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Introduction: Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 + ) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors., Methods: The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs)., Results: From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47-87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0-3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771_H773dup) (n = 3) and p.(A767_V769dup) (n = 3). The ORR was 28% (95% CI, 12-49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7-27.6). The median PFS was 6.8 months (95% CI, 4.6-9.1) and the median OS was 15.2 months (95% CI, 14.3-16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%)., Conclusion: The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)