BELLE-2 is a randomised double blind phase III clinical trial of buparlisib in combination with fulvestrant in postmenopausal women hormone receptor positive HER2 negative advanced breast cancer progressed on or after with anti-aromatase inhibitor. Randomisation was stratified into activation of the PI3 kinase pathway and presence of visceral disease. The primary endpoint was PFS in the full population and the PI3 kinase activity group. PFS in subpopulation patients detected by liquid biopsy was an exploratory endpoint.
The key inclusion criteria were postmenopausal women with ER and/or PR positive breast cancer, HER2 inoperable or locally advanced or metastatic breast cancer, disease progression on/after anti-aromatase therapy defined by recurrence during or less than twelve months from the end of adjuvant anti-aromatase therapy, progression during or less than one month from the end of anti-aromatase therapy for locally advanced metastatic breast cancer, measurable disease or not measurable disease, lytic or mixed bone lesions, adequate tumour tissue for analysis of PI3 kinase related biomarkers. The key inclusion criteria prior therapy with PI3, inhibitor or fulvestrant, not more than one prior chemotherapy line for metastatic disease, a history of or active anxiety, depression or major disorder.
The most common all grade adverse event were grade 3 and 4 from the combination of BKM and fulvestrant which increases liver enzyme, hypoglycaemia, rash and mood disorder.
The study met its primary endpoint. For the full study population median progression free survival of the combination arm was 6.9 months versus 5 months for those in the placebo arm with a reduction rate of 22% risk of progression. For the study population of PI3 kinase activity the median PFS was 6.8 versus 4.0 in the placebo arm but is not statistically significant.
We evaluated in a prospective subpopulation of patients with the PI3 kinase mutation detected by liquid biopsy. Liquid biopsies were a blood sample drawn from cancer patients to analyse traces among the free floating tumour in the blood. The minimally invasive test offers several advantages over conventional tumour biopsy: since surgery is not needed the patient can be tested more frequently and in BELLE-2 blood samples from 587 patients were analysed for this PI3 kinase mutation in the liquid biopsy.
The association of BKM and fulvestrant improved the median of progression for in the subpopulation of patients with a PI3 kinase mutation detected by liquid biopsy, 7 months versus 3.2 months compared to the placebo arm with a 44% reduction in risk for progression. There is no difference in terms of progression free survival in the non-mutant PI3 kinase subpopulation patients detected by liquid biopsy between the two arms.
In conclusion, the BELLE-2 met its primary endpoint demonstrating prolonged PFS for combining buparlisib and fulvestrant in postmenopausal women with ER positive HER2 negative breast cancer that had progressed after prior anti-aromatase therapy. It is the first time we showed that inhibiting the PI3 kinase pathway may be a viable option for patients with hormone therapy resistant breast cancer. Frequent discontinuation due to adverse events reduced treatment duration in the buparlisib arm potentially limiting the efficacy of combination therapy. Patients with tumours harbouring PI3 kinase mutations detected by liquid biopsy performed poorly on fulvestrant monotherapy, achieving a clinical meaningful PFS in buparlisib and fulvestrant 3.8 months with a response rate of 20% compared to 4% in the patient population.
The BELLE-2 study suggests the assessment of PI3 kinase mutation in liquid biopsy may help select patients who would benefit from adding a PI3 kinase inhibitor to endocrine therapy. Further studies are warranted to confirm the and the predictive value of PI3 kinase mutation detected by liquid biopsy and the tumour to see in the SOLAR study clinical trial. Thank you for your attention.