Abstract 2254: Solid tumor activity with a selective PI3Kdelta inhibitor as a single agent and in combination with anti-PD-1

Abstract

Inhibitors of PI3Kdelta are approved as monotherapy for the treatment of hematologic malignancies such as follicular B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Recent reports suggest that inhibition of PI3Kdelta in mice is effective against solid cancers as well. Mechanistic studies by several groups have suggested a possible adaptive immune-mediated anti-tumor response involving immunosuppressive Tregs and/or MDSCs in the tumor microenvironment. Our structure-guided discovery program led to the identification of a novel heterocycloalkyl purine inhibitor class with excellent isoform and kinome selectivity, as well as good solubility. Optimization included potency enhancements, addressing metabolism and increasing half-life in preclinical species to provide a PI3Kdelta inhibitor with a low once-daily predicted human dose. In FoxP3 reporter mice harboring MC38 tumors treated with inhibitor, we observed reduced peripheral Treg function and an increased ratio of CD8 to Treg in both spleen and tumor-infiltrating lymphocytes. In three-week efficacy studies, modest tumor growth inhibition was found in 4T1, MC38 and CT26 syngeneic tumor models when our inhibitor was dosed as a single agent and we demonstrated a trend towards better efficacy when our inhibitor was dosed in combination with an anti-mPD-1 antibody in CT26 tumor-bearing mice as compared to anti-mPD-1 alone. These preliminary studies confirm the impact of PI3Kdelta inhibition on T-cell subpopulations, and support continued exploration of PI3Kdelta inhibitors for the treatment of solid tumors, either as monotherapy or in combination with other agents. Citation Format: Joey L. Methot, Hua Zhou, Meredith A. McGowan, Benjamin W. Trotter, Michael Altman, Xavier Fradera, Charles Lesburg, Chaomin Li, Stephen Alves, Craig P. Chappell, Renu Jain, Ruban Mangado, Elaine Pinheiro, Sybil M. Williams, Peter Goldenblatt, Armetta D. Hill, Lynsey Shaffer, Dapeng Chen, Robbie L. McLeod, Hyun-Hee Lee, Sanjiv Shah, Jason D. Katz. Solid tumor activity with a selective PI3Kdelta inhibitor as a single agent and in combination with anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2254.