Background: Non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutation (uC-EGFRm), excluding exon 20 insertion, is a heterogenous rare fraction consisting of 10% of all EGFR mutations. Key drugs for metastatic NSCLC (mNSCLC) uC-EGFRm are limited, with only afatinib being FDA approved. Data on the efficacy of osimertinib for previously untreated metastatic patients (pts) harboring uC-EGFRm NSCLC is limited. Methods: UNICORN study for previously untreated mNSCLC pts harboring uC-EGFRm, excluding exon 20 insertion mutation, evaluating osimertinib with a dose of 80 mg QD orally is a multicenter, open-label, single-arm phase 2 study. The primary endpoint was the overall response rate (ORR) evaluated by central review according to the Response Evaluation Criteria in Solid Tumors (version 1.1), and key secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Results: Between March 2020 to May 2022, a total of 42 pts were registered. Among the eligible 40 pts, 45.0% were female; the median age was 72 years (range 39-88); 42.5% were never smokers or light smokers; 92.5% were adenocarcinomas, solitary uC-EGFRm/compound mutation ratio was 57.5%/42.5%. The most common mutations were G719X (50.0%), followed by S768I (25.0%), L861Q (20.0%), and others, including compound mutation data. The ORR was 55.0 % (90% confidence interval [CI]; 40.9-68.5), the DCR was 90.0 % (95% CI; 76.3-97.2), the mPFS was 9.4 months (95% CI; 3.7-15.2) after a median follow-up of 27.0 months, the mOS was not reached (NR) (95% CI, 19.23- NR), and the mDoR 22.7 months (95% CI; 9.43-NR). In solitary and compound mutations with uC-EGFR m NSCLC, ORR was 52.2%/58.8%, mPFS was 5.4 months/11.4 months, mOS 23.0 months/NR, and mDoR was 22.7 months/NR, respectively. Safety was similar to previous reports and Grade 3/4 AEs were reported in 8 of 36 pts (27.5%) and 12.5% of pts developed pneumonitis. All of the AEs were manageable and there were no treatment-related deaths. Conclusions: Osimertinib in mNSCLC pts harboring uC-EGFRm other than exon 20 insertions showed clinical activity with manageable toxicities. These results suggest that osimertinib can be considered as a treatment option for this specific population. Clinical trial registration: jRCTs071200002. The study was funded by AstraZeneca. Clinical trial information: jRCTs071200002.