BEECH: A Randomised Phase 2 Study Assessing the Efficacy of AKT Inhibitor AZD5363 Combined with Paclitaxel in Patients with ER+ve Advanced or Metastatic Breast Cancer, and in a PIK3CA Mutant Sub-Population

Background: AZD5363 (AZD) potently and selectively inhibits AKT1–3. PIK3CA mutations increase sensitivity to AZD in vitro and in vivo. We conducted a randomised Phase 2 trial (NCT01625286), to compare the efficacy of AZD versus placebo, in combination with weekly paclitaxel, in advanced or metastatic ER+ve/HER2−ve breast cancer, and in a PIK3CA mutation sub-population (PIK3CA+). Methods: Female patients (N = 110) aged ≥18 years with ER+ve/HER2−ve advanced or metastatic breast cancer who had received no prior chemotherapy in the advanced or metastatic setting were enrolled. Patients were randomised 1:1, stratified by PIK3CA mutation status (PIK3CA+ vs PIK3CA− in tissue or circulating tumour DNA), to receive paclitaxel 90 mg/m2 i.v. once weekly for 3 weeks out of 4, plus oral AZD 400 mg, or matched placebo twice daily 4 days on, 3 days off, starting on the day after each paclitaxel administration. Enrolment was capped to ensure 50 PIK3CA+ patients were enrolled. Progression status and tumor response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: Median PFS was 10.9 months (95% CI 8.3–12.4) on AZD plus paclitaxel versus 8.4 months (95% CI 8.2–10.8) on placebo plus paclitaxel (HR 0.80, 80% CI 0.6–1.06, p = 0.31). In the PIK3CA+ subgroup, median PFS was 10.9 months (95% CI 8.7–11.5) on AZD plus paclitaxel versus 10.8 months (95% CI 8.3–14.3) on placebo plus paclitaxel (HR 1.11, 80% CI 0.73–1.68, p = 0.76). Objective response rate was 59% on AZD plus paclitaxel versus 57% on placebo plus paclitaxel. The most common adverse events were diarrhoea (76% AZD vs 27% placebo), alopecia (52% vs 49%), nausea (39% vs 24%) and anaemia (33% vs 27%). Adverse events grade 3 or higher included diarrhoea (24% vs 2%), hyperglycaemia (13% vs 0%) and neutropenia (11% vs 9%). Discontinuation rates due to adverse events were 13% on AZD and 7% on placebo. Conclusions: Adding AZD to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ subgroup of ER+ve/HER2−ve advanced or metastatic breast cancer. Clinical trial identification: ClinicalTrials.gov NCT01625286 Other Study ID Numbers: D3610C00002; 2011-006312-31 (EudraCT Number) Legal entity responsible for the study: AstraZeneca (Study Director: Justin PO Lindemann) Funding: AstraZeneca Disclosure: N. Turner: Advisory board honoraria and research funding from AstraZeneca. A. Armstrong: Fees from Roche and Syndax for consulting/advisory roles. M-P. Sablin: Within the last year, travel/accommodation expenses paid/reimbursed by Pfizer. K. Tamura: As the responsible project lead (e.g., Principal Investigator), Direct research support from AstraZeneca, Daiichi Sankyo, MSD and Pfizer. A. Gomez Villanueva: Research funding from AstraZeneca, PPD, Quintiles. J.A. Pérez-Fidalgo: Fees from AstraZeneca, Ipsen, Novartis, Pfizer and Roche for participation in speaker bureaus. Travel/accommodation expenses paid/reimbursed by AstraZeneca, Roche and Sandoz. A. Foxley, J. Lindemann, R. Maudsley, P. Rugman: Employee at AstraZeneca (and shareholder). E. Outhwaite: Employee of AstraZeneca via freelance contract with Aptus Clinical. M. Pass: Employee at AstraZeneca (and shareholder with intellectual property interests). G. Schiavon: Employee at AstraZeneca. M. Oliveira: Fees from Genentech/Roche and PUMA Biotechnology for consulting/advisory roles. Research funding to the institution from AstraZeneca and Genentech/Roche. All other authors have declared no conflicts of interest.