Abstract PD2-07: Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results
Authors: Rugo Hope S. , Lerebours Florence , Juric Dejan , Turner Nicholas , Chia Stephen , Drullinsky Pamela , Prat Aleix , Vázquez Rafael Villanueva , Akdere Murat , Arce Christina , Shen Yu-Ming , Ciruelos Eva 
Published: February 2021

Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is &gt;30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting.

Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vázquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-07.