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.

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

“…Inhibition of PI3K has particularly become a highly desirable avenue for pharmacological intervention, with dozens of PI3K inhibitors, including taselisib, copanlisib, pictilisib, buparlisib, and others, being in clinical trials and idelasib being approved for a set of leukemias and lymphomas (4,35). Although initially very promising, targeted inhibition of PI3K often suffers from the development of resistance to drugs.…”

“…This observation clearly illustrates that targeting a single protein/ pathway may not provide a long-lasting therapeutic effect because of the highly heterogeneous nature of cancer, in which multiple signaling cascades are impaired, and that alternative approaches with the focus on synergistic inhibition of more than one deregulated or compensating pathway have to be developed. Currently, a number of clinical trials are ongoing to apply PI3K inhibitors in combination with other drugs (35).…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…PKI-587, a potent novel dual inhibitor of PI3K and mTORC1/C2; inhibitors of mTORC1 and mTORC2, e.g. AZD2014, OSI-027) warrant further investigation based on preclinical studies (Freitag et al 2016, Massacesi et al 2016, Vandamme et al 2016. Another promising combination therapy is metformin and everolimus.…”

“…both broad and selective inhibitors will provide data on distinct efficacies (Massacesi et al 2016).…”

Magic power of phosphoinositide 3-kinase inhibitors

“…Another strategy is to find the optimal administration [4] . From our experience, we found that the dose of PI3K inhibitors administered intratracheally was about 50-60 folds less than that given orally to gain the same efficacy, when PI3K inhibitors were used to prevent and treat the inflammation-induced acute lung injuries [5] .This was an initial study to define the therapeutic windows of PI3K inhibitors between local and systemic drug deliveries in non-cancer pathology.…”