Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor

Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

Time frame: Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to approximately 4 years

Population: Full Analysis Set (FAS) in the Full Population, the Main Study Cohort (known PI3K pathway activation status \[activated, non activated\]) and the PI3K unknown cohort (PI3K pathway unknown status) were considered.

Clinical Benefit Rate (CBR) is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. CBR was analyzed in the full population. Only descriptive analysis performed.

Time frame: From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 5 years

Population: Full Analysis Set (FAS) in the Full Population, the Main Study Cohort (known PI3K pathway activation status \[activated, non activated\]) and the PI3K unknown cohort (PI3K pathway unknown status) were considered.

The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL. Patients were assessed up to approx. 8.3 months. Only descriptive analysis performed.

Time frame: Cycle 1 day 1, cycle 1 day 15, 6 weeks after randomisation and then every 8 weeks until end of treatment

Population: Full Analysis (FAS)

Time to definitive deterioration of the ECOG PS was defined as the time between the date of randomization and the date of the assessment at which definitive deterioration was seen. Only descriptive analysis performed.

Time frame: Up to approx 27 months

Population: Full Analysis (FAS)

Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths. Only descriptive analysis performed.

Time frame: From first dose of study treatment to 30 days after last dose of study treatment, assessed for approximately 5 years

Population: Safety Set (SS) in Full Population

Overall Response Rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. ORR was analyzed in the full population. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (\< 10 mm short axis)); Partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Only descriptive analysis performed.

Time frame: From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 5 years

Population: Full Analysis Set (FAS) in the Full Population, the Main Study Cohort (known PI3K pathway activation status \[activated, non activated\]) and the PI3K unknown cohort (PI3K pathway unknown status) were considered.

Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive. Patients were followed up for the duration of the study and for an expected average of every 3 months after end of treatment.

Time frame: Every 3 months following end of treatment visit, assessed for approximately 5 years

Population: Full Analysis Set (FAS) in the Full Population, the Main Study Cohort (known PI3K pathway activation status \[activated, non activated\]) and the PI3K unknown cohort (PI3K pathway unknown status) were considered.

Plasma samples were collected from the first 200 BKM120-treated patients on Cycle 2 Day 1 (at pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h \[before Cycle 2 Day 2 dose\] post-dose). Each cycle is 28 days. Only descriptive analysis performed.

Time frame: Cycle2 Day1 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours post-dose). Each cycle is 28 days.

Population: Full Pharmacokinetic Analysis Set (FPAS) included the subset of the patients in the buparlisib PAS who:~* Received all planned doses of BKM120 100mg + Fulvestrant preceding full PK profile assessment~* Did not vomit within 4 hours of buparlisib dosing after administration~* Had an evaluable full PK profile available

Pre-dose samples were collected for trough concentrations at Cycle 2 Day 1, Cycle 2 Day 15 and Cycle 3 Day 1. Each cycle is 28 days. Only descriptive analysis performed.

Time frame: Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1. Each cycle is 28 days.

Population: BKM120 Pharmacokinetic Analysis Set or Buparlisib pharmacokinetic analysis set (Buparlisib PAS) included all patients who received at least one dose of study medication buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.