Lead Researcher Discusses Alpelisib in PIK3CA+ Breast Cancer

Fabrice André, MD, PhD

The addition of the PI3K inhibitor alpelisib to fulvestrant (Faslodex) demonstrated efficacy as a treatment for patients with hormone receptor (HR)—positive, HER2-negative metastatic breast cancer who harbor PIK3CA mutations.

The combination of alpelisib (BLY719) and fulvestrant nearly doubled median progression-free survival (PFS) compared with endocrine therapy alone, according to findings from the SOLAR-1 trial that were presented at the 2018 ESMO Congress.

At a median follow-up of 20 months, the median PFS by local assessment in the subset of patients with PIK3CA mutations was 11.0 months (95% CI, 7.5-14.5) for those who received the alpelisib combination versus 5.7 months (95% CI, 3.7-7.4) for those who received placebo plus fulvestrant. These data translated into a 35% reduction in the risk of progression or death, with a hazard ratio of 0.65 in favor of alpelisib (95% CI, 0.50-0.85; P = .00065).

There was no PFS advantage to alpelisib in patients without PIK3CA mutations, said lead investigator Fabrice Andre, MD, PhD.

In the study, 572 postmenopausal patients with HR-positive, HER2-negative advanced breast cancer were randomized 1:1 to oral alpelisib at 300 mg daily or placebo plus fulvestrant at a dose of 500 mg every 28 days and on days 1 and 15 of treatment cycle 1.

Participants had received 1 or more prior lines of hormonal therapy, but no chemotherapy for advanced breast cancer. Patients could have received endocrine therapy in the neoadjuvant or adjuvant setting and then relapsed, followed by endocrine therapy for advanced disease until progression, or received endocrine therapy after diagnosis for advanced disease and then experienced disease progression.

OncLive: Please share some background of the SOLAR-1 trial.

In an interview with OncLive, Andre, a professor of Medical Oncology at the Institut Gustave Roussy in Villejuif, France, discussed the SOLAR-1 findings and their impact on the breast cancer landscape.Andre: We know that patients with HR-positive, HER2-negative metastatic breast cancer present with poor outcomes. The median survival is usually around 40 months. We know the vast majority of these patients will have progressive disease after 2 years under endocrine therapy and CDK4/6 inhibition. Based on this, there is a need to develop new therapies to improve outcomes for these patients. We know that 40% present with PIK3CA mutations. These genes respond to PI3K inhibition.

What were the data presented at the 2018 ESMO Congress?

What is the significance of the findings in this patient population?

What is the prevalence of genetic testing in breast cancer?

Therefore, this led us to the SOLAR-1 trial, which was a randomized trial. The eligible patients were postmenopausal with HR-positive, HER2-negative breast cancer who previously received an aromatase inhibitor. There were 2 different cohorts. The first were the patients with PIK3CA mutations and the second were patients without the mutations. The patients were randomized to fulvestrant plus placebo or fulvestrant plus alpelisib. The primary endpoint was PFS in patients with these mutations.The data we presented at this meeting showed that, in patients with PIK3CA mutations, there was an improvement in PFS. For those without mutations, there was no signal of efficacy, confirming the PIK3CA is an effective indication of who is sensitive to this treatment. In terms of safety profile, the drug has 2 main toxicities. One is hyperglycemia, with 36% presenting with this side effect. The other is rash—10% of patients had grade 3 rash.For patients, it means they have 1 more line of therapy that provides 11 months of disease control. We know that the treatment strategy for patients with metastatic breast cancer is to sequence 1 treatment after the other. The goal is to increase the duration of disease control. This new therapy perfectly fits this strategy. These are clinically meaningful data.Until recently, genomic testing was really only used to drive patients to clinical trials. In Europe, genetic testing for breast cancer is done almost only in the context of clinical trials. If alpelisib is approved and becomes more mainstream, genetic testing is going to have be more prominent for these patients. We would have to implement this.

André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA3.