Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor–Positive Breast Cancer

Abstract

. (2016). Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. Journal of Clinical Oncology, 34(17), 1987-1994. DOI: 10.1200/JCO.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. PurposePreclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and MethodsIn this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. ResultsThere was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, $ 79.0%) for the combination and 66.0% (95% CI, # 75.4%) for anastrozole (geometric mean ratio [combination: anastrozole], 0.48; 95% CI, # 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, # 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. ConclusionAdd...

NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma

“…breast cancer [27] and NSCLC [28]. In these malignancies, activation of the PI3K-pathway ( PI3KCA mutations or PTEN loss) was consistent with good response to PI3K-inhibitors [28, 29]. However, in a phase II study including glioblastoma patients no association between pathway activation in tumour tissues and efficacy of PI3K-inhibitor treatment was found [28].…”

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

“…Pictilisib was chosen to show the proof of principle in this study merely because it has already reached the Phase II clinical trial stage (17,18,38). We believe other PI3K inhibitors could possibly achieve similar effects as we previously showed with another PI3K inhibitor BEZ235 (5).…”

“…The OPPORTUNE clinical trial combining pictilisib and anastrozole showed significantly increased antitumor response in patients with early stage breast cancer than anastrozole alone (38). In contrast, the phase II PEGGY clinical trial, Vuylsteke et al (18) reported that patients with hormone receptor-positive, HER2-negative locally recurrent or metastatic breast cancer did not get significant benefit from pictilisib plus paclitaxel treatment compared with paclitaxel alone.…”

Neoadjuvant Trials in ER+ Breast Cancer: A Tool for Acceleration of Drug Development and Discovery

“…The combination was significantly superior to anastrozole alone in suppressing Ki67. Luminal B gene expression but not presence of PIK3CA mutations in the diagnostic tumor biopsy was predictive of benefit from pictisilib (53). In metastatic breast cancer, the FERGI trial reported a longer progression free survival (PFS) with the combination of fulvestrant and pictisilib compared to fulvestrant (54), and the BELLE-2 trial showed an improvement in PFS in favor of fulvestrant and the pan-PI3K inhibitor buparlisib over fulvestrant in patients with PIK3CA mutations detected in plasma tumor DNA (54).…”