Infantile Fibrosarcoma With NTRK3–ETV6 Fusion Successfully Treated With the Tropomyosin‐Related Kinase Inhibitor LOXO‐101

Abstract

Infantile fibrosarcoma (IFS) is a rare pediatric cancer typically presenting in the first 2 years of life. Surgical resection is usually curative and chemotherapy is active against gross residual disease. However, when recurrences occur, therapeutic options are limited. We report a case of refractory IFS with constitutive activation of the tropomyosin‐related kinase (TRK) signaling pathway from an ETS variant gene 6–neurotrophin 3 receptor gene (ETV6–NTRK3) gene fusion. The patient enrolled in a pediatric Phase 1 trial of LOXO‐101, an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO‐101 to provide benefit for IFS harboring NTRK gene fusions.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors

“…The second patient was a 2-year-old girl with an ETV6-NTRK3 fusion-positive recurrent infantile fibrosarcoma of the right neck and base of skull who had progressed despite numerous attempted surgical resections and multiple lines of combination chemotherapy. A greater than 90% tumor regression was achieved in response to larotrectinib (18), followed by progression after 8 months, upon which repeat biopsy revealed an acquired TRKC G623Rmutation.…”

Successful Targeted Therapy of Refractory Pediatric ETV6-NTRK3 Fusion-Positive Secretory Breast Carcinoma

“…14 Substantial tumor regressions with larotrectinib have been reported in a child with congenital fibrosarcoma bearing the ETV6-NTRK3 fusion, as well as an adult with a soft tissue sarcoma harboring an LMNA-NTRK1 fusion. 15,16 Preliminary activity has also been described in multiple other NTRK fusion-positive cancer types with larotrectinib. 17 In July 2016, the FDA granted breakthrough designation to larotrectinib for the treatment of unresectable or metastatic solid tumors bearing NTRK fusions.…”

ETV6–NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study

“…Furthermore, ETV6–NTRK3 fusion kinase is an actionable molecular target for TRK‐inhibitors (e.g., LOXO‐101). These inhibitors show high response rates in adult as well as in pediatric cancer; an inhibitory effect has also been shown in infantile fibrosarcoma, the soft tissue counterpart of cellular MN . Hence, it could potentially be of use in translocation‐positive MN in case of inoperability.…”