Weekly osimertinib dosing to prevent EGFR mutant tumor cells destined to home mouse lungs.

Abstract

e20504 Background: The recent ADAURA trial concludes daily dosing of adjuvant osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), improves disease-free survival with stage IB/II/IIIA EGFR-mutated non-small cell lung cancerpatients in comparison to placebo. We have developed a preclinical orthotopic mouse model, using luciferase tagged lung adenocarcinoma cells harboring EGFR TKI sensitive exon 19 deletion, to model and extend trial implications comparing a weekly vs daily dosing outcome of osimertinib to a first-generation TKI- erlotinib. Methods: We present an assessment of the homing of PC9-luciferase cells to the lungs of mice injected through mouse tail vein. Thirty NOD-SCID mice were divided into five groups as follows: two groups each for daily and weekly treatment and one group for vehicle control. For all the mice in the respective groups, erlotinib (25 mg/kg) and osimertinib (15 mg/kg) was orally administered. Homing of cells in the lungs of mice was assessed by bioluminescence imaging regularly. Results: In the control group, 100% of the mice showed homing and retention of cells in the lungs of mice 18 days post-injection. In mice receiving erlotinib daily, homing of the cells in lungs was absent in all four mice, except in one mouse where emergence was observed after day eight post-injection. In the case of erlotinib weekly group, out of four only one mouse showed absence of homing of cells in the lungs of mice. Interestingly, 100% of the mice in both the groups receiving osimertinib daily or weekly showed complete absence of homing of cells in the lungs of mice from day 3 onwards post-injection (Table). The tumors observed in the lungs, when dissected at day 30, confirmed the colonization of the injected cells homing to the organ. Conclusions: Based on the complete absence of the homing of cells in lungs of osimertinib treated mice, in both weekly and daily regimens, adjuvant osimeritinib may represent a viable treatment option in delaying the onset of disease post resection of early stage tumors or among patients with pre-disposition to EGFR mutant lung cancers harboring germline EGFR mutations. In addition, low-dose once-a-week osimertinib could potentially have several advantages over daily dosing, including lower toxicity, affordability, ease of administration and delaying or preventing acquired resistance that remains to be explored. [Table: see text]