Background: METamp is a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). METamp occurs in ̃30% of patients who progress on EGFR TKI therapy as measured using fluorescence in situ hybridization (FISH). There is an unmet need for targeted treatment options in these patients. Combination treatment with a MET TKI may overcome MET-related osimertinib resistance. Tepotinib is an oral, once daily (QD), highly selective, potent MET TKI. In the INSIGHT study (NCT01982955), the combination of tepotinib and the EGFR TKI gefitinib improved outcomes in patients with EGFR-mutant METamp NSCLC and EGFR TKI resistance compared to chemotherapy (INSIGHT). Median progression-free survival (PFS) was 16.6 vs 4.2 months (hazard ratio [HR] = 0.13; 90% confidence interval [CI]: 0.04, 0.43) and median overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). Methods: INSIGHT 2 is a global, open-label, Phase II trial of tepotinib + osimertinib in patients with advanced EGFR-mutant NSCLC. Following a protocol amendment in Apr 2020, the study is enrolling patients with acquired resistance to 1L osimertinib (radiological documentation of disease progression following previous objective clinical benefit) due to METamp by FISH (GCN ≥5 or MET/CEP7 ratio ≥2). Patients must be ≥18 years old, have an Eastern Cooperative Oncology Group performance status of 0/1, and normal organ function. Both tissue and liquid biopsy, obtained at the time of progression to osimertinib, will be sent for central confirmation of METamp. Liquid biopsy samples will also be used for exploratory biomarker evaluation. Enrollment is allowed based on local FISH testing while awaiting central confirmation of METamp. Patients will receive 500 mg QD (450 mg active moiety) tepotinib + 80 mg QD osimertinib until disease progression, unacceptable toxicity, or consent withdrawal. The study is anticipated to enroll 120 patients. The primary endpoint is objective response rate (ORR) by independent review (RECIST v1.1) in patients with METamp, centrally confirmed by FISH. Secondary endpoints include ORR by investigator assessment, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety. An exploratory tepotinib monotherapy arm will enroll 12 patients to assess the contribution of tepotinib to the activity of the combination. At progression (determined by independent review committee), monotherapy patients can switch to combination treatment. These patients will be analyzed separately. Recruitment is ongoing, with > 300 patients prescreened. Approximately 100 sites in 17 countries in Europe, Asia, and North America are expected to participate. Approximately 15 sites will recruit patients in the US. Clinical trial information: NCT03940703