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

N C Turner, E Alarcón, A C Armstrong, M Philco, Y A López Chuken, M-P Sablin, K Tamura, A Gómez Villanueva, J A Pérez-Fidalgo, S Y A Cheung, C Corcoran, M Cullberg, B R Davies, E C de Bruin, A Foxley, J P O Lindemann, R Maudsley, M Moschetta, E Outhwaite, M Pass, P Rugman, G Schiavon, M Oliveira, N C Turner, E Alarcón, A C Armstrong, M Philco, Y A López Chuken, M-P Sablin, K Tamura, A Gómez Villanueva, J A Pérez-Fidalgo, S Y A Cheung, C Corcoran, M Cullberg, B R Davies, E C de Bruin, A Foxley, J P O Lindemann, R Maudsley, M Moschetta, E Outhwaite, M Pass, P Rugman, G Schiavon, M Oliveira

Abstract

Background: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen 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 Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II 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 (b.i.d.) 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 end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population.

Results: Capivasertib was well tolerated, with a 400 mg b.i.d. 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). Based on the Common Terminology Criteria for Adverse Event v4.0, 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.ClinicalTrials.gov: NCT01625286.

Keywords: PIK3CA; AKT inhibitor; ER+; HER2–; capivasertib; metastatic breast cancer.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Trial profile. (A) Part A and (B) part B. Screen failure was largely attributable to patients with no PIK3CA mutations identified after 25 September 2015 when enrolment of PIK3CA– patients had ceased because the target number of PIK3CA– patients had been reached. All randomised patients received paclitaxel and all but one, randomised to the placebo group, received either capivasertib or matching placebo as assigned per the randomisation schema. b.i.d., twice daily; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide.
Figure 2.
Figure 2.
Progression-free survival (PFS) in part B. (A) PFS in the overall population of part B. (B) PFS in the PIK3CA+ sub-population of part B. ●, a censored observation, assessed using RECIST v1.1 criteria. HR, hazard ratio; PFS, progression-free survival; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; RECIST, Response Evaluation Criteria In Solid Tumours Version 1.1.

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Source: PubMed

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