Nearly 20% of stage III non-small cell lung cancers (NSCLC) present with a mutated epidermal growth factor receptor. For these patients, tyrosine kinase inhibitors (TKIs), which have been shown to dramatically delay disease progression in metastatic patients, are now being investigated to be used in combination with chemo-radiation (CRT) in locally advanced (LA) NSCLC patients. While clinical trials are ongoing to test combined TKIs plus definitive CRT treatment regimens, the design of these multimodal treatment regimens is largely qualitative with a vast design parameter space, leading to great variation in clinical trial protocols. The purpose of this study is to develop and apply a model encompassing targeted drug resistance and radiobiology for quantitative, in-silico analyses of varying TKI + CRT treatment schedules to inform clinical trial design. We developed a novel evolutionary and radiobiological model of local (LR) and distant tumor recurrence (DR) following CRT with TKI induction and maintenance for quantitatively optimizing the administration of targeted agents in this setting. We show that our tumor progression model accurately captures the LR and DR dynamics in EGFR-mutant and wild-type NSCLC populations treated with TKIs and CRT and can be used to optimize TKI use in future clinical trials of multimodality therapy for oncogene-driven LA-NSCLC.

David "Bo" McClatchy is a 3rd medical physics resident in the Harvard Medical Physics Residency Program. During his one-year dedicated research rotation, he worked in the Radiation - Drug Treatment Design Lab at MGH under the supervision of Clemens Grassberger and Harald Paganetti, modeling acquired drug resistance to targeted therapies and studying novel multimodal treatment regimens to limit resistance. Before joining the residency program, he received in A.B. and Ph.D. in Engineering Sciences from Dartmouth College, where he worked on developing imaging methods for intraoperative margin assessment during breast conserving surgery.