2021
DOI: 10.1038/s41467-021-23912-4
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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 … Show more

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Cited by 19 publications
(15 citation statements)
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References 54 publications
(73 reference statements)
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“…The sensitivities of dacomitinib and osimertinib were explained by the most common molecular interaction, thereby, implying that dacomitinib and osimertinib have similar mechanisms of action and pharmacological profiles. Previous studies support our result that the combination of osimertinib and dacomitinib could induce more durable responses by preventing the emergence of resistance [ 44 ]. The sensitivity of almost EGFR-TKIs can be explained by common molecular interactions, while afatinib has common features with only erlotinib.…”
Section: Resultssupporting
confidence: 89%
“…The sensitivities of dacomitinib and osimertinib were explained by the most common molecular interaction, thereby, implying that dacomitinib and osimertinib have similar mechanisms of action and pharmacological profiles. Previous studies support our result that the combination of osimertinib and dacomitinib could induce more durable responses by preventing the emergence of resistance [ 44 ]. The sensitivity of almost EGFR-TKIs can be explained by common molecular interactions, while afatinib has common features with only erlotinib.…”
Section: Resultssupporting
confidence: 89%
“…Only daughter cells are allowed to mutate. All simulations use a carrying capacity between 10 9 and 10 11 cells. The growth rate is scaled by at each time step, where n is the total number of cells and K is the carrying capacity.…”
Section: Methodsmentioning
confidence: 99%
“…Researchers within evolutionary medicine leverage knowledge of evolutionary processes to develop new treatments and improve existing paradigms [2][3][4] . Recently, computational studies of the evolution of resistance have been used to optimise dosing schedules in silico, in vitro, and in clinical trials [5][6][7][8][9][10][11] .…”
Section: Introductionmentioning
confidence: 99%
“…The use of osimertinib (a third generation of EGFR TKI) is usually accompanied by chemo-resistance in the terminal treatment of advanced EGFR- mutated NSCLC patients; the reason maybe because the second-site mutations appear in the EGFR . Therefore, osimertinib plus dacomitinib (a pan-HER inhibitor) could reduce drug resistance appearing in therapy, in a phase I/II trial (NCT03810807 (first posted: 22 January 2019) ) ( 147 ). Moreover, the combination of osimertinib and navitoclax (an inhibitor of BCL-2 that could increase apoptosis and reduce chemo-resistance) was feasible in patients with EGFR -mutated NSCLC in a phase IB trial ( NCT02520778 (first posted: 13 August 2015) ) ( 148 ).…”
Section: Treatments For Lung Cancermentioning
confidence: 99%