Background: EGFR is the most commonly altered biomarker in East Asian NSCLC patients. Common driver mutations (L858R or exon 19 deletions (del)) are the focus of conventional hotspot testing which may overlook less common activating alterations such as single nucleotide variants (SNVs) in the tyrosine kinase or extracellular domain as well as exon 20 insertions (ins). We investigated the prevalence of uncommon EGFR mutations in ctDNA from NSCLC patients in East Asia tested by a commercially available comprehensive next generation sequencing (NGS) assay (Guardant360). This assay identifies SNVs, ins and del, fusions, and amplifications (amp), with complete exon sequencing of EGFR. Methods: Guardant360 test results from Hong Kong, Korea, Japan, Taiwan, and Southeast Asia were reviewed (cut-off December 2019). We identified cases with a diagnosis of “lung cancer,” excluding pure squamous, small cell, neuroendocrine, carcinoid and sarcomatoid histology. Patients enrolled in certain prospective clinical trials were excluded at the investigators’ request. Clinically relevant biomarkers were mutations in EGFR, BRAF (V600E), ERBB2, or KRAS; MET amp or exon 14 skipping; and ALK, ROS1, or RET fusions. Uncommon EGFR mutations were defined as those other than L858R, exon 19 del, or resistance SNV in codons 790-797; synonymous mutations and amp were excluded. Results: Plasma from 820 non-squamous NSCLC patients was tested. Samples came from 436 women and 384 men, median age 61 years. ctDNA was identified in samples from 701 patients (85% detection rate). Alterations in at least one clinically relevant gene were detected in 75% of the ctDNA positive cases: EGFR (54%), KRAS (8%), ALK (5%), ERBB2 (5%), RET (2%), MET (2%), BRAF (1%), ROS1 ( < 1%). Uncommon EGFR alterations were found in 115 samples (16%), with 63 (9%) potentially actionable (exon 19 ins (1); exon 20 ins (22); activating SNV (40), some with multiple mutations, including L718Q (6), L718V (5), G719A (5), L861Q (5), S768I (4), and others) and 52 (7%) variants of unknown significance. Uncommon EGFR mutations were the only clinically relevant biomarker in 53 samples (8%). Conclusions: Uncommon, potentially actionable EGFR mutations were found in 9% of plasma samples from East Asian NSCLC patients. In this clinical practice dataset, uncommon EGFR mutations were more prevalent than actionable biomarkers in other genes. These data support the use of NGS testing methods to identify NSCLC patients for appropriate EGFR-targeted therapy.