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396 Background: For patients with advanced EGFR-mutant non-small cell lung cancer (EGFRm aNSCLC) progressing after osimertinib (OSI) and platinum-based chemotherapy (PBC) no uniformly accepted standard of care exists. The study was to provide updated results with a refreshed dataset for a previous study describing clinical outcomes of treatment regimens initiated after OSI and PBC in real-world patients with similar baseline characteristics to those in HERTHENA-Lung01 (HL-01), a multinational single-arm phase II trial evaluating the safety and efficacy of patritumab deruxtecan [1]. Methods: This study analyzed data from the US nationwide Flatiron Health electronic health record–derived aNSCLC de-identified database from approximately 280 US cancer clinics (~800 sites of care). Adult patients with an aNSCLC diagnosis (after 01 January 2011) and prior treatment with OSI and PBC, who initiated a subsequent line of therapy (index LOT) before 01 August 2022 were included in the study. Patients were chosen to closely match the HL-01 eligibility criteria (documented exon 19 deletion or L858R mutation; Eastern Cooperative Oncology Group Performance Status of 0 or 1; and absence of relevant comorbidities at index date). To further balance patient characteristics, the sample was propensity-score (PS) weighted based on nine covariates. Real-world overall survival (rwOS), progression-free survival (rwPFS) and overall response (rwORR, defined as partial or complete response with ≥2 assessments ≥28 days apart) were assessed from the start of the index LOT with corresponding 95% confidence intervals (CI). Results: 179 patients in the database fulfilled the eligibility criteria, increasing the sample size by 42% compared to the previous study1. Median age of the unweighted sample at index was 68 years, 65.9% of patients were female, 40.2% had a history of smoking and 26.3% received more than 3 LOTs prior to the index LOT. In the PS-weighted cohort (standard mean difference of all covariates was ≤0.127) the median rwOS was 9.1 months (95% CI: 7.3 – 11.3) and median rwPFS was 3.5 months (95% CI: 2.7 – 4.6). For a subsample of 75 patients with qualifying response assessments, rwORR was 12.7% (95% CI: 4.8 – 25.7). Conclusions: These observations in patients with EGFRm NSCLC after OSI and PBC demonstrate a limited clinical benefit with currently available therapies. The results are consistent with the previously published study and increase precision of the outcome estimates1. They highlight the high unmet need and provide further context on clinical outcomes of HL-01 trial results. [1] Patel et al. Clinical Outcomes of Real-World Treatment for Metastatic EGFRm NSCLC after Osimertinib and Platinum-Based Chemotherapy. 2023 Sep 9-12 Singapore. P2.31. [ABSTRACT FROM AUTHOR]