Background: In patients with advanced non-small cell lung cancer (aNSCLC) with non-squamous histology, treatment guidelines recommend molecular testing for EGFR mutations and first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) in those with sensitizing EGFR mutations. We investigated real-world treatment regimens and outcomes in aNSCLC patients with EGFR-sensitizing mutations from US community oncology clinics. Methods: The Flatiron Health electronic health record-derived database contains deidentified data from > 55,000 aNSCLC patients. Our retrospective cohort included patients diagnosed from Jan-2014 to Mar-2018 who had a positive EGFR test prior to initiation of 1L therapy. Patients with EGFR T790M mutations were excluded. Demographics, clinical characteristics, treatment and survival outcomes were compared between patients receiving 1L EGFR TKIs vs other 1L anti-cancer therapies. Minimum follow-up after initiation of 1L therapy was 4 months. Results: 23,321 patients had non-squamous or NOS histology. Of those, 1107 had sensitizing EGFR mutations detected prior to 1L treatment (median age 70 years, 67% women, 58% Caucasian). 910 (82%) received EGFR TKIs and 197 (18%) received other 1L therapies (including chemotherapy, immunotherapy and anti-VEGF therapy). 2L treatment data were available for 519 patients: 317 (61%) received EGFR TKIs and 202 (39%) received other therapies. In the 1L setting, median treatment duration was longer for patients receiving EGFR TKIs than for those receiving other therapies (8 vs. 4 months, unadjusted HR 1.70; 95% CI 1.45–1.99; p < 0.0001). Median overall survival (OS) was not affected by the type of 1L treatment (21 months vs 20 months, p = 0.55). Conclusions: Real-world examination of treatment patterns and outcomes in US community oncology clinics showed that nearly 20% of aNSCLC patients with non-squamous or NOS histology and EGFR sensitizing mutations prior to initiation of 1L therapy did not receive 1L EGFR TKIs. In those who did, guideline-concordant use of EGFR TKIs was associated with longer 1L treatment duration but no improvement in OS, supporting the generalizability of results from randomized clinical trials.