First PI3K Inhibitor to Improve Outcomes in HR+/HER2− Breast Cancer

The PI3K inhibitor alpelisib combined with fulvestrant prolonged progression-free survival (PFS) over placebo and fulvestrant in a cohort of patients with hormone receptor–positive, HER2-negative breast cancer and a mutation in the PIK3CA gene.

“We have had HER2-targeted drugs … but until now, the use of tumor genomics has not really entered the practical care of breast cancer, unlike melanoma or lung cancer,” said Fabrice André, MD, PhD, of the Institut Gustave Roussy in Villejuif, France, according to a press release. He presented results of the SOLAR-1 trial at the European Society for Medical Oncology (ESMO) 2018 Congress, held in Munich.

Among all HR-positive breast cancer patients, approximately 40% have PIK3CA mutations, which leads to endocrine therapy resistance and disease progression. The SOLAR-1 trial included a total of 572 postmenopausal women with HR-positive, HER2-negative breast cancer; of those, 341 had a PIK3CA mutation and were included in the analysis. They were randomized to receive either alpelisib plus fulvestrant or placebo plus fulvestrant.

After a median follow-up period of 20.0 months, the primary endpoint of the trial was met, with significantly longer PFS with alpelisib than without. The alpelisib patients had a median PFS of 11.0 months, compared with 5.7 months with placebo, for a hazard ratio of 0.65 (95% CI, 0.50–0.85; P = .00065). A secondary analysis of those without a PIK3CA mutation was also conducted, but the PFS in this group did not meet predefined criteria for proof-of-concept.

In a subset of 262 patients with measurable PIK3CA-mutated advanced breast cancer, 36% responded to the alpelisib-fulvestrant combination, compared with 16% in the placebo-fulvestrant group (P = .0002).

The most frequent adverse events of any grade included hyperglycemia (64% with alpelisib vs 10% with placebo), diarrhea (58% vs 16%), and nausea (45% vs 22%); 37% of alpelisib patients had grade 3/4 hyperglycemia, compared with less than 1% of placebo patients. Five percent of alpelisib patients discontinued the drug due to adverse events, compared with 1% of placebo patients.

“Alpelisib offers the potential for increased life expectancy in patients with HR-positive, HER2-negative advanced breast cancer with PIK3CA mutations,” André said. “For now, the follow-up is short so we cannot say whether there is a long-term survival benefit.” He said that the improvement in PFS, though, will hopefully translate to overall survival improvement.

Angelo Di Leo, MD, PhD, of the Hospital of Prato in Italy, commented on the study, and noted this is the first time a PI3K inhibitor yielded a clinically meaningful improvement in outcome in this setting.

“The next critical step will be to understand when, and how, this compound should be incorporated into the current treatment algorithm-upfront, in combination with endocrine therapy and a CDK4/6 inhibitor, or sequentially, after disease progression on the combination of endocrine therapy and a CDK4/6 inhibitor,” Di Leo said. He and André both noted that if PI3K inhibitors become a standard treatment option, it will require genetic testing in this setting also becoming standard practice.