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BELLE-trial: Buparlisib in combination with fulvestrant improves progression-free survival in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer progressed on everolimus

The phase III BELLE-3 trial demonstrated that the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib, in combination with endocrine therapy, improved outcomes for patients with hormone receptor (HR)-positive advanced breast cancer that had progressed after treatment with everolimus plus exemestane. For the first time, there is 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. Activation of the PI3K/mTOR pathway, driven in some cases by a mutation in the gene PIK3CA, plays a major role in promoting resistance to endocrine therapies such as aromatase inhibitors. Preclinical and clinical data suggested that adding a PI3K inhibitor to endocrine therapy may overcome this resistance. The goal of BELLE-3 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. In the BELLE-3 trial patients were randomly assigned (2:1) to a combination of buparlisib (100mg/day) plus fulvestrant (500mg per standard of care) 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 was progression-free survival (PFS) and secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), safety, and efficacy based on PI3KCA gene status in circulating tumour DNA (ctDNA) assessed using patients’ blood samples.

Median PFS for patients in the buparlisib-arm was 3.9 months, versus 1.8 months for those in the placebo-arm (HR 0.67; 95% CI: 0.53–0.84; p<0.001), and the 6-month PFS rates were 30.6% and 20.1% (HR 0.57; 95% CI: 0.44–0.74; p<0.001), respectively. Patients in the buparlisib-arm were 33% less likely to have their disease progress at the time of assessment. Of the 349 patients for whom data from ctDNA on PIK3CA status was available, 147 (42.1%) had mutations in the gene and the rest (57.9%) had PIK3CA-wildtype status. 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 (HR 0.50; 95% CI: 0.33–0.76). Patients with gene mutations who received buparlisib were 50% less likely to have their disease progress 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, most common (>10%; buparlisib versus placebo) grade 3/4 adverse events were increased alanine aminotransferase (21.9% versus 2.9%), increased aspartate aminotransferase (17.7% versus 2.9%), and hyperglycemia (12.2% versus 0%).These side effects may lead to a deterioration of patients’ quality of life and may be responsible for temporary or permanent treatment discontinuations. To conclude, BELLE-3 met its primary endpoint in the full population. PFS improvement in the buparlisib-arm versus placebo-arm was greater in patients with PIK3CA mutations than PIK3CA wildtype tumours, based on both ctDNA and PCR. In addition, secondary endpoints showed improved clinical benefit. Safety was in line with that previously seen with the combination.


Di Leo A, Seok Lee K, Ciruelos E, et al. 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. San Antonio Breast Cancer Symposium 2016, abstract S4-07.

Speaker Angelo Di Leo


Prof. Angelo Di Leo, MD, PhD,
Ospedale Misericordia e Dolce, Prato, Italy


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