Alpelisib for PIK3CA-Mutated Breast Cancer

PIK3CA mutations are common in hormone receptor (HR)–positive, HER2-negative breast cancer, occurring in about 40% of patients. Early studies of PI3K inhibitors demonstrated antitumor activity in patients with PIK3CA mutations, but the benefit is questionable in light of substantial gastrointestinal toxicity.

Now, investigators report primary results of the industry-funded, randomized, phase III SOLAR-1 trial, which tested the efficacy and safety of the alpha-specific PI3K inhibitor alpelisib in 572 patients (median age, 63 years) with advanced HR-positive, HER2-negative disease who had received prior endocrine therapy; of these patients, 72% had tumor-tissue PIK3CA mutations and 86% had endocrine-resistant disease. No chemotherapy for advanced disease was permitted, but prior treatment with an aromatase inhibitor in the neoadjuvant or adjuvant setting was allowed. Six percent of patients had previously received a CDK4/6 inhibitor. Patients were assigned to receive the estrogen receptor antagonist fulvestrant plus either alpelisib or placebo.

In patients with PIK3CA mutations, progression-free survival (PFS) was improved with alpelisib versus placebo (PFS; 11.0 vs. 5.7 months; hazard ratio, 0.65; P<0.001), as was objective response rate (35.7% vs. 16.2%). In patients without PIK3CA mutations, proof of concept was not met for alpelisib versus placebo (PFS, 7.4 vs. 5.6 months; HR, 0.85). Grade 3/4 hyperglycemia was more common with alpelisib than with placebo (36.6% vs. 0.7%). However, grade 3 diarrhea occurred in only 6.7% of patients receiving alpelisib, and no grade 4 diarrhea was observed.