Intermittent high dose scheduling of AZD8835, a novel selective inhibitor of PI3K{alpha} and PI3K{delta}, demonstrates treatment strategies for PIK3CA-dependent breast cancers

The PIK3CA gene, encoding the p110α catalytic unit of PI3Kα is one of the most frequently mutated oncogenes in human cancer. Hence PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here we report studies with a novel PI3K inhibitor, AZD8835, currently in Phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3K with selectivity vs. PI3Kβ, PI3K and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in ER+ breast cancer cell lines BT474, MCF7 and T47D (sub-µM GI50s). Consistent with this, AZD8835 demonstrated anti-tumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced anti-tumor activity (up to 92% regression). Combination partners were prioritized based on our mechanistic insights demonstrating signaling pathway crosstalk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong anti-tumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation.

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