rearrangements are recognized drivers in lung cancer, representing a small subset (1-2%) of non-small cell lung cancer (NSCLC). Additionally, fusions also serve as a rare acquired resistance mechanism in -mutant NSCLC. Only a few NSCLC cases have been reported with co-occurrence of mutations and fusions as an acquired resistance mechanism induced by EGFR-tyrosine kinase inhibitors (TKIs). A 68-year-old man diagnosed with lung adenocarcinoma harboring L858R mutation initially responded well to dacomitinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI). Afterward, he developed acquired resistance accompanied by a rearrangement. Next-generation sequencing (NGS) analysis revealed that the tumor possessed both the new fusion and the L858R mutation. Subsequently, he was treated with a combination of cisplatin, pemetrexed, and bevacizumab resulting in a partial response. Nevertheless, his condition deteriorated as the disease progressed, manifesting as hydrocephalus, accompanied by altered consciousness and lower limb weakness. The subsequent combined treatment with dacomitinib and selpercatinib resulted in a significant improvement in neurological symptoms. Here, we first identified acquired fusion with a coexisting L858R mutation following dacomitinib treatment. Our findings highlight the importance of NGS for identifying fusions and suggest the potential combination of dacomitinib and selpercatinib to overcome this resistance. For NSCLC patients with rearrangements and no access to RET inhibitors, pemetrexed-based chemotherapy provides a feasible alternative.