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Background: Patients with infantile fibrosarcoma (IFS) have shown strong and long-lasting responses to larotrectinib, a tropomyosin receptor kinase inhibitor (TRKi), in single-arm clinical trials. Conventional chemotherapy has also shown important efficacy. But, until now, no comparative data exist. This study aims to assess the therapeutic benefit of larotrectinib over the current standard of care (SOC) of chemotherapy in paediatric patients with locally advanced or metastatic IFS., Patients and Methods: EPI VITRAKVI is a retrospective, observational, externally controlled study (NCT05236257). Data of patients aged ≤21 years with locally advanced or metastatic IFS treated with larotrectinib in the phase I/II SCOUT trial (NCT02637687) were compared with those of an external historical control group (data of Institut Curie and Cooperative Weichteilsarkom Studiengruppe) treated with a chemotherapy-based regimen. Between-group differences were assessed after balancing groups using inverse probability of treatment weighting (IPTW)., Results: In total, 93 patients were compared, 51 in the larotrectinib arm and 42 in the external control arm. After therapy, 4 patients (7.8%) in the larotrectinib group had a medical treatment failure event [start of new systemic treatment (2 cases), mutilating surgery (2 cases)] versus 15 (35.7%) in the external control group [start of new systemic treatment (6 cases), mutilating surgery (5 cases), radiation therapy (2 cases), and death (2 cases)]. Larotrectinib was associated with an 80% reduced likelihood of encountering a medical treatment failure event, when compared to the external control group (weighted and stratified hazard ratio 0.20, 95% confidence interval 0.06-0.63, P = 0.0060). These results were confirmed by sensitivity analyses, including exact matching, and subgroup analyses for number of lines of treatment., Conclusions: Treatment with larotrectinib reduced the need of subsequent therapies compared to SOC with chemotherapy in children with locally advanced or metastatic IFS, regardless of the line of treatment., Competing Interests: Disclosure SKK, MF, and MK are Bayer employees. DO had a consultant activity for Bayer and Roche and is an Independent Data Monitoring Committee (IDMC) member for a Lilly product and is a consultant for Novartis Pharma France and Eusapharm. MC had a consultant activity for Bayer. MSS had advisory activity for Bayer, Roche, and Sobi. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This case report reviews the case of a 13-year-old patient who presented with a 9 cm NTRK1-rearranged cervical sarcoma with fibrosarcoma like morphology. At presentation the lesion filled her vagina and pelvis and any attempt at surgical removal would have been morbid and led to loss of fertility. These neoplasms are extremely rare with 18 cases of the uterine cervix reported in the literature, none of which have occurred in a paediatric patient, and none of whom have received neo-adjuvant therapy prior to excision. Based upon evidence that has shown good tolerability and responses of paediatric NTRK fusion-positive solid tumours to TRK inhibitors, both in the neo-adjuvant and upfront setting, this patient was managed with neo-adjuvant entrectinib. Following a dramatic reduction in tumour size confirmed by imaging, she underwent conservative fertility sparing surgery with final histopathology showing no residual disease.

Background: Apart for infantile fibrosarcoma (IFS), very little is known about NTRK-rearranged mesenchymal tumors (NMTs). The objective of this study is to describe the distribution, characteristics, natural history, and prognosis of NMT., Patients and Methods: This study was carried out as a translational research program, retrospectively from a cohort of 500 soft tissue sarcoma (STS; excluding IFS) and prospectively both in routine practice and from the RNASARC molecular screening program (N = 188; NCT03375437)., Results: Using RNA-sequencing, NTRK fusion was detected in 16 patient tumors diagnosed as STS: 8 samples of sarcoma with simple genomics (4 NTRK-rearranged spindle cell neoplasm, 3 ALK/ROS wild-type inflammatory myofibroblastic tumor, and 1 quadruple Wild-type gastrointestinal stromal tumor) and 8 samples of sarcomas with complex genomics (dedifferentiated liposarcoma, intimal sarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma, high-grade uterine sarcoma, malignant peripheral nerve sheath tumor). Among the eight patients with simple genomics, four were treated with tyrosine receptor kinase inhibitor (TRKi) at different stages of the disease and all benefited from the treatment, including one complete response. Among the eight other patients, six evolved with metastatic spreading and the median metastatic survival was 21.9 months, as classically reported in these tumor types. Two of them received a first-generation TRKi without objective response., Conclusions: Our study confirms low frequency and histotype diversity of NTRK fusion in STS. While the activity of TRKi in simple genomics NMT is confirmed, our clinical data encourage subsequent studies focusing on the biological relevance of NTRK fusions in sarcomas with complex genomics together with the efficacy of TRKi in this population., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)