456P - Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer (NSCLC) brain metastases (BM)

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Dong-Wan Kim
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors D. Kim1, J. Yang2, D. Cross3, P. Ballard4, P. Yang5, J. Yates6, L. Xie5, M. Cantarini7, S. Ghiorghiu7, P.A. Janne8
  • 1Department Of Internal Medicine, Seoul National University Hospital (SNUH)-Yongon Campus, 110-744 - Seoul/KR
  • 2Department Of Oncology, National Taiwan University Hospital, TW-100 - Taipei/TW
  • 3Oncology Imed, AstraZeneca, SK10 4TG - Macclesfield/GB
  • 4Imed Oncology, AstraZeneca, Macclesfield/GB
  • 5Innovation Centre China, AstraZeneca, Shanghai/CN
  • 6Dmpk, AstraZeneca, Macclesfield/GB
  • 7Global Medicines Development, AstraZeneca, Macclesfield/GB
  • 8Thoracic Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US

Abstract

Aim

AZD9291 is a potent, selective, oral irreversible EGFR-TKI effective against the EGFR-TKI-sensitising (EGFRm+) and resistance T790M mutations. We researched the potential efficacy of AZD9291 against EGFRm+ NSCLC BM.

Methods

Preclinical brain exposure of AZD9291 and an active circulating metabolite (AZ5104) were evaluated in mouse models. In vivo efficacy of AZD9291 was assessed in a mouse EGFRm+ (exon 19 deletion) BM xenograft (PC9) model. Human doses that could potentially deliver BM efficacy were predicted using a preclinical pharmacokinetic/pharmacodynamic (PK/PD) mathematical model, adapted to account for the differential exposure and binding of AZD9291 and AZ5104 in brain compared with plasma. Selected case reports of clinical activity in EGFRm+ NSCLC BM were available from a Phase I, open-label, dose-escalation study of AZD9291 (AURA; NCT01802632). Collection of cerebrospinal fluid and plasma PK samples are ongoing.

Results

In preclinical studies, AZD9291 showed significant exposure in the brain. Concentrations in mouse brain tissue compared with plasma were 5–25-fold higher for AZD9291 and approximately equivalent for AZ5104. At clinically relevant doses, AZD9291 distribution to the brain is ∼10-fold higher than gefitinib. In the PC9 BM model, AZD9291 5 mg/kg/day showed tumour growth inhibition of BM. Using an adapted preclinical PK/PD model, simulations with clinical AZD9291/AZ5104 PK data predicted that a human dose of 80 mg would be sufficient to target EGFRm+ BM. In AURA, extracranial objective responses according to RECIST were observed at all dose levels (20–240 mg) and for some patients shrinkage in BM was reported. Clinical cases will be presented.

Conclusions

Preclinical studies indicate AZD9291 has significant exposure in the brain and activity against EGFRm+ BM. In light of early clinical evidence of AZD9291 activity in patients with EGFRm+ NSCLC BM, further investigation into the potential benefit of AZD9291 in patients with EGFRm+ NSCLC and BM is warranted.

Disclosure

J. Yang: Advisory boards: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, Clovis Oncology. Corporate-sponsored research: Boehringer Ingelheim; D. Cross, P. Ballard, P. Yang, J. Yates, M. Cantarini and S. Ghiorghiu: Employment and stock ownership: AstraZeneca; L. Xie: Employment: 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.