A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer

**Purpose:** This study aims to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and preliminary efficacy of combining alpelisib or buparlisib with tamoxifen and goserelin in premenopausal patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC).

**Patients and Methods:** The study included premenopausal women with HR+, HER2- ABC. Participants received tamoxifen (20 mg daily) and goserelin acetate (3.6 mg every 28 days), alongside either alpelisib (350 mg daily; n = 16) or buparlisib (100 mg daily; n = 13) in 28-day cycles until the MTD was identified.

**Results:** Neither alpelisib nor buparlisib reached the criteria for MTD. The RP2Ds were established at 350 mg for alpelisib and 100 mg for buparlisib, both in combination with tamoxifen and goserelin. Both combinations were considered tolerable according to the study protocol. The most frequent grade 3/4 treatment-emergent adverse events (TEAEs) for alpelisib were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%), while for buparlisib, they were elevated alanine aminotransferase (30.8%), increased aspartate aminotransferase (23.1%), and anxiety (15.4%). Treatment discontinuation due to TEAEs occurred in 18.8% of patients on alpelisib and 53.8% of those on buparlisib. Progression-free survival was reported at 25.2 months for the alpelisib group and 20.6 months for the buparlisib group.

**Conclusions:** The RP2Ds for alpelisib and buparlisib were determined to be 350 mg and 100 mg, respectively. No unexpected safety issues were observed. Although this is an early-phase study, the results indicate that alpelisib combined with endocrine therapy could be a promising treatment option deserving further investigation in premenopausal patients with HR+, HER2- ABC.