Benefits versus risk profile of buparlisib for the treatment of breast cancer

ABSTRACT

Introduction: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination.

Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib.

Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α–selective PI3K inhibitors for ongoing and future trials.

KEYWORDS:

• Breast cancer
• PI3K/AkT/mTOR pathway
• therapy resistance
• buparlisib
• α –selective PI3K inhibitors
• alpelisib

Article highlights

• Activation of PI3K/AKT/mTOR pathway, presented in 70% of breast cancer is associated with poor prognostic and therapeutic resistance

• Targeting PI3K/AKT/mTOR pathway include mTOR inhibitors, PI3K inhibitors and dual mTOR/PI3K inhibitors studied especially in ER+/HER2- and HER2+ metastatic breast cancer. Akt inhibitors have shown signal in triple negative breast cancer.

• Two generation of PI3K inhibitors have been developped: pan-class I PI3K inhibitors (buparlisib/BKM120 and pictilisib) and isoform specific PI3Kα inhibitor (taselisib/GDC-0032 and alpelisib/BYL719).

• Buparlisib has shown efficacy in 2 phases III trial in combination with fulvestrant in patients with aromatase inhibitor resistant metastatic ER+/HER2- breast cancer. No significant efficacy has been reported in association with chemotherapy or with anti-HER2 therapy.

• However, in view of the toxicity profile included hyperglycemia, psychiatric disorders, second generation of PI3K inhibitors will be preferred for ongoing and future trials.

• Results of SOLAR-1 phase III study has been reported at ESMO 2018 meeting with efficacy of alpelisib in combination with fulvestrant in ER+/HER2- mBC harboring PIK3 activating mutation.

This box summarizes key points contained in the article.

Box 1. Drug summary.

Declaration of interest

M Campone reports conflicts of interest with Pfizer, Lilly, Accord, Sandoz, AstraZeneca, Novartis (board member), Pierre Fabre and Sanofi (consultancy) without research grant. JS Frenel declares conflicts of interest with Pfizer, Roche and AstraZeneca (board member and travel fees). P Augereau declares conflicts of interest with Pfizer, Astra Zeneca and Novartis (travel fees). M Robert reports conflicts of interest with Amgen, Merck and Novartis (travel fees and honoraria). A Patsouris declares conflicts of interest with Roche, Eisai and Pfizer (travel fees). E Bourbouloux reports conflicts of interest with Amgen (travel fees). 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.