454P - Pre-clinical and clinical evaluation of AZD9291, a mutation-specific inhibitor, in treatment-naïve EGFR mutated NSCLC

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Suresh Ramalingam
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors S.S. Ramalingam1, Y. Ohe2, N. Nogami3, J. Yang4, C. Eberlein5, S. Ashton6, M. Mellor6, P. Spitzler7, C. Meador7, E. Ichihara7, D. Cross6, W. Pao8, P. Ballard5, G. Hughes5, M. Cantarini9, P. Frewer10, S. Ghiorghiu9, P.A. Janne11
  • 1Division Of Medical Oncology, Emory University Winship Cancer Institute, 30322 - Atlanta/US
  • 2Thoracic Oncology, National Cancer Center Hospital East, JP-277-8577 - Kashiwa/JP
  • 3Department Of Thoracic Oncology, Shikoku Cancer Center, 791-0280 - Matsuyama/JP
  • 4Department Of Oncology, National Taiwan University Hospital, Taipei/TW
  • 5Imed Oncology, AstraZeneca, Macclesfield/GB
  • 6Imed Oncology, AstraZeneca, SK10 4TG - Macclesfield/GB
  • 7Department Of Medicine, Vanderbilt University Medical Center, Nashville/US
  • 8Hematology/oncology, Vanderbilt University, Nashville/US
  • 9Global Medicines Development, AstraZeneca, Macclesfield/GB
  • 10Early Clinical Development, AstraZeneca, Macclesfield/GB
  • 11Thoracic Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US

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-naïve), 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-naïve 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-naïve 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.