Median progression-free survival was improved by 2.1 months with the addition of the pan-PI3K inhibitor buparlisib to fulvestrant for women with HR-positive/HER2-negative advanced breast cancer who received a prior aromatase inhibitor and progressed on or after an mTOR inhibitor.
Ruth O'Regan, MD
Median progression-free survival (PFS) was improved by 2.1 months with the addition of the pan-PI3K inhibitor buparlisib (BKM120) to fulvestrant (Faslodex) for women with HR-positive/HER2-negative advanced breast cancer who received a prior aromatase inhibitor (AI) and progressed on or after an mTOR inhibitor, according to findings from the phase III BELLE-3 trial presented at the 2016 San Antonio Breast Cancer Symposium.
The median PFS with buparlisib plus fulvestrant was 3.9 versus 1.8 months for placebo plus fulvestrant, representing a 33% reduction in the risk of progression or death (HR, 0.67; 95% CI, 0.53-0.84;P<.001). However, there was a high rate of grade 3/4 adverse events (AEs) with the combination, specifically transaminitis and psychological issues. There was 1 confirmation of Hy’s law following treatment with the combination, representing a high-risk for fatal liver injury.
"The BELLE-3 trial met its primary endpoint. Buparlisib plus fulvestrant prolonged PFS compared with placebo plus fulvestrant in postmenopausal women with HR+/HER2- advanced breast cancer," said lead investigator Ruth O'Regan, MD, from the University of Wisconsin Carbone Cancer Center. "The higher rate of toxicity in patients receiving buparlisib plus fulvestrant, including transaminase elevations and mood disorders, may represent a clinically relevant challenge."
In the study, 432 postmenopausal women with HR-positive/HER2-negative locally advanced or metastatic breast cancer were randomized in a 2:1 ratio to receive fulvestrant plus either buparlisib (n = 289) or placebo (n = 143). Fulvestrant was administered at 500 mg in each arm and buparlisib was given orally at 100 mg per day. Prior treatment with fulvestrant was not allowed in the study.
The median age of patients was 61 years (range, 32-84). Seventy-three percent had visceral disease and 65% of patients had ≥3 metastatic sites. All patients enrolled in the study had progressed on or after an AI, and 35% had received prior chemotherapy for metastatic disease. Sixty-nine percent of patients had received ≥2 lines of endocrine therapy for metastatic disease prior to entering the trial.
The most commonly administered mTOR inhibitors prior to the study were everolimus (99%) and temsirolimus (1%). Ninety-one percent of patients in the combination arm and 84% in the placebo group had progressed on an mTOR inhibitor or had progressed within 30 days of stopping therapy. The median duration of prior mTOR inhibitor therapy was 8.0 and 8.6 months, for the combination and control arms, respectively.
The primary endpoint was PFS and secondary outcome measures focused on overall survival, overall response rate (ORR), and safety.PIK3CAtesting was conducted on archival tissue and using by BEAMing for circulating tumor DNA (ctDNA). Seventeen percent of findings from the 2 tests were discordant, with 10% testing wild-type in the tissue and mutant by ctDNA and 7% testing mutant by the tissue and wild-type by ctDNA.
The ORR with buparlisib was 7.6% (95% CI, 4.8-11.3) versus 2.1% with placebo (95% CI, 0.4-6.0). This response rate consisted of 1 complete response (CR) and 21 partial responses (PR). The clinical benefit rate (PR + CR + stable disease) with the PI3K inhibitor was 24.6% versus 15.4% with placebo.
The 6-month PFS rate was 31% with buparlisib versus 20% with placebo. Data for overall survival were not yet mature, with some patients still in follow-up at 26 months. O'Regan anticipated the OS results would be available soon, as 40% of the required events for this analysis had occurred.
In a subgroup analysis, patients who derived no clinical benefit from prior endocrine therapy plus mTOR inhibition experienced the greatest PFS benefit with the addition of buparlisib (HR, 0.47; 95% CI, 0.32-0.71). Other factors associated with better PFS included progesterone receptor positivity (HR, 0.66; 95% CI, 0.50-0.85) and ECOG performance status of 0 (HR, 0.58; 95% CI, 0.43-0.78).
"The patients who did not benefit from an endocrine therapy and an mTOR inhibitor prior to going on the study actually did benefit from buparlisib," said O'Regan. "This supports the idea that PI3 kinase inhibition may be useful in cancers that are resistant to mTOR inhibitors."
In a group of patients withPIK3CA-mutated tumors by tissue testing (n = 321), the median PFS with the buparlisib combination was 4.7 versus 1.4 months with fulvestrant alone (HR, 0.39; 95% CI, 0.23-0.65;P<.001). Limited benefit was seen for those withPIK3CAwild-type tumor, with a median PFS of 2.8 versus 2.7 months, for buparlisib and placebo, respectively (HR, 0.83; 95% CI, 0.60-1.14;P= .117).
InPIK3CA-positive tumors by ctDNA, the median PFS was 4.2 months with buparlisib versus 1.6 months with placebo (HR, 0.46; 95% CI, 0.29-0.73;P<.001). In the wild-type group by ctDNA, the PFS with the PI3K inhibitor was 3.9 versus 2.7 months with placebo (HR, 0.73; 95% CI, 0.53-1.00;P= .026).
Those with visceral disease (n = 315) had a median PFS of 3.1 months with buparlisib versus 1.5 months with placebo (HR, 0.56; 95% CI, 0.43-0.74). In the non-visceral disease arm (n = 117), the median PFS was 4.2 versus 4.1 months, for buparlisib and placebo, respectively (HR, 0.96; 95% CI, 0.61-1.50). At the time of the analysis, findings for those with visceral disease had not been correlated withPIK3CAstatus.
"The PI3 kinase inhibitors might be more effective in tumors withPIK3CAmutations," said O'Regan. "The buparlisib arm was superior to the control group in the tumor and ctDNAPIK3CAanalysis. There's possibly a signal in cancers that arePIK3CAmutant and for those with visceral disease."
Dose interruptions were required for 36% of patients in the buparlisib arm due to adverse events (AEs) compared with 9% in the placebo group. Dose reductions were also more common with buparlisib versus placebo (31% vs 8%). AEs led to treatment discontinuation for 21% of patients in the buparlisib arm versus 8% of those in the placebo group. There was 1 potentially treatment-related death in each arm.
Grade 3/4 adverse events (AEs) occurred in 62% of patients treated with buparlisib compared with 34% in the placebo arm. The most frequently occurring grade 3/4 AEs with buparlisib versus placebo, respectively, were increased ALT (22% vs 3%), increased AST (18% vs 3%), and hyperglycemia (12% vs 0%). Other AEs of interest with buparlisib were depression (21% vs 8%) and anxiety (18% vs 10%).
"There were more adverse events in the buparlisib arm compared with the control arm," said O'Regan. "There were increased transaminases and also psychiatric issues, like depression and anxiety. There were a few patients who attempted suicide on the buparlisib arm."
There are several ongoing studies assessing more selective PI3K inhibitors in breast cancer. The phase III SOLAR-1 study is currently assessing the alpha-specific PI3K inhibitor alpelisib (BYL719) in combination with fulvestrant as a treatment for postmenopausal women with endocrine-resistant advanced breast cancer.PIK3CAmutation status by ctDNA will be assessed as a secondary endpoint (NCT02437318).
Di Leo A, Keun SL, 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 . Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10; San Antonio, TX. Abstract S4-07.