Off-target resistance to larotrectinib in two patients with NTRK fusion-positive pediatric solid tumors

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions have been identified in various pediatric malignancies. 1 Amatu A. Sartore-Bianchi A. Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016; 1e000023 Abstract Full Text Full Text PDF Scopus (414) Google Scholar Larotrectinib is a highly selective small-molecule inhibitor targeting all three TRK proteins. Although some trials have demonstrated impressive responses to larotrectinib, 2 Drilon A. Laetsch T.W. Kummar S. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018; 378: 731-739 Crossref PubMed Scopus (1788) Google Scholar ,3 Laetsch T.W. DuBois S.G. Mascarenhas L. et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018; 19: 705-714 Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar most cancers develop resistance to it over time. Herein, we report two rare cases of pediatric solid tumors that were resistant to larotrectinib via an off-target mechanism for the first time.