Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data

Abstract: Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers. There has been much advancement in the treatment of HR+/HER2 negative metastatic breast cancer (MBC), in particular the development of more tailored and targeted therapies. Recently, greater understanding of the role of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer has led to the development of PI3K inhibitors, which have proven to be effective in the treatment of HR+/HER2 negative MBC. In this review, we will discuss the role of the PI3K/AKT/mTOR pathway in breast cancer and therapies that have been developed to inhibit PI3K. We will discuss in detail the development of PI3K inhibitor alpelisib, indications for use in HR+/HER2 negative MBC, safety and tolerability and the future direction of this therapy in the treatment of breast cancer.

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Keywords: PI3K, PIK3CA, alpelisib

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INTRODUCTION

Breast cancer is the leading cause of cancer and the second leading cause of cancer death in women.¹ Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2 negative) breast cancer accounts for over 70% of all breast cancers.¹ Recently, there has been a paradigm shift in the treatment of HR+/HER2 negative metastatic breast cancer (MBC) with development of targeted therapies, which have led to patients living longer and with less toxicity. Cyclin dependent kinase 4/6 inhibitors (CDK 4/6i) including palbociclib, ribociclib and abemaciclib, in combination with either aromatase inhibitor (AI) or fulvestrant, have revolutionized the treatment of HR+/HER2 negative MBC and has become the standard first-line treatment in this setting.^2–5 Additional treatment options in HR+/HER2 negative MBC include estrogen receptor (ER) antagonist fulvestrant as a single agent and mammalian target of rapamycin (mTOR) inhibitor everolimus, both of which have shown to be an effective treatment in HR+/HER2 negative MBC.^6,7 However, resistance to endocrine and targeted therapies ultimately occurs, warranting the need for new therapeutic strategies. In this review, we will discuss the role of the Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway in breast cancer and the development of PI3K inhibitors as a therapeutic option for breast cancer patients. We will also discuss in detail Alpelisib, the first approved PI3K inhibitor for the treatment of HR+/HER2 negative MBC.

The PI3K/AKT/mTOR Pathway and Breast Cancer

The PI3K/AKT/mTOR pathway plays a critical role in regulating cell proliferation, growth and survival. In breast cancer, therapeutic strategies have been developed to target these three important sites in this pathway. BOLERO-2 was a randomized, double-blinded Phase III placebo controlled study that compared the mTOR inhibitor everolimus in combination with exemestane versus exemestane and placebo in HR+/HER2 negative MBC.⁷ Median progression free survival (PFS) by central assessment was improved from 4.1 month to 10.6 months (HR 0.36, p<0.001).⁷ The AKT inhibitor capivasertib was studied in the Phase II FAKTION trial.⁸ This study compared capivasertib plus fulvestrant versus fulvestrant and placebo in HR+/HER2 negative MBC. Median PFS was 10.3 months in the capivasertib group versus 4.8 months in the placebo group (HR 0.58, p= 0.0018).⁸

PI3Ks are a family of lipid kinases.⁹ Stimulation of receptor tyrosine kinase activates this pathway, which in turn triggers activation of PI3K (Figure 1).¹⁰ Class I PI3K is further divided into subclass IA and IB.¹¹ Class IA PI3Ks are heterodimers consisting of a p110α catalytic subunit and p85 regulatory subunit.¹¹ There are four catalytic isoforms of PI3K including α, β, γ and Δ.¹¹

PIK3CA is an oncogene that encodes the p110α catalytic isoform.¹¹ Three common mutations in PIK3CA include E545K and E542K on exon 9 and H1047R on exon 20.¹¹ Mutation of PIK3CA leads to gain of function activation of the p110α catalytic isoform, which causes a downstream effect that ultimately leads to unregulated cell growth, proliferation and survival.¹¹

PIK3CA has been found to be one of three somatic mutations that occur commonly in breast cancer.¹² Approximately 20–50% of all breast cancers harbor a PIK3CA mutation.¹¹ HR positive and HER2 positive breast cancers are the two subtypes that exhibit this mutation most commonly, with incidence 35% and 23%, respectively.^11,13 Greater understanding of the role of PIK3CA mutation in cancer cell growth and survival has led to the development of targeted therapeutics aimed at directly inhibiting the PI3K pathway.

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