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Improved progression-free survival of patients with HR+, HER2- advanced breast cancer treated with the PI3K inhibitor alpelisib

About 40% of patients with hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer has PIK3CA mutations, activating the PI3K pathway leading to cancer progression and resistance to endocrine therapy. Alpelisib is an oral PI3K inhibitor that is alpha specific. The alpha isoform of PI3K is mutated in breast cancer. Results of the double blind, randomised phase III SOLAR-1 trial demonstrated that targeting PIK3CA mutations in patients with HR+, HER2- advanced breast cancer with alpelisib significantly improved progression-free survival.

The phase III SOLAR-1 trial investigated the efficacy and safety of alpelisib in patients with HR+, HER2- advanced breast cancer. In this study 572 postmenopausal women or men with HR+, HER2- advanced breast cancer were randomised to oral alpelisib (300 mg/day) or placebo plus intramuscular fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle). The primary endpoint was locally assessed progression-free survival (PFS) in patients with PIK3CA mutations.

Patients included in this study had good performance status (ECOG status of ≤1) and had received one or more prior lines of hormonal therapy but no chemotherapy for advanced breast cancer. They had not previously received fulvestrant, or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy. PIK3CA mutations were present in tumour tissue of 341 patients.

The result of the SOLAR-1 trial showed that the PFS in patients harbouring a PIK3CA mutation treated with alpelisib + fulvestrant was significantly longer compared to the patients receiving placebo + fulvestrant (HR: 0.65; 95%CI: 0.50–0.85; p=0.00065; median 11.0 versus 5.7 months) at a median follow-up of 20.0 months. Just over one-third (36%) of patients with measurable PIK3CA-mutated advanced breast cancer (n=262) responded to alpelisib plus fulvestrant, while the overall response rate in the placebo + fulvestrant group was 16% (p=0.0002). The secondary endpoint of locally assessed PFS in patients without PIK3CA mutations did not meet the predefined proof of concept endpoint (HR: 0.85, 95%CI: 0.58-1.25, median 7.4 versus 5.6 months).

The most frequent adverse events with alpelisib were hyperglycaemia (64% versus 10%), diarrhoea (58% versus 16%), nausea (45% versus 22%), decreased appetite (36% versus 10%) and rash (36% versus 6%). Grade 3/4 hyperglycaemia (fasting plasma glucose >250 mg/dL) was observed in 37% of patients treated with alpelisib versus <1% for the patients in the placebo-arm; grade 3/4 rash was reported in 10% of the patients in the alpelisib-arm versus <1% in the placebo-arm. Treatment was discontinued by 5% of the patients treated with alpelisib due to adverse events compared to 1% in the placebo-arm.

In conclusion, alpelisib significantly extended the PFS versus placebo and demonstrated a manageable tolerability profile in patients with PIK3CA-mutant HR+, HER2- advanced breast cancer. This is the first study to show statistically significant, clinically meaningful PFS improvement with an α-specific PI3K inhibitor in PIK3CA-mutant HR+, HER2– advanced breast cancer.


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. Presented during ESMO 2018; Abstract LBA3.

Speaker Fabrice André


Fabrice André, MD, PhD, Breast Cancer Unit, Department of Medical Oncology, Gustave Roussy – Cancer Campus, Villejuif, France


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