To report the first described case of a patient diagnosed with uterine sarcoma with neurotropic tyrosine kinase (NTRK) rearrangement who developed isolated leptomeningeal progression while on an NTRK inhibitor.

While NTRK fusions represent rare oncogenic drivers (<1% of solid cancers), the recent development & approval of NTRK inhibitors (larotrectinib and entrectinib) has led to dramatic responses in patients with NTRK fusion+ tumors. Both drugs have phase I data demonstrating efficacy in the central nervous system (CNS), including both primary brain tumors and brain metastases.

A 29 year-old woman was diagnosed with NTRK3-SPECC1L fusion+ undifferentiated uterine sarcoma 5 years ago and underwent resection, chemotherapy, and radiotherapy. Two years later, lung metastases were discovered. She was started on larotrectinib with complete response. She remained stable on larotrectinib until she presented with altered mental status and seizures. MRI demonstrated leptomeningeal enhancement, but because leptomeningeal progression from sarcoma is exceedingly rare (occurring in ~0.2% of sarcoma cases) and her symptoms improved dramatically with antiepileptics, these findings were initially attributed to seizures. After two unrevealing lumbar punctures and stable systemic imaging, a brain biopsy demonstrated metastatic sarcoma, still NTRK positive by immunohistochemistry. She underwent whole brain radiotherapy and was switched to entrectinib but had clinical progression one month later and transitioned to hospice.

This case demonstrates the efficacy of NTKR inhibitors in rare and aggressive cancer but highlights that these patients can develop isolated CNS progression even in the setting of CNS-penetrant drugs. CNS progression can occur if there is incomplete CNS drug penetration, discordance in molecular profiles between CNS and systemic disease, or acquired NTRK inhibitor resistance. In this case, the CNS disease maintained NTRK fusion status, but either inadequate CNS penetration or development of a resistance gene may explain the isolated CNS progression.