High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure-response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure-toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1-Q3 group (12.2 months [CI95% = 8.0-not reached (NR)] vs. 22.7 months [CI95% = 17.1-34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure-survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1-Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6-37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.