Tumor Boards

NTRK3 Fusion

  • Our patient with underlying Neurofibromatosis type 1 (NF1) and a history of MPNST treated with adjuvant chemotherapy and radiation, presented ten years later with recurrent left pelvic disease.
  • MPNSTs are a heterogeneous and highly aggressive subtype of soft tissue sarcoma (STS), often lacking effective treatment options outside of surgical intervention.
    • Due to the rarity of MPNST, there have been no phase II or III trials evaluating chemotherapy sensitivity for this subtype. Historically, standard metastatic STS regimens have been used including doxorubicin and ifosfamide.
  • NF1-associated MPNSTs, as seen in this patient, have poorer prognosis with a 5-year disease-free survival rate of 34-60%.
    • NF1 is an autosomal pathogenic variant that results in reduced activity of the protein neurofibromin, a tumor suppressor, and occurs in approximately 10% of patients.
      • MEK (mitogen-activated protein kinase) and mTOR inhibitors are being investigated in clinical trials in patients with loss or inactivation of NF1.
  • The patient was found to have disease progression and declining health after treatment with both left hemipelvis marginal tumor resection and 3 cycles of chemotherapy.
  • Biomarker studies were performed and revealed neurotrophic tyrosine kinase 3 (NTRK3) fusion.
    • NTRKs are a family of receptors known to be involved in the development, differentiation, and metabolism of neural and other tissues and are found at high frequencies in rare cancer types.
  • She was not a candidate for a high risk hemipelvectomy therefore targeted treatment was pursued.
    • The 1st generation tyrosine kinase inhibitor, larotrectinib, has previously demonstrated response in both adult and pediatric NTRK fusion-positive cancers.
    • Of the two 1st generation TK inhibitors (larotrectinib and entrectinib), larotrectinib is a more specific TRK inhibitor that has shown potency and selectivity in its inhibition of all three NTRK proteins.
  • Larotrectinib has been tested in three phase I and II adult and adolescent clinical trials, with initial analysis estimating a median time to response of 1.8 months, an overall response rate of 75% and a complete response of 13%. Fifty-five percent of patients remained progression-free after 1 year of treatment.
    • NTRK3 fusions are rare in sarcomas and thus their prognostic significance is difficult to assess currently. However, there has been some success eliciting a response in infantile fibrosarcoma and other soft tissue sarcomas (24/27 patients).
  • Unfortunately, our patient had aggressive disease recurring swiftly after surgical resection and refractory to chemotherapy and targeted therapy with larotrectinib. She succumbed to her disease merely eight months after diagnosis.