NTRK gene fusions are a critical marker for pediatric soft tissue tumors and are used for precision medicine in these tumors. NTRK gene fusions are used as diagnostic markers for infantile fibrosarcoma, congenital mesoblastic nephroma, and secretory carcinomas, and they play a critical role in the management of these tumors.

P2, N=32, Completed, The University of Sydney | Active, not recruiting --> Completed

Combination therapy with osimertinib and entrectinib induced regression of pulmonary lesions, but the patient ultimately discontinued all targeted agents due to the development of severe hepatorenal failure and Escherichia coli-associated sepsis. This case highlights the need for additional research into the safety profile of EGFR-TKI/NTRK inhibitor combination regimens in resistant NSCLC.

Critically, pharmacological co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in both patient-derived organoids and xenograft models, producing marked synergistic anti-tumor effects without evidence of exacerbated toxicity. Clinical analyses of two independent patient cohorts further confirmed that elevated NGF expression is significantly associated with poor response to lenvatinib, shorter recurrence-free survival, and worse overall survival. Our findings unveil a critical and previously underappreciated role for tumor-derived NGF in orchestrating adaptive signaling through a precise post-transcriptional regulatory circuit and propose a readily translatable, biomarker-guided combination strategy to overcome lenvatinib resistance in HCC.

Notably, Entrectinib ameliorated LPS-induced memory impairments in vivo. Collectively, these findings indicate that Entrectinib attenuates neuroinflammation and improves memory performance, supporting its potential therapeutic relevance for neuroinflammation-associated cognitive disorders.

Molecular docking revealed higher binding affinities for both Idarubicin (- 9.98 kcal/mol) and Larotrectinib (- 9.42 kcal/mol) compared to the reference drug Erlotinib (-8.91 kcal/mol). Additionally, they demonstrated favorable predicted cytotoxicity against NSCLC cell lines. In conclusion, our integrated bioinformatics analysis identifies idarubicin and larotrectinib as putative candidates for drug repurposing targeting EGFR in NSCLC, providing a rational foundation for future experimental validation and further preclinical and clinical investigations.

Owing to the presence of neural tissue, NTRKs are highly positive in IHC, making these genes unsuitable as biomarkers for assessing NTRK inhibitor sensitivity and resistance, which are tissue-agnostic drugs. The observed low fusion rate is consistent with the literature, and the significance of the numerous point mutations identified as agnostic markers warrants further investigation. NTRK expression, fusion, and point mutations were not associated with clinical parameters or survival.

These studies demonstrate that NTRK wild-type receptors are important drivers of brain metastatic colonization and progression in different subtypes of lung cancer, independent of their driver alterations. Thus, they provide rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases.

P3, N=71, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Sep 2033 --> Jun 2030 | Trial primary completion date: Aug 2032 --> Dec 2026

P3, N=220, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

After adjuvant chemotherapy, maintenance larotrectinib was initiated based on proven TRK inhibitor efficacy in metastatic NTRK-fusion tumors and emerging evidence for targeted therapy benefit in driver-positive early stage lung adenocarcinoma. Our findings demonstrate the value of molecular pathology in the diagnostic journey of pulmonary malignancies, guiding rare fusion detection and supporting therapeutic decisions based on rare fusions in early stage disease.