BEECH: a dose-finding run-in followed by a randomised phase 2 study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with oestrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population

Abstract

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with first-line weekly paclitaxel for advanced or metastatic oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase 1b safety run-in (Part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase 2 expansion (Part B) in 110 women with ER+/HER2- metastatic breast cancer. In Part A, patients received paclitaxel 90?mg/m2 (Days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (BID) at two intermittent ascending dosing schedules. In Part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary endpoint for Part A was safety to recommend a dose and schedule for Part B; primary endpoints for Part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400?mg BID 4 days on/3 days off treatment schedule selected in Part A. In Part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo (hazard ratio [HR] 0.80; P = 0.308). In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). The most common Grade ?3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.