Abstract 2079: Osimertinib, an irreversible mutant selective EGFR tyrosine kinase inhibitor, exerts anti tumor activity in NSCLC harbouring exon 20 insertion mutant-EGFR

EGFR exon 20 insertion (Ex20Ins) mutations represent a combination of in-frame insertions and/or duplications that account for 4-10% of all EGFR mutants in non-small cell lung cancer (NSCLC). To date, more than one hundred different Ex20Ins mutations have been identified. With the notable exception of the rare A763_Y764insFQEA insertion ( Using CRISPR-Cas 9 genome editing technology, we engineered cellular disease relevant models carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%). Using these models, we show that osimertinib and AZ5104 inhibit signalling pathways and cellular growth of Ex20Ins CRISPR-Cas9 engineered cell lines in vitro. This translates into sustained tumor growth inhibition in vivo in both the Ex20Ins SVD (65%, p EGFR signal. Two patients from the AURA Phase 2 osimertinib trials with plasma positive Ex20Ins (concurrent with Ex19del and T790M) had durable PFS responses of 6.4 and 13.9 months, supporting the premise that osimertinib has the potential to be clinically beneficial in tumors harboring Ex20Ins. The work presented herein demonstrates that osimertinib has the potential to improve upon the current treatment options for NSCLC patients whose tumors harbour an Ex20Ins mutation, and warrants its further clinical investigation. Citation Format: Nicolas Floc9h, Susan Ashton, Ambra Bianco, Nicola Colclough, Darren AE Cross, Maria Emanuela Cuomo, M. Raymond V. Finlay, Matthew J Martin, Ludovic Menard, Darren McKerrecher, Daniel J O9Neill, Jonathan P Orme, Anna D Staniszewska, Richard A Ward, James W T Yates. Osimertinib, an irreversible mutant selective EGFR tyrosine kinase inhibitor, exerts anti tumor activity in NSCLC harbouring exon 20 insertion mutant-EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2079. doi:10.1158/1538-7445.AM2017-2079