TPM3–NTRK1 Fusion-Positive Thoracic Sarcoma: Integrated Diagnosis and Drug Repurposing

Abstract Poorly differentiated or unclassifiable sarcomas may harbor targetable molecular alterations, and next-generation sequencing is valuable for an integrated diagnosis. NTRK gene fusions are identified in approximately 1% of sarcomas, and tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors demonstrate superior and durable responses compared with conventional chemotherapy. We present a rare case of an unclassifiable thoracic sarcoma in a young adult male, with poor response to standard chemotherapy and multiple recurrences and a poor response to standard chemotherapy. Although the tumor lacked histopathological features typically associated with NTRK-rearranged spindle cell neoplasms, massively parallel sequencing identified a TPM3-NTRK1 fusion, subsequently confirmed by pan-TRK immunohistochemistry. In the absence of access to first-line TRK inhibitors in India, crizotinib was repurposed, resulting in a RECIST partial response and 5-month progression-free survival. Upon progression, the patient was started on larotrectinib, achieving a durable partial response with a 12-month progression-free interval and near-complete radiological remission. This case highlights the diagnostic and therapeutic utility of molecular profiling in atypical sarcomas, and the potential of drug repurposing, in settings where approved NTRK inhibitors have limited accessibility.