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Background: Seminal trials with first-line pembrolizumab for metastatic non-small cell lung cancer (NSCLC) mandated a maximum two-years treatment. We describe real-world outcomes of a multi-site Australian cohort of patients who completed two-years of pembrolizumab., Methods: Retrospective data were collected from the national AUstralian Registry and biObank of thoRacic cAncers (AURORA). Primary endpoints were progression rate post pembrolizumab discontinuation; and progression free survival (PFS). Local treatment of oligoprogressive disease during pembrolizumab was allowed., Results: A total of 71 patients from six centers, median age 66.0 years, 49% male and 90% ECOG ≤ 1 were identified. Patients were Caucasian (82%) or Asian (16%); past (66%) or current (24%) smokers with mean 37 pack-years. Histology comprised 73% adenocarcinoma and 16% squamous. 18 patients (25%) had brain metastases at diagnosis. Median PD-L1 tumor proportion score (TPS) was 68%; 12 patients (17%) TPS < 1% and 43 (61%) TPS ≥ 50%. No patients had EGFR/ALK/ROS1 alterations; 29/49 tested (60%) had KRAS mutations. Median follow up was 38.7 months. Objective response rate 78.6%. Median PFS 46.1 months (95% CI 39.5-NR), not reached (46.1-NR) in PD-L1 TPS ≥ 1% versus 28.1 months (16.3-NR) in TPS < 1% (P = .013). 17 patients (24%) received additional local therapy for oligoprogression. Post pembrolizumab discontinuation, 20 patients (28%) had disease progression. Higher rates of progression occurred with TPS < 1% (OR 3.46, P = .06), without complete response (OR 5.06, P = .04), and with treated oligoprogression (OR 3.11, P = .05). 36-month landmark survival was 98.2%., Conclusion: Patients completing two-years of pembrolizumab for NSCLC in an Australian cohort had high rates of KRAS mutation and PD-L1 expression; a proportion had brain metastases and treated oligoprogression. Progression post pembrolizumab was higher in PD-L1 TPS < 1% and in those without complete response., Competing Interests: Disclosure The authors declare the following conflicts of interest: Dr Andrew Fantoni: Speaker fee/Honoraria from Novartis. Dr Lydia Warburton: Honoraria from BMS, MSD, Roche, Astrazeneca. Dr Ben Solomon: Consulting fees for Advisory for Pfizer, Roche, AstraZeneca, Glaxo Smith Kline, Bristol Myers Squibb, Amgen, Merck, Takeda, Eli Lilly, Janssen, Takeda. Honoraria from Pfizer, Amgen, Glaxo Smith Kline, AstraZeneca, Roche. Royalties/Licenses from UpToDate. Leadership role for Cancer Council Victoria, Thoracic Oncology Group of Australasia (TOGA), and International Association for the study of Lung Cancer. Ms Marliese Alexander: Travel support from Astrazenca. Advisory board Pfizer/BMS. Dr Meghana Maddula: None. Dr Lauren Julia Brown: None. Dr Ines Da Silva: Consulting fees for MSD. Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre. Travel support from BMS, MSD, Roche. Dr Adnan Nagrial: Advisory board for MSD, BMS, Takeda, Pfizer, Astra Zeneca. Dr Farah Abu Al-Hial: None. Dr Malinda Itchins: Grants from Pfizer. Consulting Fees Roche, Merck. Honoraria from Pfizer, AstraZeneca, Takeda, Roche, Novartis, BMS, MSD, Bayer, Janssen. Advisory board for Pfizer, Takeda, Bayer, MSD, Amgen, Merck, Roche, Janssen. Leadership role for Clinical Oncology Society of Australia (COSA). Dr Nick Pavlakis: Grants from Bayer, Pfizer, Roche. Consulting fees from Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Pfizer, Roche, Amgen, Beigene. Honoraria from Boehringer Ingelheim, Merck, Pfizer, Roche, Takeda, Pierre-Faber, Illumina, Bayer. Leadership role for The Thoracic Oncology Group of Australia (TOGA). Dr Samantha Bowyer: Honoraria from BMS, MSD (Australia), Sanofi. Travel support from Astrazenca, MSD (Australia). Advisory for Roche, Sanofi, MSD (Australia), Ipsen, Lilly., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)