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BACKGROUND About 10% of EGFR mutations (EGFRmut) are 'uncommon mutations' (ucEGFRmut). We aimed to collect real-world data about osimertinib for ucEGFRmut patients. METHODS This is a multi-center, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC osimertinib-treated as first EGFR inhibitor. RECIST and RANO-BM brain objective response rate (ORR) were evaluated by investigators. mPFS, mOS and mDOR were calculated from osimertinib initiation. Mutations found at resistance were collected. RESULTS 60 patients included (22 centres, 9 countries): median age - 64 years, 75% females, 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%) and de novo T790M (15%). ORR was 61%, mPFS 9.5 months (m), mDOR 17.4m, mOS 24.5m. Regarding patients with no concurrent common mutations or T790M (group A, n=44), ORR was 60%, mPFS 8.6 months, mDOR 11 months. For G719X ORR was 47%, mPFS 8.8m and mDOR 9.1m. For L861Q ORR was 80%, mPFS 16m and mDOR 16m. For de novo T790M ORR was 44%, mPFS 12.7m, mDOR 46.2m. Compound EGFRmut including common mutations had better outcome compared to only ucEGFRmut. For 13 patients with a RANO-BM evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy was analysed: 4 patients - additional EGFR mutation (C797S, D585Y, E709K), 3 - new TP53 mutation, 1 - c-Met amplification, 1 - PIK3CA mutation and 1 - neuroendocrine transformation. CONCLUSIONS Osimertinib demonstrated activity in ucEGFRmut with high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest dataset of its kind.