A Mechanistic Pharmacokinetic/Pharmacodynamic Model for Sequence-Dependent Synergy in Pemetrexed–Osimertinib Combinations Against Non-Small Cell Lung Cancer (NSCLC): Translational Insights

Background and Objectives: Combining osimertinib (OSI) with pemetrexed (PEM) can enhance antitumor efficacy; however, the benefit is schedule-dependent. Our previous pharmacodynamic (PD) study showed that concurrent PEM + OSI is limited by OSI-induced G1 arrest, attenuating early PEM cytotoxicity. In contrast, sequential PEM→OSI allows PEM to fully induce S-phase arrest and DNA damage but elicits a pro-survival EGFR rebound; subsequent OSI suppresses this rebound and promotes apoptosis of damage