PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway is frequently activated in various cancers.
• PI3K inhibitors, such as buparlisib (pan-PI3K inhibitor) and alpelisib (PI3Kα-selective inhibitor), are under clinical development as potential anticancer agents.
• Early clinical studies have shown preliminary antitumor activity and acceptable safety profiles for PI3K inhibitors.

Purpose of the Study:

• To summarize strategies employed by Novartis Oncology to maximize the benefits of clinical studies with buparlisib and alpelisib.
• To address unanswered questions regarding the optimal approach for different tumor types and identify predictive biomarkers for PI3K inhibitors.
• To provide an overview of ongoing Novartis-sponsored and supported trials utilizing these strategies across various cancer types.

Main Methods:

• Stratification of patients based on PI3K pathway activation status.
• Selective enrollment and target enrichment for patients with PI3K pathway-activated tumors.
• Non-selective enrollment with mandatory tissue collection.
• Enrollment of patients who have progressed on prior targeted therapies (e.g., mTOR inhibitors, endocrine therapy).

Main Results:

• The review outlines various clinical trial strategies for PI3K inhibitors.
• It details approaches for patient selection and biomarker identification.
• An overview of trials in breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme is provided.

Conclusions:

• Optimized clinical trial strategies are crucial for maximizing the therapeutic potential of PI3K inhibitors.
• Biomarker-driven approaches and careful patient selection are key to successful development of buparlisib and alpelisib.
• Ongoing trials are investigating these strategies across a spectrum of malignancies.