May 15, 2019
3 min read

Alpelisib plus fulvestrant extends PFS in PIK3CA-mutated advanced breast cancer

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Patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer previously treated with endocrine therapy achieved longer PFS with alpelisib and fulvestrant compared with placebo and fulvestrant, according to results of a randomized, phase 3 trial published in The New England Journal of Medicine.

 “Approximately 40% of patients with [hormone receptor]-positive, HER2-negative breast cancer have activating mutations in the gene PIK3CA, inducing hyperactivation of the alpha isoform of phosphatidylinositol 3-kinase (PI3K),” Fabrice André, MD, PhD, professor in the department of medical oncology at Institut Gustave Roussy in France, and colleagues wrote. “Endocrine therapy, with or without the use of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, is the standard treatment for patients with [hormone receptor]-positive, HER2-negative advanced breast cancer. However, acquired resistance to endocrine-based therapy remains a challenge.”

Alpelisib (BYL719, Novartis) — a small-molecule, alpha-specific PI3K inhibitor — has shown antitumor activity in combination with fulvestrant (Faslodex, AstraZeneca) in PIK3CA-mutated, ER-positive xenograft models, according to study background.

In the randomized, double-blind, placebo-controlled phase 3 trial, André and colleagues evaluated the safety and efficacy of the combination among 572 patients with hormone receptor-positive, HER2-negative advanced breast cancer who experienced progression or relapsed during or after previous endocrine therapy. Patients had either measurable disease or at least one primarily lytic bone lesion, ECOG performance status of 0 or 1, and suitable organ and bone marrow function.

The researchers randomly assigned patients to receive fulvestrant 500 mg every 28 days and once on day 15 plus either alpelisib 300 mg daily or placebo.

They divided patients into two cohorts based on tumor-tissue PIK3CA mutation status. Among the 341 patients with confirmed tumor-tissue PIK3CA mutation, 169 (median age, 63 years; range 25-87) received alpelisib plus fulvestrant and 172 (median age, 64 years; range, 38-92) received placebo plus fulvestrant.

Investigator-assessed PFS in the cohort with PIK3CA-mutated cancer served as the study’s primary endpoint. Researchers also assessed PFS in the cohort without PIK3CA-mutant disease. Secondary endpoints included overall response and safety.

PIK3CA mutations demonstrated median PFS of 11 months (95% CI, 7.5 -14.5) with alpelisib-fulvestrant vs. 5.7 months (95% CI, 3.7-7.4) with placebo-fulvestrant (HR for progression or death = 0.65; 95% CI, 0.5-0.85).

In the PIK3CA-mutated cohort, alpelisib-fulvestrant yielded a greater overall response rate (26.6%) vs. placebo-fulvesrant (12.8%), as well as a higher clinical benefit rate (61.5% vs. 45.3%) and a higher ORR among patients with measurable disease at baseline (35.7% vs. 16.2%).


Researchers did not observe a clinically relevant treatment benefit for alpelisib-fulvestrant among patients without PIK3CA-mutated disease. Among this group, median PFS was 7.4 months with alpelisib vs. 5.6 months with placebo (HR = 0.85; 95% CI, 0.58-1.25; posterior probability of HR < 1, 79.4%).

The most common grade 3 or grade 4 adverse events included hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). A greater proportion of patients in the alpelisib-fulvestrant group experienced grade 3 diarrhea (6.7% vs. 0.3%); however, no grade 4 diarrhea occurred.

Rates of treatment discontinuation due to adverse events were 25% with alpelisib-fulvestrant and 4.2% with placebo-fulvestrant.
in the alpelisib-fulvestrant group (2.5%) and 12 patients in the placebo-fulvestrant group (4.2%) died during the trial.

Alpelisib has activity in patients with PIK3CA-mutated, [hormone receptor]-positive, HER2-negative advanced breast cancer that has progressed during or after treatment with an aromatase inhibitor,” the researchers wrote. “Therefore, the integration of genomic testing for PIK3CA mutation into routine clinical practice may be useful in the selection of therapy; validated diagnostic testing procedures are not yet available.” – by Jennifer Byrne

Disclosures: André reports grants from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis and Roche. Please see the study for all other authors’ relevant disclosures.