Response and resistance to first and second generation TRK inhibitors in an NTRK1-driven sarcoma

We report here a patient with a TPM3-NTRK1 translocated sarcoma who developed resistance to larotrectenib arising from the p.G595R solvent-front substitution. The patient was treated with LOXO-195 with initial response followed by subsequent resistance. Molecular profiling of the resistant tumor identified a KRAS p.G12V substitution, with associated activation of KRAS signaling and immune infiltration into the tumor. Following cytoreductive surgery to remove the resistant lesion, the patient’s disease has continued to respond to LOXO-195. RNA-seq from NTRK-translocated sarcoma tumors, xenografts and cell line