Larotrectinib followed by selitrectinib in a novel fusion undifferentiated pleomorphic sarcoma.

Introduction: Neurotrophic receptor tyrosine kinase fusions cause overexpression or activation of kinase and are believed to confer oncogenic potential in some non-rhabdomyosarcoma soft tissue sarcomas. TRK inhibitors have recently been shown to induce responses in these tumours though current experience with these agents is still limited.

Case Report: We report a case of an adolescent with treatment-refractory non-rhabdomyosarcoma soft tissue sarcomas, carrying a novel gene fusion whose progressive disease was treated with multi-kinase and TRK inhibitors. Our patient was started on pan-TRK inhibitor larotrectinib, as his disease progressed after chemotherapy, radiation therapy and surgery, based on next-generation sequencing test showing gene fusion. He responded quickly to larotrectinib with the improvement of symptoms and reduction of masses. However, this response was short-lived due to the development of acquired solvent front resistance mutation. This patient did not respond to next-generation TRK inhibitor selitrectinib and eventually succumbed to his disease.

Discussion: The initial rapid and drastic response of our patient to larotrectinib was not sustained due to the development of acquired resistance. This case emphasizes the need for upfront and periodic next-generation sequencing testing to guide treatment of patients with refractory non-rhabdomyosarcoma soft tissue sarcomas.