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Background: Patients with non-small cell lung cancer (NSCLC) driven by activating epidermal growth factor receptor (EGFR) mutations are best treated with therapies targeting EGFR, i.e., tyrosine kinase inhibitors (TKI). Radiolabeled EGFR-TKI and PET have been investigated to study EGFR-TKI kinetics and its potential role as biomarker of response in NSCLC patients with EGFR mutations (EGFRm). In this study we aimed to compare the biodistribution and kinetics of three different EGFR-TKI, i.e., 11C-erlotinib, 18F-afatinib and 11C-osimertinib. Methods: Data of three prospective studies and 1 ongoing study were re-analysed; data from thirteen patients (EGFRm) were included for 11C-erlotinib, seven patients for 18F-afatinib (EGFRm and EGFR wild type) and four patients for 11C-osimertinib (EGFRm). From dynamic and static scans, SUV and tumor-to-blood (TBR) values were derived for tumor, lung, spleen, liver, vertebra and, if possible, brain tissue. AUC values were calculated using dynamic time-activity-curves. Parent fraction, plasma-to-blood ratio and SUV values were derived from arterial blood data. Tumor-to-lung contrast was calculated, as well as (background) noise to assess image quality. Results: 11C-osimertinib showed the highest SUV and TBR (AUC) values in nearly all tissues. Spleen uptake was notably high for 11C-osimertinib and to a lesser extent for 18F-afatinib. For EGFRm, 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-lung contrast, compared to an inverse contrast observed for 11C-osimertinib. Tumor-to-lung contrast and spleen uptake of the three TKI ranked accordingly to the expected lysosomal sequestration. Conclusion: Comparison of biodistribution and tracer kinetics showed that 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-background contrast in EGFRm positive tumors. Image quality, based on contrast and noise analysis, was superior for 11C-erlotinib and 18F-afatinib (EGFRm) scans compared to 11C-osimertinib and 18F-afatinib (EGFR wild type) scans. [ABSTRACT FROM AUTHOR]