SABCS 2016: BELLE-3 Trial of Buparlisib Plus Endocrine Therapy Meets Primary Endpoint of Progression-Free Survival in Breast Cancer Patients
The investigational PI3K inhibitor buparlisib, in combination with endocrine therapy, improved outcomes for patients with hormone receptor–positive advanced breast cancer that had progressed after treatment with everolimus (Afinitor) plus exemestane, according to data from the phase III clinical trial BELLE-3 presented at the 2016 San Antonio Breast Cancer Symposium, held December 6–10 (Abstract S4-07).
“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 [hormone receptor]–positive advanced breast cancer patients with progression on everolimus plus exemestane,” said Angelo Di Leo, MD, an oncologist at the Ospedale Misericordia e Dolce, Prato, Italy.
“This new treatment could further delay the time of starting cytotoxic chemotherapy in this particular group of patients with [estrogen receptor]–positive disease,” Dr. Di Leo added.
Prior studies have shown that activation of the cell-signaling 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.
BELLE-3 Details
The goal of BELLE-3 was to assess whether the addition of buparlisib to fulvestrant (Faslodex) is safe and effective in treating patients with hormone receptor–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 progress 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, and the secondary endpoints included overall survival, overall response rate, clinical benefit rate, safety, and efficacy based on PI3KCA gene status in circulating tumor DNA, assessed using patients’ blood samples.
Major Findings
Median progression-free survival for patients in the buparlisib arm was 3.9 months vs 1.8 months for those in the placebo arm, and the 6-month progression-free survival rates were 30.6% and 20.1%, respectively. Those 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 circulating tumor DNA on PIK3CA status was available, 147 had mutations in the gene and the rest had the normal form of the gene. Among those with PIK3CA mutations, progression-free survival was 4.7 months for those in the buparlisib arm vs 1.6 months for those in the placebo arm. Patients with the 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 tumor tissues.
“Testing for PIK3CA mutations seems to be relevant because buparlisib does not seem to have relevant activity in the absence of the mutation,” Dr. Di Leo said. “It is interesting to observe that the PIK3CA test can be done on tumor sample or on a blood sample, the so-called liquid biopsy, and that both samples seem to provide similar information,” he added.
The overall response rate and clinical benefit rate were also significantly higher for those in the buparlisib arm compared with those in the placebo arm.
Buparlisib treatment was associated with side effects, the most relevant ones being a rise in liver enzymes and some psychiatric symptoms such as anxiety or depression, Dr. Di Leo noted. These side effects may lead to a deterioration of patients’ quality of life and may be responsible for temporary or permanent treatment discontinuations, he said. “Considering all this, I believe that we need further research in the attempt to identify new PI3K inhibitors with a comparable level of activity and with a better safety profile,” he said.
“The results of this trial are important for the scientific community because the trial shows the promising activity of a new class of anticancer agent, but in my opinion, it is still premature to consider this agent as a new standard of care in the treatment of [estrogen receptor]–positive advanced breast cancer patients,” Dr. Di Leo concluded.
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