Targeted sequencing of plasma-derived circulating tumor DNA revealed the emergence of NOTCH2-NTRK1 with pre-existing EGFR L858R…Larotrectinib was obtained from abroad and administered to the patient at 100 mg twice daily from Feb 16, 2019 in combination with osimertinib. The patient had significantly improved clinical symptoms with her PS evaluated as 1, despite the absence of measurable change in the primary lung lesions. However, CT scan after 3 months showed brain and liver progression, suggesting the presence of other major signaling pathways besides EGFR and NTRK that are driving the oncogenic progression. Interestingly, sequencing at PD revealed the significant decrease in NOTCH2-NTRK1 fusion, suggesting the molecular efficacy of larotrectinib. The patient received 1 cycle of paclitaxel without benefit and shortly succumbed to the complications of metastatic disease with an overall survival of 21.5 months. In conclusion, our case suggested NOTCH2-NTRK1 could be another possible target of osimertinib resistance.