Alpelisib Plus Fulvestrant in PIK3CA-Mutant, Hormone Receptor–Positive, HER2-Negative Advanced Breast Cancer After Disease Progression

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As reported in The Lancet Oncology by Hope S. Rugo, MD, and colleagues, findings in one cohort of the phase II BYLieve trial indicated activity of the PI3Kα-selective inhibitor and degrader alpelisib plus fulvestrant in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer with disease progression after treatment with a CDK4/6 inhibitor plus an aromatase inhibitor.

Hope S. Rugo, MD

Hope S. Rugo, MD

Study Details

The ongoing study enrolled patients with hormone receptor–positive, HER2-negative advanced breast cancer and a PIK3CA mutation following progression on or after previous therapy, including CDK4/6 inhibitors, from sites in 18 countries into three cohorts (based on treatment most recently received). Patients could have received no more than two previous anticancer treatments and no more than one previous chemotherapy regimen.

In the current cohort, 121 patients with centrally confirmed PIK3CA mutation were enrolled between August 2017 and December 2019 (data cutoff). Patients received oral alpelisib at 300 mg/day continuously plus intramuscular fulvestrant at 500 mg on day 1 of each 28-day cycle and on day 15 of the first cycle. The primary endpoint was the proportion of patients alive without disease progression at 6 months on local assessment using Response Evaluation Criteria in Solid Tumors version 1.1. Overall, 98% of patients had stage IV disease.

Proportion Alive Without Disease Progression at 6 Months

At data cutoff, median follow-up was 11.7 months (interquartile range [IQR] = 8.5–15.9 months).

A total of 61 patients (50.4%, 95% confidence interval [CI] = 41.2%–59.6%) were alive without disease progression at 6 months. Progression-free survival events were progression in 47 patients and death in 6; 7 patients withdrew consent or were lost to follow-up.  

Median progression-free survival was 7.3 months (95% CI = 5.6–8.3 months). Median overall survival was 17.3 months (95% CI = 17.2–20.7 months), with 25 deaths reported. Objective responses (all partial) were observed in 21 patients (17%; 95% CI = 11%–25%); an additional 55 patients (46%) had stable disease. Median time to response was 1.84 months (IQR = 1.74–3.48 months). Median duration of response was 6.6 months (95% CI = 4.3 months–not estimable).


  • 50.4% of patients receiving alpelisib plus fulvestrant were alive without disease progression at 6 months.
  • Median progression-free survival was 7.3 months.

Adverse Events

Among 127 patients receiving alpelisib and fulvestrant, grade ≥ 3 adverse events occurred in 67%, with the most common being hyperglycemia (28%), rash (9%), maculopapular rash (9%), and diarrhea (6%). Serious adverse events occurred in 26% of patients (treatment-related in 16%), with hyperglycemia being the most common treatment-related event (6%). Adverse events led to dose interruption or adjustment in 65% of patients and to treatment discontinuation in 21%, with the most common cause of discontinuation being rash (4%). No treatment-related deaths were reported.

The investigators concluded, “BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, [hormone receptor–positive], HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.”

Dr. Rugo, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit

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