Characterization of Ntrkfusions and Therapeutic Response to Ntrk Inhibition in Hematologic Malignancies

Chromosomal rearrangements involving the neurotrophic receptor tyrosine kinases NTRK1-3produce oncogenic fusions in a wide variety of adult and pediatric cancers. Although the frequency of NTRKfusions in most cancers is <5%, efficacy in solid tumors harboring these fusions is striking with a 76% durable response rate recently reported with the highly selective pan-TRK inhibitor larotrectinib (LOXO-101) in a cohort comprised of 17 unique tumor types. By contrast, the frequency of NTRKfusions is not well appreciated in hematologic malignancies and targeting of NTRKfusions has not been clinically tested. Herein, we describe the occurrence of NTRKfusions across >7,000 patients with hematologic malignancies and characterize their signal transduction, transforming properties, and response to larotrectinib in vitroand in an AML patient and corresponding patient-derived xenograft (PDX) in vivo.