454P - Pre-Clinical and Clinical Evaluation of Azd9291, a Mutation-Specific Inhibitor, in Treatment-Naïve Egfr Mutated Nsclc

Abstract

ABSTRACT Aim: AZD9291 is an oral, irreversible EGFR-TKI effective against EGFR-TKI-sensitising (EGFRm+) and resistance T790M mutations. It is efficacious in EGFRm+ advanced NSCLC patients with acquired resistance to EGFR-TKIs. We report on the evaluation of AZD9291 in the first-line setting. Methods: In vitro and in vivo xenograft studies were performed utilising PC-9 (EGFR exon 19 del) and H3255 (EGFR L858R) cells. The efficacy of AZD9291 was compared with known EGFR inhibitors: gefitinib, afatinib and WZ4002. Transgenic mice with lung tumours driven by EGFR L858R or exon 19 del were also dosed with AZD9291. In the clinic, AZD9291 was given to patients with advanced stage NSCLC with a documented EGFR-TKI-sensitising mutation as first-line therapy (treatment-naive), in an ongoing Phase I trial (NCT01802632). Results: In vitro, compared to afatinib at 0.8nM, resistance to AZD9291 at 10nM was delayed by an average of 43 days in PC9 cells. Notably, 73% (8/11) of cell populations exposed to gefitinib or afatinib developed T790M mutation compared to none (0/14) with AZD9291. In PC9 and H3255 xenograft studies, AZD9291 demonstrated strong efficacy, evidenced by profound and sustained tumour reduction. Robust tumour shrinkage was also noted in exon 19 del and L858R in vivo transgenic models. These lines of evidence prompted the clinical investigation of AZD9291 in treatment-naive patients with advanced NSCLC. As of 2 April 2014, 22 patients ( 7 males; median age 61 yrs; WHO PS 0/1, 14/6; Asian ethnicity 18; EGFR-TKI-sensitising mutation exon 19del 6, L858R 8, other 1, unknown 7) were treated with AZD9291 at 80 mg/day. Safety and efficacy data from all evaluable patients will be presented. Conclusions: AZD9291 is a novel, mutation-specific EGFR inhibitor which demonstrates good activity in pre-clinical EGFR mutant xenograft models. Early clinical data with AZD9291 in treatment-naive patients with advanced NSCLC supports further evaluation in first-line therapy of EGFRm+ NSCLC. Disclosure: S.S. Ramalingam: Advisory boards: AstraZeneca, Boehringer Ingelheim, Genentech; N. Nogami: Speaker: AstraZeneca (not related to AZD9291); J.C. Yang: Advisory boards: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche/Genetech, Astrazeneca, Merck, Bayer, Clovis Oncology. Corporate-sponsored research: Boehringer Ingelheim; C. Eberlein, S. Ashton, M. Mellor, D. Cross, P. Ballard, G. Hughes, P. Frewer, S. Ghiorghiu and M. Cantarini: Employment and stock ownership: 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; P.A. Janne: Consultant or advisory role: AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Merrimack Pharmaceuticals, Chugai, Immunogen. Stock ownership: Gatekeeper. Other: Lab Corp. All other authors have declared no conflicts of interest.