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PI3K Inhibitor Buparlisib in Combination with Fulvestrant Prolongs PFS Compared to Placebo Plus Fulvestrant

BELLE-3 trial meets primary endpoint in HR-positive, HER2-negative advanced breast cancer
12 Dec 2016
Translational research;  Anticancer agents & Biologic therapy

The PI3K inhibitor buparlisib, in combination with fulvestrant, improved outcomes for patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer that had progressed after treatment with everolimus plus exemestane, according to data from the phase III randomised BELLE-3 study presented at the 2016 San Antonio Breast Cancer Symposium, held 6-10 December.

According to Dr Angelo Di Leo of the Ospedale Misericordia e Dolce, Prato, Italy: “For the first time, we have evidence from a phase III clinical trial that a PI3K inhibitor is a viable treatment option in combination with endocrine therapy for HR-positive advanced breast cancer patients progressing on everolimus plus exemestane”.

“This new treatment could further delay the time of starting cytotoxic chemotherapy in this particular group of patients with ER-positive disease,” dr Di Leo added in an accompanied press release.

Prior studies have shown that activation of the PI3K/mTOR pathway, driven in some cases by PIK3CA mutation, plays a major role in promoting resistance to endocrine therapies such as aromatase inhibitors.

The goal of the BELLE-3 study was to assess whether the addition of buparlisib to fulvestrant is safe and effective in treating patients with HR-positive, HER2-negative, aromatase inhibitor treated, locally advanced or metastatic breast cancer that progressed on or after treatment with the mTOR inhibitor everolimus.

The investigators randomly assigned (2:1) 432 patients to a combination of daily buparlisib plus fulvestrant or placebo plus fulvestrant. All patients had previously received aromatase inhibitor therapy and had their disease progressed within the prior 30 days during treatment with a combination of endocrine therapy and everolimus.

The primary endpoint of this trial was progression-free survival (PFS) and the secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), safety, and efficacy based on PI3KCA mutation status in circulating tumour DNA (ctDNA).

Median PFS for patients in the buparlisib arm was 3.9 months versus 1.8 months for those in the placebo arm, and the 6-month PFS rates were 30.6% and 20.1%, respectively. Those in the buparlisib arm were 33% less likely to have their disease progressed at the time of assessment.

Among 349 patients for whom data from ctDNA on PIK3CA status was available, 147 had PIK3CA mutations. Furthermore, among those with PIK3CA mutations, PFS was 4.7 months for those in the buparlisib arm, versus 1.6 months for those in the placebo arm. Patients with PIK3CA mutations who received buparlisib were 50% less likely to have their disease progressed at the time of assessment. This effect was also reflected with PIK3CA status in the tumour tissues.

The ORR and CBR were also significantly higher for those in the buparlisib arm compared with those in the placebo arm.

Buparlisib treatment was associated with some side effects, the most relevant were a rise in liver enzymes, anxiety and depression. According to dr Di Leo, further research is needed to design new PI3K inhibitors with a comparable level of activity and with a better safety profile. He concluded that it is still premature to consider buparlisib as a new standard of care in this setting.

The study was funded by Novartis.


Di Leo A, Keun SL, Ciruelos E, et al. S4-07. P4-22-01. BELLE-3: A Phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. Presented at 2016 San Antonio Breast Cancer Symposium, 6-10 December 2016, San Antonio, TX, US. 

Last update: 12 Dec 2016

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