Vitrakvi (larotrectinib)

P2, N=33, Active, not recruiting, Children's Oncology Group | Trial completion date: Mar 2026 --> Jul 2027

Although NTRK-associated fusions are significant in various cancers and have led to the development of targeted therapies, such as larotrectinib and entrectinib, the specific molecular impact of atypical PRUNE2::NTRK2 fusion remains unclear. The PRUNE2::NTRK2 gene fusions described here express a non-functional TrkB protein, and it is unclear whether the PRUNE2 function is intact or affected.

This includes work that led to the FDA approvals of immune checkpoint inhibitors in multiple rare pediatric tumor types, the NTRK inhibitors larotrectinib, entrectinib, and repotrectinib for children and adults with solid tumors with NTRK fusions, the ALK inhibitor crizotinib in children and adults with ALK-positive inflammatory myofibroblastic tumors, and the radioligand LUATHERA for adolescents and adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Despite these advances, the study of rare pediatric cancers faces multiple challenges including a limited number of patients for efficient and well-powered clinical trials and a dearth of financial incentives. Ongoing, coordinated efforts are needed to continue the advancement of novel treatments and improve survival and minimize late effects.

The patient remains stable with no evidence of local, nodal, or metastatic disease for more than three years following the initial presentation. This report aims to propose the use of larotrectinib as a management option for recurrent NTRK-positive cervical sarcomas.

This case represents the first reported instance of ESOS with an NTRK fusion. The rapid and sustained response to larotrectinib highlights the potential of precision medicine in managing rare and aggressive tumors, emphasizing the importance of molecular profiling to identify actionable targets.

The United States Food and Drug Administration (FDA) has approved pembrolizumab for MSI-high tumors or tumors with a high TMB. Larotrectinib and entrectinib have been approved for the treatment of NTRK gene fusion-positive tumors. Additionally, the combination of dabrafenib and trametinib has been approved for BRAF V600E mutations, and selpercatinib has been approved for RET fusion-positive cancers as of 2022. Positive responses to agnostic therapy, a significant milestone in cancer treatment, depend on the identification of new agnostic biomarkers. Ongoing research is focused on defining additional molecular changes, such as programmed death-ligand 1 (PD-L1), Kirsten rat sarcoma virus (KRAS), neuregulin 1 (NRG1), fibroblast growth factor receptor (FGFR), anaplastic lymphoma kinase (ALK), AKT serine/threonine kinase (AKT), human epidermal growth factor receptor 2 (HER2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and breast cancer gene (BRCA), as potential agnostic biomarkers in various cancer types.

P2, N=215, Completed, Bayer | Active, not recruiting --> Completed

P2, N=9, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

P2, N=13, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2025 --> Nov 2027 | Trial primary completion date: Nov 2025 --> Nov 2027

GLP-1 receptor agonists may have a role in improving side effects from larotrectinib. Possible mechanisms for this effect are discussed, with further research needed.

Our study provides new insights into the biology and management of NTRK-rearranged spindle cell tumors, contributing to the expanding evidence supporting the use of TRK inhibitors in these tumors. Further studies are needed to validate our findings and to explore the potential of second-generation TRK inhibitors in overcoming resistance.