Novel PI3K Inhibitor Improves Survival for Patients with PIK3CA-Mutated Breast Cancer

The alpha-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib significantly improved progression-free survival in patients with hormone receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer, according to late-breaking results reported at ESMO 2018 Congress in Munich.

Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, leading to cancer progression and resistance to endocrine therapy. These mutations are present in about 40% of patients with HR+/HER2– advanced breast cancer. Alpelisib is an oral PI3K inhibitor that is specific to the isoform that is mutated in breast cancer. "Previous PI3K inhibitors targeted all four isoforms so there were a lot of toxicities,” noted lead author Fabrice André, oncologist and professor of medical oncology at the Institut Gustave Roussy, Villejuif, France.

A previous phase 1 trial with alpelisib showed promising preliminary efficacy and manageable safety profile. The Phase 3 randomized, double-blind SOLAR-1 trial investigated the efficacy and safety of alpelisib plus fulvestrant in patients with HR+/HER2– advanced breast cancer. A total of 572 postmenopausal women or men with ECOG performance status of ≤1 who had received one or more prior lines of hormonal therapy but no chemotherapy were randomised to oral alpelisib or placebo plus intramuscular fulvestrant. A total of 341 had PIK3CA mutations when tumor tissue was tested. The primary endpoint was locally assessed progression free survival (PFS) in patients with PIK3CA mutations, detected in tumor tissue. PFS was also analyzed in the non-mutation cohort as a proof of concept.

Results showed the PFS was nearly twice as long in patients with PIK3CA mutations randomized to alpelisib compared with the placebo group. At a median follow-up of 20.0 months, the median PFS was 11.0 months in the alpelisib arm compared with 5.7 months in the placebo arm (HR = 0.65, 95% CI: 0.50-1.25, P = .00065).

Just over one-third (36%) of patients with measurable PI3KCA-mutated advanced breast cancer (n=262) responded to alpelisib plus fulvestrant, compared with an overall response rate in the placebo/fulvestrant group of 16% (P = .0002). The secondary endpoint of locally assessed PFS in patients without PI3KCA mutations did not meet the predefined proof of concept endpoint (HR = 0.85, 95% CI: 0.58-1.25).

The most frequent all-grade adverse events were hyperglycemia (64% vs 10%), diarrhea (58% vs 16%), nausea (45% vs 22%), decreased appetite (36% vs 10%), and rash (36% vs 6%). Grade 3/4 hyperglycemia was observed in 37% of patients in the alpelisib plus fulvestrant group vs <1% in the placebo plus fulvestrant group, and grade 3/4 rash was observed in 10% vs <1% of patients in the two groups, respectively. Discontinuations due to AEs occurred in 5% vs 1% of patients in the alpelisib plus fulvestrant group and the placebo plus fulvestrant group, respectively.

This is the first study to show statistically significant, clinically meaningful PFS improvement with an alpha-specific PI3K inhibitor in HR+/HER2– advanced breast cancer with PIK3CA mutations.

 “Alpelisib is the first drug to show a benefit in a genomic subgroup of breast cancer patients,” said Dr André. “Alpelisib offers the potential for increased life expectancy in patients with HR+/HER2- advanced breast cancer with PI3KCA mutations.”

He cautioned, however, that it remains to be seen whether there is a long-term survival benefit.—Kara Rosania