Clinical and molecular characteristics and targeted therapy of pediatric non-infantile fibrosarcoma NTRK rearrangement–related tumors.

10048 Background: Neurotrophic tyrosine receptor kinase (NTRK) rearrangement is rare in tumors and relevant to targeted therapy. Pediatric NTRK rearrangement-related tumors have distinct clinical and molecular features compared to adults, and previous studies on pediatric NTRK rearrangement-related tumors has focused on infantile fibrosarcoma (IFS), the most common subtype. However, the clinical behaviors and molecular profiles of other subtypes of pediatric NTRK rearrangement-related tumors are largely unknown. Methods: In this study, we evaluated the molecular features, treatment response, and prognosis of 28 pediatric patients with non-IFS NTRK rearrangement-related tumors. Next-generation sequencing was performed in 21 patients to identify the NTRK fusion types and their co-occurring alterations, and pathway enrichment analysis was performed to explore the potential mechanisms involving NTRK rearrangement and resistance to tyrosine receptor kinase (TRK) inhibitors. Results: The NTRK fusion partners were diverse and tumor-specific. Several novel NTRK fusions were identified, including SNIP1-NTRK1, AGAP1-NTRK2, CRCT1-NTRK1, ZBTB7B-NTRK1, and SLC6A15-NTRK3. RTK-RAS, NOTCH, TP53, and WNT pathways were top 4 significantly enriched in tested samples. Twelve of 17 patients (70.6%) received TRK inhibitors as salvage treatment achieved complete or partial response. Patients who did not develop DDR, NOTCH, or TP53 pathway-related gene mutations had a high objective response rate of 82%, 82%, and 83%, respectively. Conclusions: Our findings may have important implications for the diagnosis and treatment of non-IFS NTRK fusion-positive tumors in pediatric patients. We also provide potential therapeutic targets for tumors resistant to TRK inhibitors. Clinical trials with TRK inhibitors, either alone or in combination, are required to establish the optimal treatment regimen and sequence in large-cohort pediatric patients with non-IFS NTRK rearrangement-related tumors. Clinical trial information: NCT05076071 .