1. Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer
- Author
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Kamrine E. Poels, Chelsi Napoli, Yosef Tobi, Helena A. Yu, Manli Shi, Weiwei Tan, Tom O. McDonald, Franziska Michor, Scott L. Weinrich, Shaon Chakrabarti, Yuli Wang, Aaron N. Hata, Adam J. Schoenfeld, Heidie Frisco-Cabanos, and Alex Makhnin
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Combination therapy ,Cancer therapy ,Cell Survival ,Science ,General Physics and Astronomy ,Phases of clinical research ,Antineoplastic Agents ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Computer Simulation ,Osimertinib ,Dosing ,Lung cancer ,Quinazolinones ,EGFR inhibitors ,Acrylamides ,Aniline Compounds ,Models, Statistical ,Multidisciplinary ,business.industry ,General Chemistry ,Models, Theoretical ,medicine.disease ,Applied mathematics ,Dacomitinib ,ErbB Receptors ,Clinical trial ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,business - Abstract
Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting., Osimertinib and dacomitinib are approved as first-line treatment of EGFR-mutant NSCLC but resistance can arise. Here, the authors use a computational model to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy that was confirmed tolerable and effective in an ongoing phase I clinical trial.
- Published
- 2021