title: PI3K inhibitors as new cancer therapeutics: implications for clinical trial design.
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.
authors.affiliation: Novartis Oncology, Paris, France.
authors.forename: Cristian
authors.initials: C
authors.lastname: Massacesi
authors.affiliation: Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Di Tomaso
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Urban
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Germa
authors.affiliation: Novartis Pharmaceuticals KK, Tokyo, Japan.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.affiliation: Novartis Oncology, Paris, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Trandafir
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Aimone
authors.affiliation: Novartis Oncology, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fretault
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Bharani
authors.initials: B
authors.lastname: Dharan
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Tavorath
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Samit
authors.initials: S
authors.lastname: Hirawat
keywords: PI3K inhibitors; PI3K–AKT–mTOR pathway; biomarkers; clinical trial design; patient selection