Triplet Therapy for Bad-Acting ER+ Breast Cancer

The typical first-line treatment for ER+/HER2− metastatic breast cancer — an endocrine agent combined with a CDK4/6 inhibitor — affords a progression-free survival (PFS) benefit over endocrine therapy alone, but the magnitude of benefit appears to be smaller in the roughly 40% of patients whose tumors harbor PIK3CA mutations. For patients with PIK3CA mutations and disease progression in the first-line setting, combining fulvestrant with either a PI3K inhibitor or an AKT pathway inhibitor for the next treatment provides longer PFS than endocrine therapy alone. Based on these findings, investigators examined whether combining endocrine therapy with a CDK4/6 inhibitor and a PI3K inhibitor could improve outcomes in patients with these more-aggressive tumors.

In an industry-sponsored, phase 3 trial, 325 patients with PIK3CA-mutated, ER+/HER2− metastatic breast cancer were randomly assigned to receive first-line treatment with either inavolisib (an oral selective PI3Kα inhibitor) or placebo, plus fulvestrant and palbociclib. Patients had poor prognostic features, including disease recurrence or progression during or within 12 months after adjuvant endocrine therapy (100%), metastases in at least three organs (≈50%), and liver metastases (≈50%). The median PFS was approximately twice as long in the inavolisib group as in the placebo group (15.0 vs. 7.3 months). Objective response was more frequent with inavolisib than placebo (58.4% vs. 25.0%). Hyperglycemia, a class effect of PI3K inhibitors, occurred in approximately 60% of patients, but grade 3 or 4 hyperglycemia, stomatitis, and diarrhea each occurred in ≤6%.