Abstract OT3-05-02: BYLieve: A phase 2 study of alpelisib with fulvestrant or letrozole for treatment of PIK3CA mutant, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) progressing on/after cyclin-dependent kinase (CDK)4/6 inhibitor therapy
Authors: Rugo HS , Turner N , Chia S , Ciruelos E , Nienstedt C , Ridolfi A , Kong O , Sankaran B , Juric D 
Published: February 2018

Abstract
Background: Endocrine therapy (ET) is the standard of care for treatment of HR+, HER2– aBC. However, ET resistance occurs frequently leading to disease progression. Dysregulation of the PI3K/AKT/mTOR pathway, specifically mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K, has been implicated in ET resistance. In a phase 1 study, alpelisib, a PI3Kα-specific inhibitor, in combination with fulvestrant has shown antitumor activity in patients with PIK3CA mutant, HR+, HER2– aBC. The present BYLieve (NCT03056755) study aims to assess the efficacy and safety of alpelisib + fulvestrant/letrozole in PIK3CA-mutant, HR+, HER2– aBC progressing on/after prior CDK4/6 inhibitor (CDK4/6i) therapy.
Methods: BYLieve is a phase 2, multicenter, open-label, 2-cohort, non-comparative study. Men and postmenopausal women (≥ 18 years) with PIK3CA-mutant, HR+, HER2− locally advanced or metastatic breast cancer that has progressed on/after prior CDK4/6i therapy are eligible. Other eligibility criteria include ≥ 1 measurable lesion (RECIST v1.1) or predominantly lytic bone lesion; ECOG PS ≤ 2; and no prior PI3K inhibitor therapy. Patients are allocated to 2 cohorts based on the prior ET partner (aromatase inhibitor (AI) or fulvestrant) used in combination with CDK4/6i. Cohort A (patients who had received CDK4/6i + AI): oral alpelisib (300 mg once daily) + intramuscular fulvestrant (500 mg on days 1 and 15 of cycle 1, and day 1 of cycles ≥ 2 [28-day cycles]) and cohort B (patients who had received CDK4/6i + fulvestrant): oral alpelisib (300 mg once daily) + oral letrozole (2.5 mg once daily). Study treatment will continue until disease progression or intolerable toxicity. The primary end point is the proportion of patients who are alive without disease progression at 6 months (RECIST v1.1; local assessment), which will be evaluated separately in each cohort and presented together with 2-sided 90% confidence intervals using Clopper and Pearson (1934) exact method. Evidence of treatment effect will be demonstrated if the lower bound of the 90% CI is greater than 30%. A total sample size of 80 patients in each cohort is planned. Secondary end points include progression-free survival (PFS), PFS on next-line treatment (PFS2), overall response rate, clinical benefit rate, duration of response, safety, and tolerability. Detection of frequency of PIK3CA mutations in ctDNA and its correlation with response is an exploratory end point.
Citation Format: Rugo HS, Turner N, Chia S, Ciruelos E, Nienstedt C, Ridolfi A, Kong O, Sankaran B, Juric D. BYLieve: A phase 2 study of alpelisib with fulvestrant or letrozole for treatment of PIK3CA mutant, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) progressing on/after cyclin-dependent kinase (CDK)4/6 inhibitor therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-02.