Buparlisib in combination with tamoxifen in pretreated patients with hormone receptor-positive, HER2-negative advanced breast cancer molecularly stratified for PIK3CA mutations and loss of PTEN expression

Abstract

The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor-positive (HR⁺ ), HER2-negative advanced breast cancer patients after failure of prior endocrine therapy. In this open-label, single-arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100 mg) and tamoxifen (20 mg) once daily on a continuous schedule (28-day cycle) until progression or unacceptable toxicity. Primary endpoint was overall 6-month progression-free survival (PFS) rate. Key secondary endpoints included the 6-month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety. Overall, the 6-month PFS rate was 33.3% (n/N = 7/21, one-sided 95% CI 16.8-100) and median PFS was 6.1 (CI 2.6-10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA-mutated subgroup consistently showed the highest 6-month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk-benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR⁺ breast cancer. Further biomarker-stratified studies with isoform-specific PI3K inhibitors are warranted. EudraCT No: 2014-000599-24.

Keywords: PI3K; breast cancer; buparlisib; clinical trial; drug therapy; phase II.

FIGURE 1

CONSORT flow diagram. The reason “adverse event” includes both inacceptable toxicity and (serious) adverse events. After prescreening for identification of biomarker status, patients were screened for eligibility and assigned to the respective subgroup by molecular stratification. Study recruitment was terminated by sponsor due to reevaluation of the risk‐benefit profile of buparlisib. Abbreviations: n: number (of events); PIK3CA: Phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha isoform; PTEN, Phosphatase and tensin homolog; ITT, intention‐to‐treat; SAF, safety set

FIGURE 2

Kaplan‐Meier Estimate of Progression‐Free Survival. Displayed are progression‐free survival in the total patient population (A) and in the prespecified subgroups: PIK3CA mut = “PIK3CA mut/ PTEN preserved”; PTEN loss = “PIK3CA mut or wt/ PTEN loss”; wild‐type = “PIK3CA wt/ PTEN preserved” (B) in the SAF population. Abbreviations: CI, confidence interval; n, number (of events); NA, not reached; PFS, progression‐free survival