Background: METamp is a common resistance mechanism developed in patients (pts) with EGFRm NSCLC treated with osimertinib. MET tyrosine kinase inhibitors (TKIs) such as tepotinib may be effective in treating these pts after osimertinib. Here we report interim data from the INSIGHT 2 study evaluating tepotinib + osimertinib in EGFRm NSCLC with METamp previously treated with osimertinib. Methods: In this open-label Phase II study (INSIGHT 2, NCT03940703), pts with advanced EGFRm NSCLC with METamp after progression on 1L osimertinib received tepotinib 500 mg (450 mg active moiety) + osimertinib 80 mg once daily. METamp was centrally detected in tissue biopsy (TBx) by FISH (MET gene copy number [GCN] ≥5 and/or MET/CEP7≥2) and/or in liquid biopsy (LBx) by NGS (MET plasma GCN ≥2.3; Archer). The primary endpoint was objective response by Independent Review Committee in tepotinib + osimertinib treated pts with centrally detected METamp by FISH (FISH+). Efficacy data are reported for pts with ≥3 months’ follow-up, and safety for all pts who received one dose of tepotinib + osimertinib by Sep 26, 2022 (data cut-off). Results: Among 472 pts prescreened, 451 pts had METamp results by either TBx FISH and/or LBx NGS, of which 175 (38.8%) were positive for METamp. 122 pts received tepotinib + osimertinib (median age 61 years [range 20–84], 59.8% female, 59.8% Asian, 68.0% never smoker, 72.1% ECOG PS 1). In 98 pts with FISH METamp (29.6% had < 12 months on 1L osimertinib; median GCN 11 [range 5.0–50.6]; mean ± SD sum of target lesion diameters [SOLD] 73.2 ± 47.1 mm), objective response rate (ORR) was 43.9% (95% CI 33.9, 54.3), median (m) DOR was 9.7 months (95% CI 5.6, ne), mPFS was 5.4 months (95% CI 4.2, 7.1), and mOS was not reached (95% CI 11.1, ne). Of the 98 pts, treatment is ongoing in 42 pts. In 31 pts with METamp detected by LBx NGS, of which 24 were also FISH+ (mean ± SD SOLD 93.9 ± 51.4 mm), ORR was 51.6% (95% CI 33.1, 69.8), mDOR was 5.6 months (95% CI 2.9, ne), mPFS was 4.6 months (95% CI 2.7, 6.9), and mOS was not reached (95% CI 6.8, ne). Of 122 pts treated with tepotinib + osimertinib, any grade treatment-related AEs were reported by 99 (81.1%) pts including 34 (27.9%) Grade ≥3. Most common ( > 15% pts) treatment-related AEs included diarrhea 46.7% (0% Grade ≥3), peripheral edema 34.4% (4.1% Grade ≥3), paronychia 20.5% (0.8% Grade ≥3), decreased appetite 18.0% (3.3% Grade ≥3), and nausea 16.4% (1.6% Grade ≥3). Treatment-related AEs led to a dose reduction in 21 (17.2%) pts, following either or both treatments and led to treatment discontinuation in 7 pts (5.7%). Conclusions: In this interim analysis of INSIGHT 2, tepotinib + osimertinib was highly active with durable responses, and was well tolerated in pts with EGFRm NSCLC with METamp after progression on 1L osimertinib. Tepotinib + osimertinib provides a potential chemotherapy-sparing oral targeted therapy option in this population with a high unmet need. Clinical trial information: NCT03940703.