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Afatinib is an oral epidermal growth factor receptor (EGFR) driver mutation metastatic non-small cell lung cancer (NSCLC) small molecule kinase inhibitor (SMKI). The majority of SMKIs have pH-dependent solubility, despite the convenience of oral administration. However, no human studies on the drug-drug interactions between afatinib and proton-pump inhibitors (PPIs) have been conducted. Therefore, we conducted a three-period, randomised cross-over research. There were no noticeable changes in toxicity. In conclusion, esomeprazole did not alter how much afatinib patients with NSCLC were exposed to. The coadministration of esomeprazole and afatinib is safe because there is no clinically significant drug-drug interaction. Due to the fact that other EGFR-SMKIs, such as erlotinib and gefitinib, do interact with acid suppressive drugs in clinically meaningful ways, this is crucial for clinical practise.