The U.S. Food and Drug Administration (FDA) has approved alpelisib (Piqray®; formerly BYL719), a kinase inhibitor developed by Novartis, in combination with fulvestrant (Faslodex®; AstraZeneca), for the treatment of postmenopausal women, and men, with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-), and a phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA)-mutated gene, advanced or metastatic, breast cancer, as detected by an FDA-approved test following progression on or after an endocrine-based regimen. 
PIK3CA is the most commonly mutated gene in HR+/HER2- breast cancer. Approximately 40% of patients living with HR+/HER2- breast cancer have this mutation .
PIK3CA mutations are associated with tumor growth, resistance to endocrine treatment and a poor overall prognosis . Alpelisib targets the effect of PIK3CA mutations and may help overcome endocrine resistance in HR+ advanced breast cancer.
“The FDA approval of alpelisib, which was discovered at the Novartis Institutes for BioMedical Research, marks the first ever treatment specifically for HR+/HER2- advanced breast cancer with a PIK3CA mutation. We are proud to offer a new treatment option that specifically addresses the needs of the patients living with this mutation,” said Susanne Schaffert, PhD, CEO, Novartis Oncology.
“We are grateful to our researchers’ bold and unrelenting pursuit of a first-in-class treatment for this incurable disease, and to the patients, investigators and administrators who participated in the clinical trials leading to this remarkable milestone,” Schaffert added.
The FDA approval is based on results of the Phase III trial, SOLAR-1, that showed alpelisib plus fulvestrant nearly doubled median progression-free survival (PFS) compared to fulvestrant alone in HR+/HER2- advanced breast cancer patients with a PIK3CA mutation (median PFS 11.0 months vs 5.7 months; HR=0.65, 95% CI: 0.50-0.85; p<0.001)
Alpelisib provided consistent progression free survival results across pre-specified subgroups, including among patients previously treated with a CDK4/6 inhibitor. 
Overall response rate (ORR), an indicator of the proportion of patients who experience at least a 30% reduction in overall tumor size (in patients with measurable disease), was more than doubled when alpelisib was added to fulvestrant in patients with a PIK3CA mutation, (ORR= 35.7% vs 16.2% for fulvestrant alone, p=0.0002).
Alpelisib and its associated companion diagnostic test from QIAGEN was the first combination product approved under the FDA Oncology Center of Excellence Real-Time Oncology Review (RTOR) pilot program.
“Alpelisib is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer. The ability to target treatment to a patient’s specific genetic mutation or biomarker is becoming increasingly common in cancer treatment, and companion diagnostic tests assist oncologists in selecting patients who may benefit from these targeted treatments,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
“For this approval, we employed some of our newer regulatory tools to streamline reviews without compromising the quality of our assessment. This drug is the first novel drug approved under the Real-Time Oncology Review pilot program. We also used the updated Assessment Aid, a multidisciplinary review template that helps focus our written review on critical thinking and consistency and reduces time spent on administrative tasks,” Pazdur added.
“Today’s approval is expected to change the way we practice medicine in advanced breast cancer. For the first time, physicians can test for PIK3CA biomarkers and develop a treatment plan based on the genomic profile of a patient’s cancer,” said 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, and global the principal investigator SOLAR-1 clinical trial (NCT02437318)
“In the SOLAR-1 Phase III trial, alpelisib plus fulvestrant nearly doubled median PFS and more than doubled overall response rate in patients with a PIK3CA mutation, offering them new hope for longer life without progression,” André added.
Patients with HR+/HER2- advanced breast cancer can be selected for treatment with alpelisib based on the presence of PIK3CA mutations.
Concurrent with the approval of alpelisib, the FDA also approved the companion diagnostic test, therascreen®* PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. The test, developed by QIAGEN is now available for patient testing.
“If you are facing a complex disease like metastatic breast cancer, you want to follow a path that is specific to your type of disease,” said Shirley Mertz, President, Metastatic Breast Cancer Network.
“Finding the right treatment team and getting the right tests, like testing for the PIK3CA mutation, will help your healthcare team identify accurate, precise treatment options for your disease,” Mertz.
Approximately 40% of HR+ advanced breast cancer patients have a mutation that may activate the PI3K-alpha isoform, called PIK3CA mutations . These mutations are associated with resistance to endocrine therapy, disease progression and a poor prognosis  prognosis.
Alpelisib works by inhibiting the PI3K pathway, predominantly the PI3K-alpha isoform, to address the effect of PIK3CA mutations.
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying alpelisib in combination with fulvestrant for postmenopausal women, and men, with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor. SOLAR-1 is the pivotal Phase III trial that supported the FDA approval of alpelisib.
The trial randomized 572 patients. Patients were allocated based on central tumor tissue assessment to either a PIK3CA-mutated cohort (n=341) or a PIK3CA non-mutated cohort (n=231). Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with alpelisib (300 mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment. 
Patients and investigators are blinded to PIK3CA mutation status and treatment.
The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with a PIK3CA mutation. The key secondary endpoint is overall survival, and additional secondary endpoints include, but are not limited to, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability.
SOLAR-1 is ongoing to assess overall survival and other secondary endpoints.
Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (SOLAR-1) – NCT02437318
 Piqray (alpelisib) Prescribing Information. East Hanover., New Jersey, USA: Novartis Pharmaceuticals Corporation; May 2019.
 André F, Ciruelos E, Rubovszky G. Alpelisib for PIK3CA-Mutated, Hormone-Receptor-Positive Advanced Breast Cancer. N Eng J Med 2019.
 André F, Ciruelos EM, Rubovszky G et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the phase III SOLAR-1 trial. Annals of Oncology, Vol 29, Suppl 8, October 2018, Abstract LBA3_PR.
 Juric D, Ciruelos EM, Rubovszky G et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Phase 3 SOLAR-1 trial results. Presented at the San Antonio Breast Cancer Symposium (SABCS) (Abstract #GS3-08) on December 6, 2018.
 Tolaney S, Toi M, Neven P, et al. Presented at: 2019 American Association for Cancer Research (AACR) Annual Meeting; March 29-April 3, 2019; Atlanta, GA.
 Di Leo A, Johnston S, Seok Lee K, et al. Lancet Oncol. 2018;19(1):87-100.
 Moynahan ME, Chen D, He W, et al. Br J Cancer. 2017;116(6):726-730002E
 The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.
 Sobhani N, Roviello G, Corona SP et al. The prognostic value of PI3K mutational status in breast cancer: a meta-analysis. J Cell Biochem. 2018;119(6):4287-4292.
 Sabine V, Crozier C, Brookes C, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. Journal of Clinical Oncology. 2014;32:2951-2958.
 Miller TW, Rexer BN, Garrett JT, et al. Mutations in the Phosphatidylinositol 3-Kinase Pathway: Role in Tumor Progression and Therapeutic Implications in Breast Cancer. Breast Cancer Res. 2011.
 Saal LH, Johansson P, Holm K. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. PNAS. 2007;104(18):7564-7569.
*therascreen is a registered trademark of QIAGEN N.V.