Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer Journal Article

   

Authors:	Poels, K. E.; Schoenfeld, A. J.; Makhnin, A.; Tobi, Y.; Wang, Y.; Frisco-Cabanos, H.; Chakrabarti, S.; Shi, M.; Napoli, C.; McDonald, T. O.; Tan, W.; Hata, A.; Weinrich, S. L.; Yu, H. A.; Michor, F.
Article Title:	Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer
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. © 2021, The Author(s).
Journal Title:	Nature Communications
Volume:	12
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-06-17
Start Page:	3697
Language:	English
DOI:	10.1038/s41467-021-23912-4
PUBMED:	34140482
PROVIDER:	scopus
PMCID:	PMC8211846
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108119112&doi=10.1038%2fs41467-021-23912-4&partnerID=40&md5=544120662901b1ed87365f665ae81e45
Notes:	Erratum issued, see DOI: 10.1038/s41467-022-33355-0 -- Source: Scopus

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