466P - Targeting resistance in EGFR-mutant non-small cell lung cancer (NSCLC): Preclinical evidence supporting the combination of EGFR tyrosine kinase inh...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Drug Development
Translational Research
Presenter Darren Cross
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors D. Cross1, C. D'Cruz2, C. Eberlein1, P. Spitzler3, E. Ichihara3, C. Meador3, S. Ashton1, M. Mellor1, R. Stewart4, P. Smith1, A. Schuller2, M. Frigault5, W. Pao6, P.J. Jewsbury1
  • 1Imed Oncology, AstraZeneca, SK10 4TG - Macclesfield/GB
  • 2Prin Sci Ii Biosci, AstraZeneca, 02451 - Waltham/US
  • 3Department Of Medicine, Vanderbilt University Medical Center, Nashville/US
  • 4Oncology, MedImmune, Cambridge/GB
  • 5Imed Oncology, AstraZeneca, 02451 - Waltham/US
  • 6Hematology/oncology, Vanderbilt University, Nashville/US



First-generation EGFR-TKIs, such as gefitinib, are active in first-line, EGFR-TKI-sensitising-mutant (EGFRm+), advanced NSCLC, but the duration of clinical benefit is limited by acquired tumour resistance. A common resistance mechanism is gain of an additional mutation, T790M, and about 5–15% of patients also develop MET amplification, with or without T790M. The recently developed novel third-generation EGFR-TKI, AZD9291 (a selective EGFR-TKI of EGFRm+ and T790M mutations), overcomes T790M-mediated resistance. Combining EGFR-TKIs with selective molecularly targeted agents has the potential to delay the emergence of EGFR-TKI resistance across lines of therapy. Finally, immunotherapeutics, such as checkpoint inhibitors, have the potential to target cancers orthogonally; thus studies to optimise their use with EGFR-TKIs would be of high value to patients.


In vitro and in vivo preclinical models representing EGFRm+ and T790M NSCLC were used to investigate the potential of combining AZD9291 or gefitinib with immunotherapeutics, and selective small molecule kinase inhibitors, namely selumetinib (AZD6244, ARRY-142886; MEK1/2 inhibitor) and AZD6094 (MET inhibitor).


Preclinical models harbouring MET overexpression demonstrated AZD6094 plus EGFR-TKI was well tolerated and effective in reversing MET-driven resistance. In models of acquired resistance mediated by increased MEK dependency, resistance could be delayed in vitro and in vivo by addition of selumetinib. Finally, a genetically engineered mouse model of mutant EGFR NSCLC was used to assess the impact of AZD9291 treatment on T-cell infiltration; results will be presented.


These preclinical studies provide a strong rationale for the clinical evaluation of AZD9291 and gefitinib in combination with molecularly targeted agents, such as AZD6094 and selumetinib, to delay and/or overcome acquired resistance to single-agent EGFR-TKI therapy. Rational combinations with immunotherapeutics are also worth further investigation.


D. Cross, C. Eberlein, S. Ashton, M. Mellor, P. Smith, M. Frigault and P.J. Jewsbury: Employment and stock ownership: AstraZeneca; C. D'Cruz: Employment: AstraZeneca; R. Stewart: Employment: MedImmune. Stock ownership: AstraZeneca; A. Schuller: Employment: AstraZeneca; W. Pao: Rights to EGFR T790M testing licensed on WP's behalf by MSKCC to MolecularMD. Research funding and travel and consulting funds: AstraZeneca. All other authors have declared no conflicts of interest.