BYLieve Study Results Support the Use of Alpelisib Combined with Fulvestrant for Hormone Receptor–Positive, HER2-Negative, PIK3CA Mutation–Positive Advanced Breast Cancer

BYLieve study results show that alpelisib combined with fulvestrant demonstrates clinically meaningful efficacy and manageable toxicity in patients with hormone receptor–positive, HER2-negative, PIK3CA mutation–positive advanced breast cancer.

In approximately 40% of patients with hormone receptor–positive, HER2-negative advanced breast cancer, PIK3CA mutations occur and are associated with treatment resistance and poor prognosis. The demonstrated efficacy of alpelisib, a PI3K-alpha inhibitor, plus fulvestrant for the treatment of PIK3CA mutation–positive, hormone receptor–positive advanced breast cancer had been shown previously in the phase 3 SOLAR-1 trial.¹

There is a dearth of clinical data and prospective studies on which to base treatment decisions for patients with hormone receptor–positive, HER2-negative, PIK3CA mutation–positive advanced breast cancer if they have previously been treated with a CDK4/6 inhibitor. In the first trial to assess this treatment paradigm, BYLieve evaluates alpelisib plus endocrine therapy (fulvestrant or letrozole) in patients with hormone receptor–positive, HER2-negative, PIK3CA mutation–positive advanced breast cancer whose disease progressed on/after previous therapy, including a CDK4/6 inhibitor.

Patients (N = 112) with centrally confirmed PIK3CA mutation in tumor tissue are currently enrolled in each cohort based on immediate previous treatment of a CDK4/6 inhibitor plus an aromatase inhibitor, a CDK4/6 inhibitor plus fulvestrant, or systemic chemotherapy or endocrine therapy, in this ongoing phase 2, open-label, noncomparative study.

Enrollment is complete in previous CDK4/6 inhibitor plus aromatase inhibitor and CDK4/6 inhibitor plus fulvestrant cohorts but is ongoing in a previous systemic chemotherapy or endocrine therapy cohort. Here, Hope S. Rugo, MD, Director, Breast Oncology and Clinical Trials Education, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, reported on the CDK4/6 inhibitor plus aromatase inhibitor as an immediate previous treatment cohort.

Alpelisib 300 mg daily plus fulvestrant 500 mg was prescribed to patients. The proportion of patients alive without disease progression at 6 months per local assessment was the primary end point. All patients were assessed for safety.

Patients (N = 127) whose immediate previous treatment was CDK4/6 inhibitor plus aromatase inhibitor were enrolled. A subset of patients (N = 121) with centrally confirmed PIK3CA mutation were included in this study. The median follow-up was 11.7 months. The proportion of patients without disease progression at 6 months was 50.4% (95% confidence interval, 41.2-59.6), suggesting the primary end point was met.

The most commonly reported all-grade adverse events were diarrhea (60%), hyperglycemia (58%), and nausea (46%). Slightly less than one-third of patients reported fatigue, decreased appetite, and rash. Discontinuation due to adverse events was low; 5 (3.9%) patients discontinued due to rash and 2 (1.6%) patients experienced vomiting that caused discontinuation. Colitis, hyperglycemia, and urticaria were also reported as other sources of discontinuation.

With ongoing follow-up, the BYLieve study demonstrates that in a large sample size, patients receiving alpelisib combined with fulvestrant benefit in a clinically meaningful way. A growing body of evidence highlights the efficacy of this combination, as well as the manageable toxicity profile after treatment with a CDK4/6 inhibitor. Building on findings from SOLAR-1, BYLieve further supports use of alpelisib combined with fulvestrant for the treatment of patients with hormone receptor–positive, HER2-negative, PIK3CA mutation–positive advanced breast cancer.

Source: Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. J Clin Oncol. 2020;38(15_suppl). Abstract 1006.

Reference
1. André F, Ciruelos E, Rubovszky G, et al; for the SOLAR-1 Study Group. Alpelisib for PIK3CA-muatated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940.