Preclinical Evidence and Clinical Cases of Azd9291 Activity in Egfr-Mutant Non-Small Cell Lung Cancer (Nsclc) Brain Metastases (Bm)

Abstract

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.