Optimal Dosing Strategies in Non-Small Cell Lung Cancer: A Multi-Scale Modelling Approach to Combat Drug Tolerance

Mahule Roy, Subhas Roy

Abstract: Drug resistance remains a formidable challenge in the treatment of Non-Small Cell Lung Cancer with EGFR tyrosine kinase inhibitors. This study develops a comprehensive multi-scale mathematical model that integrates pharmacokineticpharmacodynamic relationships with tumor cell population dynamics to identify optimal dosing strategies that delay resistance through phenotypic switching mechanisms. We constructed a hybrid model capturing transitions between drug-sensitive cells, drug-tolerant persisters, and drug-tolerant expanded persisters under Osimertinib treatment, calibrated against extensive experimental data. Our model incorporates a novel clinical translation framework featuring circulating tumor DNA monitoring and algorithmic treatment triggers. Results demonstrate that pharmacokinetic-pharmacodynamic-informed adaptive dosing reduces resistant cell burden by 62% compared to maximum tolerated dose and by 45% compared to intermittent dosing, while decreasing cumulative drug exposure by 58%. Global sensitivity analysis identified drug-tolerant expanded persister proliferation rate and drug penetration efficiency as dominant resistance drivers. We propose a clinically actionable adaptive protocol with circulating tumor DNA-guided decision thresholds that outperforms standard care across 92% of parameter ensembles, demonstrating robust superiority. This work provides both theoretical insights and a practical framework for evolution-informed adaptive therapy in EGFR-mutant non-small cell lung cancer.