Treatment with the PI3K inhibitor buparlisib plus fulvestrant showed a 1.9-month extension in progression-free survival compared with fulvestrant alone in women with endocrine-resistant HR-positive/HER2-negative advanced breast cancer.
Mario Campone, MD, PhD
Treatment with the PI3K inhibitor buparlisib (BKM120) plus fulvestrant (Faslodex) showed a 1.9-month extension in progression-free survival (PFS) compared with fulvestrant alone in women with endocrine-resistant HR-positive/HER2-negative advanced breast cancer, according to data from the BELLE-2 trial presented at the 2015 San Antonio Breast Cancer Symposium.
In the phase III study, median PFS with buparlisib plus fulvestrant was 6.9 versus 5.0 months for placebo plus fulvestrant (HR, 0.78; 95% CI, 0.67-0.89; P <.001). In a group of patients with PIK3CA mutations identified by circulating tumor DNA (ctDNA), the benefits seen with buparlisib were more substantial. In this group, median PFS with the PI3K inhibitor was 7.0 versus 3.2 months with placebo (HR, 0.56; P <.001).
“The BELLE-2 study met its primary endpoint, demonstrating prolonged PFS for combined buparlisib and fulvestrant in postmenopausal women with HR-positive/HER2-negative advanced breast cancer that had progressed after prior AI therapy,” said senior author Mario Campone, MD, PhD, Institut de CancÃ©rologie de l'Ouest—RenÃ© Gauducheau Centre de Recherche en CancÃ©rologie, Nantes, France. “Patients with tumors harboring PIK3CA mutations detected in circulating DNA performed poorly on fulvestrant monotherapy, achieving a clinically meaningful PFS improvement with buparlisib and fulvestrant."
In the study, 1147 postmenopausal women with HR-positive/HER2-negative locally advanced or metastatic breast cancer were randomized to receive fulvestrant plus either buparlisib (n = 576) or placebo (n = 571). Fulvestrant was administered at 500 mg in each arm. Buparlisib was administered at 100 mg per day.
All patients enrolled in the study had progressed on or after an aromatase inhibitor, and 28% had received prior chemotherapy for metastatic disease. Most patients were sensitive to prior endocrine therapy (69%). A majority of patients had an ECOG PS of 0 or 1 (98%) and 61% of patients had visceral disease.
The primary endpoint was PFS in the full population and in those with PIK3CA mutations and/or PTEN loss. The secondary endpoints of the study were overall survival, overall response rate (ORR), and safety. PIK3CA/PTEN testing was conducted on archival tissue and using an exploratory liquid biopsy test for ctDNA that was conducted prior to the initiation of treatment.
Across the full population, the ORR with buparlisib was 12% versus 8% with placebo. The clinical benefit rate with the PI3K inhibitor was 44% versus 42% with placebo. For the primary endpoint of PFS, Kaplan-Meier curves separated early and remained divided at 30 months. At the 2-year interval, approximately 18% of patients remained progression-free with buparlisib versus around 10% with placebo.
“A lot of studies in metastatic breast cancer show these modest benefits, and then when you take the treatment earlier in the course of the disease, such as the adjuvant setting, you see a much more dramatic benefit,” said breast cancer expert C. Kent Osborne, MD, professor, director, Baylor College of Medicine Dan L Duncan Comprehensive Cancer Center. “I think, while this is modest, it is the first time that a PI3K inhibitors has shown a benefit. I would say this is still an advance that gives us more information about this pathway in endocrine resistant disease.”
In a group of patients with PI3K activation on archival tissue (n = 372), there was a trend toward improvement in PFS with buparlisib; however, it was not statistically significant. The median PFS was 6.8 versus 4.0 months, for buparlisib and placebo, respectively (HR, 0.76; 95% CI, 0.60-0.97; P = .014). At the time of the analysis, overall survival data were not yet mature.
In the group of patients with PIK3CA mutations identified by ctDNA during a liquid biopsy, the ORR with buparlisib was 18.4% compared with 3.5% with fulvestrant and placebo. The clinical benefit rate was 47% versus 32%, with buparlisib versus placebo, respectively.
In those with non-mutant PIK3CA by liquid biopsy, there was no difference observed between the two arms for PFS (6.8 vs 6.8; HR, 1.05; P = .642). The ORR was 12% with buparlisib versus 11% with placebo. The clinical benefit rates were 43% and 50%, for buparlisib and placebo, respectively.
“We showed for the first time that inhibiting the PI3K pathway may be a viable option for patients with endocrine therapy-resistant breast cancer," lead investigator JosÃ© Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, said in a statement. “The primary outcome was quite dramatic in patients whose tumors had mutant PIK3CA–a median progression-free survival of 7 months in those who received buparlisib plus fulvestrant versus 3.2 months in those who received placebo plus fulvestrant.”
Potentially relevant imbalances existed between the two arms in the ctDNA PIK3CA-mutant group. The median time from diagnosis to study entry was 73.8 months in the buparlisib arm versus 51.3 months in the placebo group. Additionally, more patients in the placebo arm had visceral disease (60.9% vs 68.1%), specifically lung metastases (27.6% vs 37.2%). A multivariate analysis, however, did show an interaction between these factors and outcomes. Overall, the adjusted hazard ratio in the multivariate analysis was the same as the unadjusted numbers.
“BELLE-2 study suggests that assessment of PIK3CA mutations in circulating DNA may help select patients who benefit from adding a PI3K inhibitor to endocrine therapy," remarked Campone. "Circulating DNA obtained from blood samples has emerged as a sensitive, reliable, and minimally invasive way to measure current PIK3CA mutation status.”
Grade 3/4 adverse events (AEs) occurred in 77.3% of patients treated with buparlisib compared with 32% in the placebo arm. The most frequently occurring grade 4 AEs with buparlisib were increased ALT (6.8%), increased AST (3.0%), and depression (0.7%). For grade 3 AEs, the most frequently observed with buparlisib were ALT and AST increase (18.7% and 15%, respectively), hyperglycemia (15.2%), rash (7.7%), anxiety (4.9%), fatigue (4.9%), depression (3.7%), and diarrhea (3.7%).
"Frequent discontinuations due to AEs reduced treatment duration in the buparlisib arm, potentially limiting theÂ efficacy of combination therapy," said Campone.
The most common causes of treatment discontinuation were disease progression and AEs. In the buparlisib arm, 13% of patients stopped therapy due to AEs versus 2% in the placebo arm. The on-treatment death rate was similar between the two arms, with 12 deaths in each group.
“PI3K is an important pathway for normal cellular functions; therefore, as one would expect, side effects from buparlisib were substantial,” said Baselga. “We are hopeful that future, newer-generation PI3K inhibitors would be less toxic.”
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. PIK3CA mutation status by ctDNA will be assessed as a secondary endpoint (NCT02437318).
Baselga J, Im S-A, Iwata H, et al. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2—advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S6-01.