The standard of care for patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast is endocrine therapy with or without a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor. Despite improvements in patient outcomes, a majority of patients eventually develop acquired resistance to endocrine-based therapy that is challenging to treat. Approximately 40% of patients with HR-positive, HER2-negative breast cancer harbor activating mutations in the PIK3CA gene. However, use of targeted therapy with phosphatidylinositol 3-kinase (PI3K) inhibitors in breast cancer has been historically disappointing. These agents have been associated with modest clinical benefit and high rates of toxicity. Alpelisib is a novel, oral, small-molecule PI3K inhibitor that is specific for the alpha isoform and showed synergistic antitumor activity with the antiestrogen fulvestrant in preclinical trials. Furthermore, in a phase Ib trial in heavily pretreated patients with PIK3CA-mutated breast cancer, this combination yielded a complete or partial response in 29% of patients. In the randomized phase III SOLAR-1 trial (N = 572, including 341 with confirmed PI3KCA mutations in tumor tissue), the combination of alpelisib and fulvestrant was compared to fulvestrant alone in patients with HR-positive, HER2-negative advanced breast cancer who had previously been treated with aromatase inhibitor and were eligible for further endocrine therapy.
At a median follow-up of 20 months, the median progression-free survival (PFS) in patients with PI3KCA mutations was 11.0 months in patients receiving alpelisib plus fulvestrant, compared to 5.7 months in patients receiving fulvestrant and placebo (HR 0.65, P<.001), corresponding to a 35% reduction in the risk of progression or death. These results were supported also by blinded independent review. The estimated 12-month PFS rates were 46.3% and 32.9% with alpelisib plus fulvestrant and fulvestrant plus placebo, respectively. The PFS benefit was observed across multiple prespecified subgroups, including 20 patients previously treated with CDK4/6 inhibitor. Among patients with PI3KCA mutations, the overall response rate (ORR) favored alpelisib and fulvestrant over fulvestrant in the total population (26.6% vs 12.8%) and in patients with measurable disease at baseline (35.7% versus 16.2%). In contrast, in 231 patients with wildtype PI3KCA, treatment with alpelisib plus fulvestrant did not result in a clinically relevant treatment benefit (median PFS of 7.4 months vs 5.6 months; HR 0.85).
Alpelisib was associated with a manageable adverse event (AE) profile, with much lower rates of severe AEs than seen with the pan-PI3K inhibitors previously studied in breast cancer. Serious AEs occurred in 34.9% of patients receiving alpelisib plus fulvestrant and 16.7% of patients receiving fulvestrant and placebo. The most common grade 3/4 AEs were hyperglycemia (36.6% vs 0.7%), rash (9.9% vs 0.3%), and diarrhea (6.7% vs 0.3). A total of 71 patients (25.0%) receiving alpelisib plus fulvestrant and 12 patients (4.2%) receiving placebo plus fulvestrant discontinued treatment due to AEs.
The investigators concluded that the addition of the alpha-specific PI3K inhibitor alpelisib to fulvestrant in patients with PI3KCA-mutated, HR-positive, HER2-negative advanced breast cancer after disease progression on previous endocrine therapy significantly prolonged PFS. Furthermore, these results validate PI3K as an important therapeutic target and indicate that PI3KCA genomic testing may be useful for treatment selection in HR-positive, HER2-negative advanced breast cancer. Given that current standard first-line therapy for HR-positive, HER2-negative advanced breast cancer most often includes CDK 4/6 inhibitors, the role of alpelisib in the patients with PIK3CA mutations who progressed during or after treatment with a CDK4/6 inhibitor is currently being evaluated in the ongoing BYLieve trial.