Piqray® approved for the treatment of postmenopausal women with breast cancer

The US Food and Drug Administration (FDA) has approved Piqray® (alpelisib, formerly BYL719) in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.[1]

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. [8],[10]. PIK3CA mutations are associated with tumor growth, resistance to endocrine treatment and a poor overall prognosis[11],[12]. Piqray targets the effect of PIK3CA mutations and may help overcome endocrine resistance in HR+ advanced breast cancer.

The FDA approval is based on results of the Phase III trial, SOLAR-1, that showed Piqray 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)[2]. Piqray provided consistent PFS results across pre-specified subgroups, including among patients previously treated with a CDK4/6 inhibitor[2],[3].

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 Piqray was added to fulvestrant in patients with a PIK3CA mutation, (ORR= 35.7% vs 16.2% for fulvestrant alone, p=0.0002)[2]. Piqray and its associated companion diagnostic test from QIAGEN N.V. was the first combination product approved under the FDA Oncology Center of Excellence Real-Time Oncology Review pilot program.

About Piqray® (alpelisib)
Piqray is a kinase inhibitor approved in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer, as detected by an FDA-approved test following progression on or after endocrine-based regimen[1].

Approximately 40% of HR+ advanced breast cancer patients have a mutation that may activate the PI3K-alpha isoform, called PIK3CA mutations[5],[6],[7],[8]. These mutations are associated with resistance to endocrine therapy, disease progression and a poor prognosis[11],[12]. Piqray works by inhibiting the PI3K pathway, predominantly the PI3K-alpha isoform, to address the effect of PIK3CA mutations.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying Piqray 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[1],[2],[3]. SOLAR-1 is the pivotal Phase III trial that supported this approval.

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 Piqray (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[1],[2],[3]. 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[1],[2],[3]. SOLAR-1 is ongoing to assess overall survival and other secondary endpoints.

[1]    Piqray (alpelisib) Prescribing Information. East Hanover., New Jersey, USA: Novartis Pharmaceuticals Corporation; May 2019.
[2]    André F, Ciruelos E, Rubovszky G. Alpelisib for PIK3CA-Mutated, Hormone-Receptor-Positive Advanced Breast Cancer. N Eng J Med 2019.
[3]    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.
[4]    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.
[5]    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.
[6]    Di Leo A, Johnston S, Seok Lee K, et al. Lancet Oncol. 2018;19(1):87-100.
[7]    Moynahan ME, Chen D, He W, et al. Br J Cancer. 2017;116(6):726-730002E
[8]    The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.
[9]    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.
[10]  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.
[11]  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.
[12]  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.

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