
Page views in 2019 to date: 190
Cite this page: Yeh YA. Larotrectinib (LOXO-101). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/drugslarotrectinib.html. Accessed December 10th, 2019.
Definition / general
  • Protein tyrosine kinase inhibitor targeting tropomyosin receptor kinases TRKA, TRKB and TRKC encoded by NTRK1, NTRK2 and NTRK3, respectively (Nat Rev Clin Oncol 2018;15:731)
  • Discovered by Array BioPharma
  • Licensed to Loxo Oncology in 2013
  • Synonyms: LOXO-101, ARRY-470
Trade name
  • Vitrakvi®
Clinical information
  • Approved by U.S. Food and Drug Administration on November 26, 2018 (Drugs 2019;79:201)
  • Indications and usage (Nat Rev Clin Oncol 2018;15:731)
    • Treatment of adult and pediatric patients with NTRK fusion positive cancers
    • Metastatic solid tumors or when surgery would result in severe morbidity
    • No alternative treatments or poor response to other treatments
  • Adverse reaction (N Engl J Med 2018;378:731)
    • General: fatigue, pyrexia, peripheral edema, weight gain
    • Neurotoxicity: delirium, dysarthria, dizziness, gait disturbance, headache
    • Hepatotoxicity: increased ALT and AST
    • Embryofetal toxicity: malformations
    • Cardiovascular: hypertension
    • Respiratory: cough, dyspnea
    • Gastrointestinal: nausea, vomiting, constipation, diarrhea, abdominal pain
    • Musculoskeletal: arthralgia, myalgia
  • Discontinue larotrectinib if adverse reactions persist for 4 weeks
  • Approximate cost: $32,800 per month (oral capsules); $11,000 (liquid oral formulation)
Pathophysiology
  • Neurotrophins bind to TRK receptors
    • NGF specific for TRKA (high affinity)
    • BDNF and NT-4 for TRKB (high affinity)
    • NT-3 for TRKA, TRKB, TRKC (highest affinity for TRKC)
    • p75NTR for TRKA, TRKB, TRKC (low affinity)
  • Binding of neurotrophins to extracellular domain (predominantly Ig2 domain) of TRK
  • Homodimerization of ligand dependent receptors
  • Transactivation of intracellular tyrosine kinase domains
  • Recruitment of various cytoplasmic proteins
  • Activation of the kinase domain by binding of SHC transforming protein (SHC), fibroblast growth factor receptor substrate 2 (FRS2) and phosphoinositide phospholipase CƳ (PLCƳ)
  • The adaptor proteins activate downstream signaling pathways including MAPK, PKC and PI3K signaling pathways
  • The signaling pathways activate gene transcription involved in tumor cell survival, growth and differentiation
  • Reference: Nat Rev Clin Oncol 2018;15:731

(See diagram below)
Diagrams / tables
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TRK biology and
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Larotrectinib chemical
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Uses by pathologists
  • NTRK gene fusions identified in human tumors (Target Oncol 2018;13:545, Cancer Discov 2015;5:25, Mod Pathol 2019;32:147, N Engl J Med 2018;378:731, FDA: Drug Approval Package - Vitrakvi (larotrectinib))

    NTRK1 gene fusion Tumor type
    ARHGEF2-NTRK1 Glioblastoma
    BCAN-NTRK1 Glioblastoma
    CD74-NTRK1 Lung adenocarcinoma
    CHTOP-NTRK1 Glioblastoma
    CTRC-NTRK1 Pancreatic carcinoma
    GON4L-NTRK1 Melanoma
    IRF2BP2-NTRK1 Thyroid carcinoma
    LMNA-NTRK1 Spitzoid neoplasm, colorectal carcinoma,
    congenital infantile fibrosarcoma
    MPRIP-NTRK1 Lung adenocarcinoma
    NFASC-NTRK1 Glioblastoma multiforme
    PDE4DIP-NTRK1 Soft tissue sarcoma
    PLEKHA6-NTRK1 Glioblastoma
    PPL-NTRK1 Papillary thyroid carcinoma
    RABGAP1L-NTRK1 Intrahepatic cholangiocarcinoma
    SQSTM1-NTRK1 Non small cell lung carcinoma
    TFG-NTRK1 (TRKT-3) Papillary thyroid carcinoma
    TPM3-NTRK1 (TRK) Colon adenocarcinoma, papillary
    thyroid carcinoma, pediatric glioma,
    sarcoma, lung adenocarcinoma
    TPR-NTRK1(TRKT-1/2) Papillary thyroid carcinoma
    TP53-NTRK1 Spitzoid neoplasm
    TRIM63-NTRK1 Melanoma


    NTRK2 gene fusion Tumor type
    AFAP1-NTRK2 Low grade glioma
    AGBL4-NTRK2 Pediatric glioma
    NACC2-NTRK2 Astrocytoma
    PAN3-NTRK2 Head and neck squamous cell carcinoma  
    QK1-NTRK2 Astrocytoma
    SQSTM1-NTRK2 Low grade glioma
    STRN-NTRK2 Undifferentiated sarcoma
    TRIM24-NTRK2 Lung adenocarcinoma
    VCL-NTRK2 Pediatric glioma


    NTRK3 gene fusion Tumor type
    BTB1-NTRK3 Pediatric glioma
    ETV6-NTRK3 Acute myeloid leukemia, papillary
    thyroid carcinoma, pediatric
    glioma, secretory breast
    carcinoma, congenital
    mesoblastic nephroma, mammary
    analogue secretory carcinoma
    LYN-NTRK3 Head and neck squamous cell carcinoma  
    RBPMS-NTRK3 Thyroid carcinoma
    TPM4-NTRK3 Sarcoma

  • Pan-TRK immunohistochemical staining (IHC): sensitive (95 - 97%) and specific (98 - 100%) biomarker for detecting NTRK fusions (Am J Surg Pathol 2017;41:1547, Am J Surg Pathol 2018;42:927)
    • Colorectal carcinoma, mammary analogue secretory carcinoma, glioblastoma, melanoma, secretory breast carcinoma, lung adenocarcinoma and sarcoma
    • LMNA-NTRK1 fusions: nuclear membrane accentuation in 5/5 (100%) cases
    • TPM3/4 fusions: cellular membrane accentuation in 4/4 (100%) cases
    • ETV6-NTRK3 fusions: nuclear staining in 3/6 (50%) cases
    • Staining in pediatric mesenchymal tumors: cytoplasmic in NTRK1, NTRK2 rearrangements; nuclear +/- cytoplasmic in NTRK3 rearrangements (Am J Surg Pathol 2018;42:927)
    • Staining in secretory mammary carcinoma: diffuse or at least focally strong nuclear staining (Am J Surg Pathol 2019 Sep 6 [Epub ahead of print])

  • References: J Clin Pathol 2019;72:460, Nat Rev Clin Oncol 2018;15:731
Board review question #1
    Which of the following agents targets TRKA, TRKB and TRKC receptors?

  1. Erlotinib
  2. Trametinib
  3. Larotrectinib
  4. Trastuzumab
Board review answer #1
C. Larotrectinib

Reference: Larotrectinib (LOXO-101)

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Board review question #2
    What type of tumors could be treated by Larotrectinib (LOXO-101)?

  1. NTRK fusion positive tumors
  2. BCR-ABL fusion positive tumors
  3. PD-L1 positive tumors
  4. EGFR mutations positive tumors
Board review answer #2
A. NTRK fusion positive tumors

Reference: Larotrectinib (LOXO-101)

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