A CASE OF ETV6-NTRK3 FUSION DRIVEN INFANTILE HEMISPHERIC GLIOMA (IHG) WITH ACQUIRED DRUG RESISTANCE AGAINST FIRST- AND SECOND-GENERATION NTRK-INHIBITORS

Abstract A 3-month-old girl had left cerebral infantile hemispheric glioma (IHG), H3 wild type (wt), Grade IV (WHO2020) with diffuse leptomeningeal and spinal metastasis. Craniotomies were performed twice which achieved partial resection. Histopathology revealed high grade glioma, Ki67 30-40%, mitosis and widespread necrosis. IHC showed H3wt, IDH-, and retained INI-1. RNAseq found ETV6-NTRK3 fusion. She was treated per Baby POG-9233, however after 3 cycles, there was mixed response (static for primary, partial response for metastasis). She had severe developmental delay, right hemiparesis and dysphagia. Aiming for better disease control and potential resectability, we switched to first-generation NTRK-inhibitor, Larotrectinib. MRI at 3 months showed significant interval reduction in tumour size, then became static at 6 months. She was stable with gradual neurological improvement until 10 months after Larotrectinib, there was worsening neurology and imaging confirmed tumour progression with haemorrhage. Craniotomy was performed for haemostasis and tumour debulking. Histopathology showed same IHG with ETV6-NTRK3 fusion. Targeted panel sequencing found NTRK3 p.Gly623Arg mutation, a solvent-front substitution responsible for acquired resistance to first-generation TRK-inhibitors. BRAFV600E and MET amplification were not detected. Larotrectinib was switched to second-generation NTRK-inhibitor, Selitrectinib. MRI at 1 month showed post-operative changes, but disease progressed at 3 months and in an accelerated manner over the course of 10 days while on therapy. Choice of conventional chemotherapy and radiotherapy were discussed, but the girl deteriorated rapidly and deceased (3 months from start of Selitrectinib, 19 months from diagnosis). CONCLUSION: IHG is aggressive with challenging surgery and medical treatment. The use of small molecular inhibitor requires careful consideration, i.e. treatment effect, toxicity and potential acquired drug resistance as showed in this case. For unresectable tumour, it may be inevitable as we also reported a similar case with ROS1 fusion. Access to newer novel agents is difficult while therapeutic effect is uncertain.