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

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/m 2 (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.

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

“…The successful development of a targeted AKT inhibitor such as capivasertib, either as monotherapy or in combination, may provide a new treatment option in breast cancer that helps circumvent endocrine therapy resistance from aberrant activation of the pathway (21). In a separate phase II trial (BEECH: NCT01625286), adding capivasertib to weekly paclitaxel did not prolong PFS in a population of patients with advanced ER þ /HER2 À breast cancer or in a subpopulation whose tumors harbored a PIK3CA mutation (22). Notably, no concomitant endocrine therapy was permitted during the BEECH study.…”

Cellular Plasticity in Breast Cancer Progression and Therapy

“…MK-2206, and AZD5363, two inhibitors of AKT, exhibited promising activity against breast cancer cells in preclinical studies (Crafter et al, 2015;Ribas et al, 2015;Choi et al, 2016;Baek et al, 2018;Chen et al, 2018). However, these drugs showed limited clinical efficacy in clinical trials (Kalinsky et al, 2018;Turner et al, 2019;Xing et al, 2019). A distinct attempt to target AKT activity was made by Chen and colleagues, who recently discovered that a natural methoxylated analog of resveratrol, 3,5,4 ′ -trimethoxystilbene (MR-3), can block EMT and the invasion of breast cancer cells via restoring GSK3β activity and inhibiting the phosphorylation of AKT (Tsai et al, 2013).…”

Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44

“…Recently an orally available PI3K alpha specific inhibitor termed Alpelisib has been approved for treatment of PIK3CA-mutated, hormone receptorpositive advanced breast cancer [3]. Akt inhibitors Capivasertib [4] and Ipatasertib [5] are in late stage clinical trials for breast cancers bearing PI3K or Akt mutations. However, studies to date indicate that despite encouraging initial responses, the majority of tumors display inherent resistance or develop acquired resistance to PI3K/Akt pathway inhibitors through diverse mechanisms [6,7].…”

“…This targets SGK3 to endosomal membranes, where a large pool of PtdIns(3)P is generated by the Class III PI3K family member, known as hVps34 [17,19,20]. Activation of Class I PI3K can also contribute to the pool of PtdIns(3)P at the endosomal membrane through the sequential degradation of PtdIns (3,4,5)P3 via SHIP2 and INPP4A/4B inositol phosphatases [21,22]. Studies undertaken with selective class 1 and class 3 PI3K inhibitors indicate that both PI3K family members contribute to the activation of SGK3 by growth factors [22].…”