Long-Term Disease Control with Fulvestrant plus Alpelisib in PIK3CA-Mutated HR-Positive/HER2-Negative Advanced Breast Cancer: Findings from Cohort A of the BYLieve Study

PIK3CA mutations, which are seen in approximately 40% of patients with HR-positive/HER2-negative advanced breast cancer, are associated with treatment resistance and shorter survival. Alpha-selective PI3K inhibitor alpelisib is indicated for this population in combination with fulvestrant. BYLieve was a phase 2, nonrandomized, open-label study of alpelisib plus endocrine therapy (fulvestrant in Cohort A) in patients with HR-positive/HER2-negative advanced breast cancer whose disease progressed on or following prior CDK4/6 inhibitor therapy. The BYLieve study Cohort A was analyzed for patients achieving long-term (LT) and very-long-term (VLT) disease control.

In Cohort A of the BYLieve study, median progression-free survival (PFS) was 7.26 months. LT disease control was defined as PFS of 12 months or greater, with VLT disease control defined as PFS of 18 months or greater; those patients with PFS of less than 12 months were considered to not have LT disease control. Incidence rate (IR) per 100 patient-treatment years was calculated to assess exposure-adjusted adverse events. To assess tumor complexity in patients eliciting LT or VLT disease control, median circulating tumor DNA (ctDNA) fraction, chromosome 8/11 amplification, and ESR1 mutations were determined by next-generation sequencing.

BYLieve Cohort A included 127 patients, of which 31 (24.4%) achieved LT disease control with a median PFS (mPFS) of 24.8 months (95% confidence interval [CI], 18.2 to 31.1 months) and 21 patients achieved VLT disease control (mPFS, 29.4 months; 95% CI, 24.8 to 33.1 months). Patients with LT to VLT disease control had lower BMI and ECOG score, longer time from initial diagnosis to first recurrence/relapse, more frequent bone-only lesions, and fewer liver metastases than patients without LT or VLT disease control.

Median exposure to alpelisib was 5.1, 3.6, 21.3, and 25.6 months for all Cohort A patients (n = 127), patients without LT or VLT disease control (n = 96), patients with LT disease control (n = 31), and patients with VLT disease control (n = 21), respectively. The IR per 100 patient-treatment years of diarrhea, hyperglycemia, and rash were lower in patients with LT disease control (IR 127.7, n = 25; IR 72.7, n = 20; IR 20.2, n = 10, respectively) and VLT disease control (IR 100.3, n = 17; IR 51.3, n = 12; IR 21.2, n = 8, respectively) than in patients without LT or VLT disease control (IR 253.2, n = 57; IR 251.7, n = 56; IR 86.0, n = 30, respectively). In patients with LT and VLT disease control, ctDNA fraction was <10% in 32.3% (10/31) and 40.0% (8/20) of patients, respectively, whereas ctDNA fraction was <10% in 23.2% (16/69) of patients without LT or VLT disease control. Incidence of chromosome 8/11 amplification was 10% in both patients with LT and VLT disease control, and 19% in patients without LT or VLT disease control. Incidence of ESR1 mutations was 26%, 24%, and 26% in patients with LT disease control, VLT disease control, and those without LT or VLT disease control, respectively.

In patients with PIK3CA-mutated HR-positive/HER2-negative advanced breast cancer treated with alpelisib plus fulvestrant following progression on or after CDK4/6 inhibitor therapy, LT and VLT disease control was observed in 24.4% and 16.5% of patients, respectively. Visceral disease, adverse events, and ESR1 mutations did not preclude patients from demonstrating LT or VLT disease control. Investigators concluded that these data confirm targeting PIK3CA-mutated advanced breast cancer with alpelisib plus fulvestrant post-CDK4/6 inhibitor therapy may lead to durable disease control.

Source:

Rugo HS, Chia S, Castan JC, et al. Long-term and very-long-term disease control in patients from BYLieve study cohort A with PIK3CA-mutant, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer. San Antonio Breast Cancer Symposium 2022. Abstract PD13-06.

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