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Aim: 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. Methods: 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). Results: 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. Conclusions: 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. Disclosure: 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. |
