Establishing the Therapeutic Range and Personalized Dosing Strategy of Osimertinib in Metastatic Non-Small Cell Lung Cancer (NSCLC) - A Pharmacometric Approach

This study is an observational pharmacokinetic–pharmacodynamic investigation designed to evaluate the relationship between plasma exposure of osimertinib and clinical outcomes in patients with metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The study will be conducted at Tata Memorial Centre, Mumbai, and will enroll approximately 33 adult patients who are receiving osimertinib as part of routine clinical care.

Although osimertinib is administered at a fixed dose of 80 mg once daily in standard practice, substantial variability in drug exposure exists between patients due to differences in pharmacokinetics, physiology, and concomitant clinical factors. This variability may lead to either underexposure, resulting in reduced therapeutic efficacy, or overexposure, which may increase the risk of dose-limiting toxicity. The present study aims to better characterize this exposure–effect relationship and to support development of individualized dosing strategies.

Participants who meet the eligibility criteria and provide informed consent will be enrolled while continuing their prescribed osimertinib therapy without any modification for study purposes. Clinical and demographic data will be collected using a structured case report form. These data will include patient characteristics, medical history, concomitant medications, laboratory investigations, treatment details, and reported adverse events. Imaging findings from routine clinical assessments will also be collected for evaluation of tumor response.

Blood samples will be collected during routine follow-up visits to measure plasma concentrations of osimertinib. Two samples will be obtained within the dosing interval: one approximately 6 hours after drug administration to estimate peak concentration (Cmax) and another immediately before the next scheduled dose to determine the trough concentration (Cmin). Plasma samples will be processed and stored under controlled conditions and analyzed using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method.

Clinical outcomes will be evaluated through two primary domains: toxicity and treatment response. Adverse events will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), and the occurrence of dose-limiting toxicity will be assessed in relation to measured drug concentrations. Tumor response will be evaluated using RECIST version 1.1 based on baseline and follow-up imaging studies.

Statistical analyses will be performed to explore the relationship between osimertinib exposure and clinical outcomes. Receiver operating characteristic (ROC) curve analysis will be used to determine concentration thresholds associated with treatment response and toxicity. In addition, population pharmacokinetic modeling using nonlinear mixed-effects methods will be conducted to characterize drug disposition and identify patient-specific factors influencing variability in exposure.

The findings of this study are expected to help define a clinically relevant therapeutic exposure range for osimertinib and provide a foundation for model-informed precision dosing strategies in patients with metastatic NSCLC. Such approaches may improve treatment tolerability and effectiveness by enabling clinicians to adjust dosing based on patient-specific pharmacokinetic profiles rather than relying solely on fixed-dose therapy.