# Neoadjuvant TRK inhibitors versus chemotherapy in advanced NTRK fusion-positive sarcomas: a real-world evidence analysis

## TL;DR

TRK inhibitors outperformed chemotherapy in treating advanced NTRK fusion-positive sarcomas in children, leading to better outcomes and fewer surgeries.

## Contribution

This study provides real-world evidence showing TRK inhibitors are more effective than chemotherapy for NTRK fusion-positive sarcomas.

## Key findings

- TRK inhibitors had a significantly lower treatment failure rate (2.7%) compared to chemotherapy (61.5%).
- TRK inhibitors prevented mutilating surgery in infantile fibrosarcoma and improved response rates in NTRK-rearranged spindle-cell tumors.
- TRK inhibitors enabled faster tumor shrinkage and higher pathological complete responses compared to chemotherapy.

## Abstract

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.

This real-world study directly compares outcomes of TRK inhibitors with chemotherapy.

This was a multicenter, retrospective cohort study.

50 children with advanced NTRK fusion-positive sarcomas were analyzed from three study centers (2018-2024).

Patients were assigned into two groups according to their choice of treatment,including chemotherapy or TRK inhibitors..

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.

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.

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.