Women with advanced endocrine-resistant breast cancer who had PIK3CA mutations identified in their circulating tumor DNA had an almost 4-month improvement in progression-free survival when assigned to treatment with the PIK3CA inhibitor buparlisib and fulvestrant compared with fulvestrant alone, according to data from the BELLE-2 trial presented at the 2015 San Antonio Breast Cancer Symposium (SABCS).
“Patients with tumors harboring PIK3CA mutations detected in liquid biopsy performed poorly on fulvestrant monotherapy, achieving a clinically meaningful progression-free survival improvement with buparlisib and fulvestrant,” José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, said during a press conference. According to Baselga, this study suggests that assessment of PIK3CA mutations in circulating tumor DNA may help select patients who benefit from adding a PI3K inhibitor to endocrine therapy.
The phase III BELLE-2 study enrolled 1,147 women with advanced, postmenopausal hormone receptor–positive/HER2-negative breast cancer that had progressed during or after aromatase inhibitor therapy. Patients were randomly assigned to buparlisib 100 mg per day plus fulvestrant 500 mg (n = 576) or fulvestrant plus placebo (n = 571). The patients were stratified by PI3K pathway status as measured in archival tumor tissue.
Looking at the full population of patients, there was a significant improvement in progression-free survival as assessed by local investigators for patients assigned to buparlisib plus fulvestrant compared with fulvestrant alone (median progression-free survival 6.9 vs 5 months; HR, 0.78; P < .001). However, no significant difference was found for patients with PI3K pathway-activated tumor samples (HR, 0.76; P = .014).
According to Baselga, archival tumor samples typically represent the primary tumor at the time of initial diagnosis; however, studies have suggested that a tumor’s mutation status can change as the disease progresses or as the tumor is exposed to treatments. Therefore, the researchers also assessed PIK3CA status in circulating tumor DNA in a subgroup of 587 patients.
Among patients with circulating PI3K mutations there was a significant improvement in progression-free survival from a median of 3.2 months for fulvestrant alone to 7 months for patients assigned the combination (HR, 0.56; P < .001). Patients with PI3K mutations assigned buparlisib also had improvements in overall response rate (18% vs 4%) and clinical benefit rate (47% vs 32%) compared with patients on fulvestrant alone. Patients without mutant PIK3CA had no significant differences for progression between the two treatment arms.
Up to 25% of patients assigned buparlisib had a serious adverse event. The most commonly occurring grade 3 or 4 adverse events were liver dysfunction, rash, hyperglycemia, and mood disorder.
“PI3K is an important pathway for normal cellular functions; therefore, as one would expect, side effects from buparlisib were substantial,” Baselga said in a prepared statement. “We are hopeful that future, newer generation PI3K inhibitors would be less toxic.”
Moving forward, Baselga said that additional studies are warranted to look at the predictive value of PIK3CA mutations detected in circulating tumor DNA and tumor tissue.