Neoadjuvant TRK inhibitors versus chemotherapy in advanced NTRK fusion-positive sarcomas: a real-world evidence analysis.
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IMPORTANCE: Despite the proven efficacy of tropomyosin receptor kinase (TRK) inhibitors in advanced neurotrophic tyrosine receptor kinase (NTRK) fusion-positive sarcomas, chemotherapy remains the default first-line therapy in many developing countries. OBJECTIVE: This real-world study directly compares outcomes of TRK inhibitors with chemotherapy. DESIGN: This was a multicenter, retrospective cohort study. SETTING: 50 children with advanced NTRK fusion-positive sarcomas were analyzed from three study centers (2018-2024). INTERVENTION: Patients were assigned into two groups according to their choice of treatment,including chemotherapy or TRK inhibitors.. MAIN OUTCOMES AND MEASURES: Endpoints included treatment failure rate, objective response rate (ORR), mutilating surgery, time to treatment failure, and event-free survival (EFS). Subgroup analyses were conducted for infantile fibrosarcoma (IFS) and NTRK-rearranged spindle cell tumors. RESULTS: The efficacy of TRK inhibitors (n = 37) was markedly superior compared to chemotherapy (n = 13). Treatment failure was almost eliminated (2.7% vs. 61.5%, P < 0.001), and ORR was significantly higher (91.9% vs. 53.8%, P = 0.006). Subgroup analysis revealed that TRK inhibitors prevented mutilating surgery in IFS (0.0% vs. 42.9%, P < 0.001) and improved the ORR in NTRK-rearranged spindle-cell tumors (95.0% vs. 0.0%, P < 0.001) in which chemotherapy was ineffective. TRK inhibition also induced faster tumor shrinkage, smaller preoperative burden, and 40% pathological complete responses. Finally, TRK inhibitor also prolonged the time-to-treatment failure and EFS. CONCLUSIONS AND RELEVANCE: Upfront TRK inhibition provided faster, deeper responses, avoided mutilating surgeries, and enabled curative resections. These findings support TRK inhibitors as the preferred first-line option for children with NTRK fusion-positive sarcomas.