Article Text

Download PDFPDF

419 Pharmacodynamic biomarkers demonstrate T-cell activation in patients treated with the oral PD-L1 inhibitor INCB086550 in a phase 1 clinical trial
  1. Sarina Piha-Paul1,
  2. Tara Mitchell2,
  3. Solmaz Sahebjam3,
  4. Janice Mehnert4,
  5. Thomas Karasic5,
  6. Kevin O’Hayer6,
  7. Ryan Geschwindt6,
  8. Susan Spitz6,
  9. Hao Liu6 and
  10. Johanna Bendell7
  1. 1M. D. Anderson Cancer Center, Houston, TX, USA
  2. 2Abramson Cancer Center of the University, Philadelphia, PA, USA
  3. 3Moffitt Cancer Center, Tampa, FL, USA
  4. 4Perlmutter Cancer Center of NYU Langone, New York, NY, USA
  5. 5University of Pennsylvania, Philadelphia, PA, USA
  6. 6Incyte Corporation, Willmington, DE, USA
  7. 7Sarah Cannon Research Institute, Nashville, TN, USA

Abstract

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.

References

  1. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.

  2. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704.

  3. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568–571.

  4. Herbst RS, Soria JC, Kowanetz, M, et al.. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–567.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.