Mathematical analysis identifies the optimal treatment strategy for epidermal growth factor receptor-mutated non-small cell lung cancer.

ABSTRACT

Introduction: In Asians, more than half of non-small cell lung cancers (NSCLC) are induced by epidermal growth factor receptor (EGFR) mutations. Although patients carrying EGFR driver mutations display a good initial response to EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs), additional mutations provoke drug resistance. Hence, predicting tumor dynamics before treatment initiation and formulating a reasonable treatment schedule is an urgent challenge. Methods: To overcome this problem, we constructed a mathematical model based on clinical observations and investigated the optimal schedules for EGFR-TKI therapy. Results: Based on published data on cell growth rates under different drugs, we found that using osimertinib that are efficient for secondary resistant cells as the first-line drug is beneficial in monotherapy, which is consistent with published clinical statistical data. Moreover, we identified the existence of a suitable drug-switching time; that is, changing drugs too early or too late was not helpful. Furthermore, we demonstrate that osimertinib combined with erlotinib or gefitinib as first-line treatment, has the potential for clinical application. Finally, we examined the relationship between the initial ratio of resistant cells and final cell number under different treatment conditions, and summarized it into a therapy suggestion map. By performing parameter sensitivity analysis, we identified the condition where　osimertinib-first therapy was recommended as the optimal treatment option. Discussion: This study for the first time theoretically showed the optimal treatment strategies based on the known information in NSCLC. Our framework can be applied to other types of cancer in the future.