Alpelisib plus fulvestrant - Potential new treatment option for patients with PIK3CA-mutant hormone receptor-positive, her2-negative advanced breast cancer

30 Nov 2018

Endocrine therapy resistance and disease progression in breast cancer have been associated with hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway.1 Alpelisib is an orally bioavailable and potent PI3K inhibitor, specifically of the PI3K α-isoform, demonstrating antitumor activity in preclinical data in models with PIK3CA mutations.1-3 The SOLAR-1 is a phase 3, randomized, controlled trial with the aim to evaluate the efficacy of alpelisib in both PIK3CA-mutant and non-mutant disease.1 The findings of the trial were presented at the ESMO 2018 Congress.1

Hormone receptor (HR) positive breast cancer accounts for approximately 60-70% of all cases of breast cancer.4 Current first-line treatment for hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer is endocrine therapy (with or without a CDK4/6 inhibitor), and although initial treatment yields a high rate of clinical benefit, disease progression may occur after 12 months of endocrine monotherapy.1,4 It is therefore in the patients’ interests to optimize treatment regimens to find the most clinically beneficial combination of drugs.4

Phosphatidylinositol-3-kinase (PI3K) is a key regulator of cell metabolism and survival and signal transducers for cell-surface receptors and includes catalytic and regulatory subunits, with four isoforms of the catalytic subunit; α, β, δ and γ.1,2 Previous PI3K inhibitors targeted all four isomers, resulting in drug related toxicity and leading to a termination in further development of several PI3K inhibitors.5 The PIK3CA gene encodes for the α-isoform and with PIK3CA mutations amongst the most common alterations in breast cancer (~40%), it has become an important investigational area for therapeutic development.1,3

In total, 572 men and postmenopausal women with locally advanced or metastatic HR-positive, HER2-negative breast cancer were recruited in SOLAR-1, with 314 patients tested positive for PIK3CA mutation.5 The inclusion criteria also included those in recurrence or disease progression, on or after aromatase inhibitor (AI) therapy, and those with one or more measurable lesions or predominantly lytic bone lesion.1,6 Some exclusion criteria included patients ineligible for endocrine therapy due to other diseases, e.g. symptomatic visceral disease, those whom were already treated with fulvestrant, and premenopausal patients.6

The participants in both groups (mutant and non-mutant) were randomized at a 1:1 ratio to receive alpelisib (oral, 300mg once daily [QD]) plus fulvestrant (intramuscular [IM], 500mg on days 1 and 15 of the first 28 day cycle, and then on day 1 only of the subsequent cycles) or a placebo plus fulvestrant until disease progression or treatment discontinuation.1,6 The primary endpoint of the trial was progression-free survival (PFS) in the mutant group, which will be met at the final analysis if p≤0.0199.1 The secondary endpoints included overall survival (OS) in both the mutant and non-mutant cohort, as well as PFS in the non-mutant group.1 Overall response rate (ORR) and safety were also evaluated.1

After a median follow up of 20 months, the median PFS was found to be longer with the alpelisib plus fulvestrant group compared to the placebo plus fulvestrant group (11.0 months vs 5.7 months, HR=0.65; 95% CI: 0.50-0.85) for the PIK3CA-mutant cohort.1,7 The p-value was 0.00065, crossing the prespecified p≤0.0199.1 The median PFS for the non-mutant cohort was also longer in patients with the alpelisib and fulvestrant combination, at 7.4 months compared to 5.6 months with the placebo and fulvestrant (HR=0.85; 95% CI: 0.58-1.25).1 ORR was also higher for those on the alpelisib combination in the mutant cohort compared to the placebo cohort, with an ORR of 26.6% and 12.8% (p=0.0006) respectively.1

The safety profile of both groups were analysed and found to be similar in between treatment arms in PIK3CA-mutant and non-mutant cohorts.1 The most common adverse event with alpelisib was hyperglycemia, which led to discontinuation of treatment in 18 patients.1,7 Other common side effects included nausea and rash and Prof. Fabric André, oncologist and Professor of Medical Oncology at the Institut Gustave Roussy, France, stated that “no life-threatening toxicity or major toxicity that would be expected to affect quality of life” was found with alpelisib.7

Prof. André believes that “alpelisib is the first drug to show a benefit in a genomic subgroup of breast cancer patients”, shown in the clinically relevant and statistically significant findings from SOLAR-1.1,7 However, Prof. André also noted that the follow-up is currently too short, thus cannot be conclusive on the long-term survival benefit.7

With an increased life expectancy in patients with HR-positive, HER2-negative advanced breast cancer with PIK3CA mutations, Prof. Angelo Di Leo, head of the Department of Medical Oncology, Hospital of Prata, Italy, commented “the next critical step will be to understand when, and how, this compound should be incorporated into the current treatment algorithm.”7

  1. André F, Ciruelos E, Rubovszky G et al. Alpelisib + Fulvestrant for HR+, HER2- Advanced Breast Cancer: Results of the Phase III SOLAR-1 Trial. European Society for Medical Oncology (ESMO) 2018 Congress. October 19-23, 2018; Munich, Germany.
  2. Fritsch C, Huang A, Chatenay-Rivauday C, et al. Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials. Mol Cancer Ther. 2014;13:1117-1129.
  3. Juric D, Rodon J, Tabernero J, et al. Phosphatidylinositol 3-Kinase α-Selective Inhibiton with Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J Clin Oncol. 2018;36(13)1291-1299.
  4. Matutino A, Joy A, Brezden-Malsey C, et al. Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines. Curr Oncol. 2018;25(1)S131-141.
  5. Novel PI3K inhibitor for Breast Cancer: Success at Last? Medscape. 2018. (Accessed October 26, 2018, at
  6. Rugo H, André F, Rubovszky G, et al. A phase 3 study of alpelisib (ALP) plus fulvestrant (FUL) in men and postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) ABC progressing on or after aromatase inhibitor (AI) therapy: SOLAR-1. J Clin Oncol. 2018;35(suppl 15):TPS1111.
  7. Targeting specific genomic mutation in breast cancer improves outcomes, first study shows [ESMO 2018 Press Release]. ESMO. 2018. (Accessed October 26, 2018, at
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