Alpelisib prolongs PFS for PIK3CA-mutant advanced breast cancer

MUNICH — The addition of alpelisib to fulvestrant significantly extended PFS among patients with hormone receptor-positive, HER2-negative advanced breast cancer who harbored PIK3CA mutations, according to study results presented at European Society for Medical Oncology Congress.

Alpelisib (BYL719, Novartis), an investigational alpha-specific PI3 kinase inhibitor, also appeared well tolerated.

“Alpelisib is the first drug to show a benefit in a genomic subgroup of [patients with breast cancer,” study author Fabrice André, MD, PhD, oncologist and professor of medical oncology at Institut Gustave Roussy in Villejuif, France, said in a press release. “We have had HER2-targeted drugs ... but, until now, the use of tumor genomics has not really entered the practical care of breast cancer.”

Endocrine therapy with or without a CDK 4/6 inhibitor is used as first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer. Slightly more than one-third (39%) of patients remain progression free on this treatment for 2.2 years.

The PI3 kinase is an enzyme that activates cell cycle and metabolism. Approximately 40% of hormone receptor-positive, HER2-negative breast cancers harbor activation mutations in PIK3CA, the gene that encodes the alpha isoform of PI3 kinase, according to study background.

In the randomized phase 3 SOLAR-1 trial, André and colleagues assessed the efficacy and safety of alpelisib plus fulvestrant for treatment of men or postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who had received one prior line of endocrine therapy.

Researchers randomly assigned patients 1:1 to fulvestrant (500 mg every 28 days, plus day 15 of the first cycle) plus alpelisib 300 mg daily or placebo.

PFS among patients with PIK3CA-mutant disease served as the primary endpoint; however, investigators assessed PFS in the nonmutant cohort as a proof of concept.

Other outcomes measured included safety in the total population, as well as tumor response and PFS by key prognostic subgroups.

The analysis included 572 patients, 341 of whom had PIK3CA-mutant disease.

Median follow-up was 20 months.

Among the subgroup with PIK3CA-mutant disease, patients assigned the alpelisib regimen achieved significantly longer median PFS (11 months vs. 5.7 months; HR = 0.65; 95% CI, 0.5-0.85).

In this same group, overall response rates were 36% for those assigned the alpelisib-fulvestrant regimen vs. 16% for those assigned placebo-fulvestrant (P = .0002).

The study did not meet the secondary endpoint of improved locally assessed PFS among patients without PIK3CA-mutant disease (median, 7.4 months vs. 5.6 months; HR = 0.85; 95% CI, 0.58-1.25).

The most frequent all-grade adverse events were hyperglycemia (64% for alpelisib-fulvestrant vs. 10% for placebo-fulvestrant), diarrhea (58% vs. 16%), nausea (45% vs. 22%), decreased appetite (36% vs. 10%) and rash (36% vs. 6%).

Researchers observed considerably higher rates of grade 3 or grade 4 hyperglycemia (37% vs. < 1%) and rash (10% vs. < 1%) among alpelisib-treated patients.

Five percent of patients assigned alpelisib-fulvestrant discontinued treatment due to adverse events, compared with 1% of those assigned placebo-fulvestrant.

“Alpelisib offers the potential for increased life expectancy [for] patients with hormone receptor-positive, HER2-negative advanced breast cancer with PI3KCA mutations,” André said. “The follow-up is short so we cannot say whether there is a long-term survival benefit. But alpelisib increased progression-free survival, and that will hopefully translate to improvement in outcome.” – Mark Leiser

Reference:

André F, et al. Abstract LBA3_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Disclosures: Novartis provided funding for this study. André reports grants from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche and Sanofi. He also is a founder of Pegacsy. Please see the abstract for all other authors’ relevant financial disclosures.