In this case report we present the case of a patient with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with progression on multiple EGFR tyrosine kinase inhibitors (TKIs) due to the development of mesenchymal-epithelial transition (MET) amplification, and subsequently had an excellent response to the novel combination of osimertinib and amivantamab, particularly in the central nervous system with a near complete response of parenchymal brain metastases. Amivantamab is a fully human immunoglobulin G based bispecific antibody that binds to the extracellular domains of EGFR and MET thus blocking ligand binding and subsequent signaling [1]; in EGFR exon 20 insertion mutation models, degradation of EGFR and MET was also documented. Amivantamab currently has one FDA approved use which is as second line treatment of EGFR exon 20 insertion NSCLC that is locally advanced or metastatic after progression on platinum-based chemotherapy [1]. This was based on the CHYRSALIS phase I trial which showed a 40% overall response rate (primary end point) and 22 month median overall survival (secondary end point) [2]; overall survival data from phase III studies are still pending. Notably, patients with active or untreated CNS metastases were excluded from the trial and only patients whose brain metastases were previously treated and asymptomatic were eligible and they constituted 22% of the patients treated with single agent amivantamab [3]. Therefore, there is no data on the activity of amivantamab in active CNS disease. Additionally, the effectiveness of amivantamab to overcome MET amplification as a mechanism of resistance in EGFR-mutated NSCLC is not known. Thus, we present here a case which demonstrates the novel use of amivantamab to overcome MET amplification as the mechanism of resistance in EGFR-mutated NSCLC and highlights its potential to treat active CNS disease.