Abstract B153: Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291

Background AZD9291 is a potent, oral, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for sensitizing (EGFRm) and T790M resistance mutations. Clinical activity has been demonstrated in patients with advanced EGFR T790M positive non-small cell lung cancer (NSCLC). We report results from two Phase I clinical studies, one investigating the effect of food, and another on the impact of increased gastric pH, on the pharmacokinetics (PK) of AZD9291. Design The studies were conducted in accordance with ICH/GCP guidance; protocols were reviewed and approved by IEC and IRB prior to implementation. The likely commercial formulation of AZD9291 80 mg film-coated tablet was used. The Food effect study (NCT02163733) had two parts: A and B. Part A was an open-label randomized two-period crossover design where the primary objective was to evaluate the effect of food on AZD9291 PK following oral dosing of 80 mg tablet in patients with EGFRm+ NSCLC, whose disease had progressed following treatment with a prior EGFR-TKI. Part B is an ongoing extension phase where patients may receive continuous AZD9291 80 mg dosing, if they continue to derive benefit, with safety monitoring conducted for up to 1 year. The Gastric pH interaction study (NCT02224053) was an open-label, two-fixed-period study with primary objective to evaluate the effect of omeprazole 40 mg on AZD9291 exposure in healthy, male volunteers. In Period 1, subjects received omeprazole on Days 1-4 and on Day 5 they received AZD9291 and omeprazole after a 10-hour fast. In Period 2, after a washout of at least 21 days, subjects received AZD9291 alone after a 10-hour fast. After Period 1 the AZD9291 AUC 0-72 exposure was assessed and subjects with exposures exceeding set limits were withdrawn and replaced. In both studies, blood samples were taken serially post dose in each treatment period to determine concentrations of AZD9291 and its active metabolites (AZ5104 and AZ7550). The safety and tolerability of AZD9291 was a secondary objective in the Food effect (fed and fasted state) and Gastric pH interaction studies (AZD9291±omeprazole). Results Food effect study (Part A only): 38 patients were assigned to treatment. Geometric LS mean ratios comparing fed to fasted treatments for AZD9291 C max and AUC 0-72 were 92.75% (81.40, 105.68) and 106.05% (94.82, 118.60), respectively and 90% confidence intervals were contained within the predefined equivalence limits of 70% to 143%. Gastric pH interaction study: 68 subjects were assigned to treatment and 47 subjects completed both study periods. The geometric LS mean ratios comparing AZD9291 C max and AUC when given with omeprazole compared to administration of AZD9291 alone were 101.65% (94.65, 109.16) and 106.66% (100.26, 113.46), respectively and 90% confidence intervals were within the equivalence limits of 80% to 125%. In addition, neither food nor co-administration of AZD9291 with omeprazole had a clinically relevant effect on exposure (C max and AUC) for the AZD9291 metabolites AZ5104 and AZ7550. Oral administration of 80 mg AZD9291 was well tolerated, with no deaths or discontinuations due to AE in either study. Conclusions These studies suggest that AZD9291 can be administered without regard to food and no restrictions are necessary when administered with gastric pH modifying agents. AZD9291 was well tolerated under fed or fasted conditions, and when co-dosed with omeprazole. Citation Format: Karthick Vishwanathan, Paul A. Dickinson, Khanh Bui, Doris K. Weilert, Karen So, Karen Thomas, Eleanor A. Lisbon, Ruth Plummer. Effect of food and gastric pH modifiers on the pharmacokinetics of AZD9291. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B153.