The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the PI3K inhibitor alpelisib for use in combination with fulvestrant as treatment for patients with breast cancer.
Fabrice Andre, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the PI3K inhibitor alpelisib (Piqray) for use in combination with fulvestrant as a treatment for postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer after disease progression following endocrine therapy as monotherapy.1
The recommendation is based on results from the phase 3 SOLAR-1 trial. Among a subset of patients in the trial with PIK3CA mutations, the median progression-free survival (PFS) by local assessment was 11.0 months (95% CI, 7.5-14.5) for those who received the alpelisib combination compared with 5.7 months (95% CI, 3.7-7.4) for those who received placebo plus fulvestrant.2 Those results, assessed after a median follow-up of 20 months, 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 <.001). There was no advantage to alpelisib on median PFS in patients without a PIK3CA mutation.
The European Commission will now review the CHMP recommendation and make a final decision in the next few months.
“PIK3CA is the most commonly mutated gene in HR+/HER2- advanced breast cancer, affecting approximately 40% of patients. If approved, alpelisib has the potential to transform the way we treat this cancer in Europe, offering physicians a clear treatment for patients with a PIK3CA mutation that nearly doubles the time to disease progression,” global SOLAR-1 principal investigator Fabrice André, MD, PhD, research director and head of INSERM Unit U981, professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France, stated in a press release.
In SOLAR-1, 572 postmenopausal women or men with HR-positive, HER2-negative advanced breast cancer were randomized 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 1). A total of 341 patients had PIK3CA mutations when tumor tissue was tested, with 169 receiving the alpelisib combination and 172 taking fulvestrant alone.
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.
Patients who received (neo)adjuvant endocrine therapy and relapsed >1 year were later excluded after a protocol amendment. Participants had not previously received fulvestrant, or any PI3K, AKT, or mTOR inhibitor, and were not on concurrent anticancer therapy. The primary end point was locally assessed PFS progression in patients with PIK3CA mutations.
About half of the patients in each arm had lung or liver metastases and approximately 6% had received prior CDK4/6 therapy.
When PFS was assessed by a blinded independent review committee, the median PFS was 11.1 months (95% CI, 7.3-16.8) in the alpelisib arm versus 3.7 months (95% CI, 2.1-5.6) in the placebo arm, for a 7.4-month improvement with the addition of alpelisib to fulvestrant (HR, 0.48; 95% CI, 0.32-0.71).
PFS was analyzed in the nonmutant cohort as a proof of concept. No clinically relevant effect was observed in patients with PIK3CA-nonmutant tumors, with a median PFS of 7.4 months and 5.6 months in the alpelisib and placebo arms, respectively (HR, 0.85; 95% CI 0.58-1.25).
The overall response rate (ORR) in the PIK3CA-mutant cohort was 26.6% in the alpelisib/fulvestrant arm compared with 12.8% in the placebo/fulvestrant arm (P = .0006). In the PIK3CA-mutant patients with measurable disease, the ORRs were 35.7% and 16.2%, respectively (P = .0002).
For the entire study population, the rate of grade ≥3 adverse events was 64.4% in the alpelisib/fulvestrant arm compared with 30.3% in the placebo/fulvestrant arm. Grade ≥3 hyperglycemia occurred in 32.7% of patients receiving alpelisib versus 0.3% receiving placebo.
Grade 3 rash developed in 9.9% of patients randomized to alpelisib and 0.3% randomized to placebo. The discontinuation rate of alpelisib/fulvestrant due to AEs was 5% versus 1% for fulvestrant alone.