Abstract 2079: Osimertinib, an irreversible mutant selective EGFR tyrosine kinase inhibitor, exerts anti tumor activity in NSCLC harbouring exon 20 insertion mutant-EGFR
Authors: Nicolas Floc'h, 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 O'Neill, Jonathan P Orme, Anna D Staniszewska, Richard A Ward, James W T Yates
Journal: Cancer Research (2017)

Abstract 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 (&amp;lt;1%), EGFR Ex20Ins mutations are clinically unresponsive to early generation EGFR inhibitors, the standard of care for NSCLC patients with EGFR Ex20Ins mutations is chemotherapy. Therefore, a significant unmet need remains requiring the development of an EGFR TKI agent that can more effectively target NSCLC with EGFR Ex20Ins mutations. Osimertinib is a newly developed EGFR TKI approved for the treatment of advanced NSCLC with EGFR T790M tumors. This work describes the potential of osimertinib and AZ5104, a circulating metabolite of osimertinib, in Ex20Ins tumours. 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&amp;lt;0.001 &amp; 95%, p&amp;lt;0.001 respectively at day 14) and Ex20Ins ASV (82%, p&amp;lt;0.001 &amp; 95%, p&amp;lt;0.001 respectively at day 14) xenograft models when compared to the control group. Importantly in vivo osimertinib was dosed at exposures consistent with the 80 mg osimertinib clinical dose. Moreover, a dual EGFR blockade strategy combining osimertinib or AZ5104 with cetuximab (an EGFR antibody) improved the anti tumor effect further. We also describe the anti-tumor activity of osimertinib and AZ5104 using a series of patient derived xenograft models harbouring the rarer Ex20Ins H773-V774insNPH and M766-A767insASV mutations. In addition, we performed pharmacodynamic studies to explore the relationship between efficacy and target/pathway modulation. These studies establish a clear relationship between depth and duration of phospho-EGFR inhibition and anti tumor efficacy. Interestingly, we observed that downstream signalling molecules displayed a more transient inhibition than the phospho 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 Floc'h, 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 O'Neill, 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