A pharmacokinetic evaluation of alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer

ABSTRACT

Introduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30–40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease.

Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 – PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions.

Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 – PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.

KEYWORDS:

• Alpelisib
• metastatic breast cancer
• PIK3CA mutation
• PI3K inhibitors

Article highlights

• An activating PIK3CA mutation is detected in 30-40% of HR+/HER2– advanced breast cancers. Activation of the PI3K/AKT/mTOR pathway is associated with poor outcomes and endocrine resistance.

• First generation pan-class I (buparlisib, pictilisib) and second generation isoform-specific (taselisib, alpelisib, serabelisib) PI3K inhibitors have been developed.

• While pan-PI3K inhibitors in combination with endocrine therapy showed low clinical benefit and limiting toxicities, alpelisib in combination with fulvestrant was the first PI3K inhibitor approved in postmenopausal women with HR+/HER2- PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen, in view of the progression-free survival improvement in the SOLAR-1 phase III study.

• Alpelisib thus represents a new valuable therapeutic option in these patients with limited options of treatment, but the treatment decision should follow a thorough benefit-risk assessment given its significant side effects (mostly hyperglycemia, rash and diarrhea).

Declaration of interest

M Bertho declares conflicts of interest with Pfizer (travel fees). A Patsouris received consulting fees (e.g. advisory boards) and served as a speaker (both compensed to the hospital) for Pfizer, Lilly, and received travel fees from Roche, Esai, Amgen, Pfizer. P Augereau reports speakers bureaus for Pfizer, AstraZeneca, and received travel fees from Pharmamar, Novartis and Lilly. M Robert reports conflicts of interest with Amgen, Merck and Novartis (travel fees). JS Frenel declares conflicts of interest with Pfizer, Roche, Astra Zeneca, Novartis (travel fees), and received consulting fees from Roche, Novartis, Lilly, AstraZeneca, Pfizer, Bio Cad, Daiichi, Pierre Fabre. C Blonz reports conflicts of interest with Novartis and Astellas (travel fees). M Campone reports acting as a consultant for Sanofi, Astra Zeneca, Servier, Novartis, Lilly, Pfizer, Samsung, Accord. He reports receiving travel fees from Novartis, Pfizer and Astra Zeneca. He also reports acting as a board member for Pfizer, Lilly, AstraZeneca and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer of this mansucript discloses that their laboratory has been involved in the development of PI 3-kinase inhibitors.

Additional information

Funding

This paper was not funded.