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Review
. 2016 Jan 7:9:203-10.
doi: 10.2147/OTT.S89967. eCollection 2016.

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

Cristian Massacesi  1 , Emmanuelle Di Tomaso  2 , Patrick Urban  3 , Caroline Germa  4 , Cornelia Quadt  5 , Lucia Trandafir  1 , Paola Aimone  3 , Nathalie Fretault  1 , Bharani Dharan  4 , Ranjana Tavorath  4 , Samit Hirawat  4
Affiliations
Review

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

Cristian Massacesi et al. Onco Targets Ther. .

Abstract

The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Keywords: PI3K inhibitors; PI3K–AKT–mTOR pathway; biomarkers; clinical trial design; patient selection.

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Figures

Figure 1
Figure 1
The PI3K–AKT–mTOR pathway and drug targets.
Figure 2
Figure 2
Approaches to overcome challenges in PI3K inhibitor development. Abbreviations: NSCLC, non-small-cell lung carcinoma; GBM, glioblastoma multiforme.
See this image and copyright information in PMC

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