Background Pharmacological blockade of the PD-1:PD-L1 interaction with monoclonal antibodies (mAbs) has shown durable clinical responses and overall survival benefit in a variety of malignancies.1 2 Importantly, the most meaningful responses have been associated with enhancement of the antitumor effector functions of T cells as evidenced by increased peripheral T-cell proliferation, infiltration of T cells in tumors, together with increased expression of key interferon-γ (IFNγ) pathway genes, including CXCL9, CXCL10, and granzyme B in both biopsy and peripheral blood samples.3 4 To date, available therapies targeting this pathway are mAbs, but the potential advantages of a small molecule, orally administered, direct antagonist of PD-1:PD-L1 binding have led to the development of INCB086550. INCB086550 is being evaluated in a phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with solid tumors. This preliminary report describes peripheral pharmacodynamic activity.
Methods Peripheral blood was collected at baseline and at multiple time points posttreatment from 16 patients treated with INCB086550 QD (100, 200 mg) or BID (200, 400 mg). Pharmacodynamic assessments included binding of drug to PD-L1 and secretion of cytokines, IL-2 and IFN-γ with ex vivo restimulation. Measurement of downstream pharmacodynamic effects included evaluation of immune activation markers on peripheral blood cells by flow cytometry and measurement of a panel of interferon-related cytokines in plasma.
Results Following INCB086550 treatment, the ex vivo stimulation of whole blood from patients showed a dose-related reduction of up to 85% in free PD-L1 on cells after 2 hours and increases as high as 3-fold of interleukin-2 secretion after 6 hours. Increases in the proliferation of circulating T cells, as measured by Ki-67, were dose-related and as high as 2.5-fold posttreatment. Plasma concentrations of CXCL9 and CXCL10 increased following INCB086550 treatment by 1.3- and 1.4-fold, respectively. A dose-related 1.2-fold increase in the plasma concentration of soluble target (PD-L1) and a 3.4-fold increase in IFN-γ was also observed posttreatment. Other proteins related to T-cell function, including but not limited to granzyme B, granzyme H, and LAG3, also increased following drug treatment.
Conclusions These results indicate that oral administration of INCB086550 provides dose-related pharmacodynamic T-cell activation similar to data reported for PD-(L)1 mAbs and evidence that INCB086550 is biologically active in blocking PD-1:PD-L1 interactions, leading to T-cell proliferation and activation in patients. This trial continues to evaluate the intratumoral pharmacodynamic activity, safety, and efficacy of INCB086550.
Ethics Approval The study was approved by institutional review boards or independent ethics committees of participating institutions.
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