TRK Inhibitors in NTRK-Fusion Sarcomas: A Comprehensive Review of Current Evidence and Emerging Therapies

NTRK gene fusions are rare but highly actionable oncogenic drivers, and their detection has become clinically mandatory since selective TRK inhibitors entered practice. Larotrectinib and entrectinib were approved on histology-independent evidence from pan-tumour trials, yet whether that benefit extends uniformly to sarcomas, a heterogeneous group in which registrational enrolment was small, remains incompletely defined. This review synthesises the molecular pharmacology of TRK fusion oncoproteins, the clinical evidence for approved and investigational inhibitors, the mechanisms of acquired resistance, and the diagnostic strategies available for fusion detection, with emphasis on mesenchymal tumours. Activity in sarcomas is strongly subtype-dependent: the objective response rate was 94% in newly diagnosed infantile fibrosarcoma, where neoadjuvant treatment can convert unresectable disease to resectable and avoid mutilating surgery, but 58% (95% CI, 41–74) amongst 36 adults with TRK fusion sarcomas, in whom the median duration of response was not reliably estimable. Acquired resistance arises predominantly through secondary kinase domain substitutions (solvent front, gatekeeper and xDFG) that next-generation macrocyclic inhibitors were designed to overcome, whereas bypass pathway activation calls instead for mechanism-directed combinations. Optimised pan-TRK immunohistochemistry raises screening sensitivity to 94.36%, addressing the principal barrier to case identification, although positive results still require molecular confirmation and the distinction between fusion and amplification must be maintained. Because the sarcoma-specific evidence rests on single-arm studies and small series, standardised testing algorithms, prospective registries and equitable access to next-generation agents remain the principal unmet needs.