119P - Reversible versus irreversible EGFR tyrosine-kinase inhibitors for non-small-cell lung cancer (NSCLC): A preclinical and pharmacokinetic comparison

Date 17 April 2015
Event ELCC 2015
Session Poster lunch
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Bianca Liederer
Citation Annals of Oncology (2015) 26 (suppl_1): 29-44. 10.1093/annonc/mdv050
Authors B.M. Liederer1, T. Friess2, D. Shames3, M. Wright1, C.E.C.A. Hop1
  • 1Drug Metabolism And Pharmacokinetics, Genentech, Inc., CA 94080 - San Francisco/US
  • 2Pred Oncology, Dta Research And Early Development, Roche Innovation Center Penzberg Pharma, Penzberg/DE
  • 3Oncology Biomarker Development, Genentech, Inc., San Francisco/US



The small-molecule EGFR tyrosine-kinase inhibitors afatinib, gefitinib, erlotinib, dacomitinib and AZD-9291 were developed to treat advanced NSCLC, and are classed as reversible (erlotinib, gefitinib) or irreversible (afatinib, dacomitinib, AZD-9291). Physicochemical, preclinical and clinical ADME properties were compared in an effort to differentiate these EGFR inhibitors.


The compounds were characterized in vitro using standard methodology, and the results compared with available clinical data.


MDCK cell permeability was high for erlotinib, moderate for gefitinib and afatinib, and low for dacomitinib and AZD-9291. However, no substantial clinical differentiation was observed for rate or extent of absorption, dose-linearity and elimination half-life except for dacomitinib, which had slower absorption and elimination, consistent with lower permeability (no data for AZD-9291). MDR1 and hBCRP-transfected MDCK cells showed a marked efflux ratio for all compounds (except erlotinib in MDCK-hBCRP), which may affect permeation across the blood–brain barrier. Except for erlotinib and AZD-9291, hepatic uptake via transporters seemed likely and drug–drug interaction (DDI) profiles may differ. Erlotinib, gefitinib and AZD-9291 showed time-dependent inhibition of CYP3A4; afatinib and dacomitinib did not. However, clinical DDIs of erlotinib and gefitinib with everolimus were negligible. No significant DDIs based on CYP450 inhibition are expected, except for dacomitinib, which is a potent CYP2D6 inhibitor (no data for AZD-9291). Only afatinib, dacomitinib and AZD-9291 formed glutathione conjugates in the absence of NADPH, reflecting the intrinsic reactivity expected for covalent EGFR inhibitors. Excretion was predominantly as metabolites via feces, except for afatinib, which was largely unchanged (no data for dacomitinib and AZD-9291).


Overall, afatinib, gefitinib, erlotinib, dacomitinib and AZD-9291 show similar preclinical in vitro and clinical pharmacokinetic properties. However, some relevant differences may emerge as clinical use increases.


B.M. Liederer, D. Shames and M. Wright: employee of Genentech, Inc.

T. Friess: employee of Roche.

C.E.C.A. Hop: employee of Genetech, Inc. Dr Hop is also a shareholder of Roche and is on the board of directors of the International Consortium for Innovation and Quality in Pharmaceutical Development.