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Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors.
- Source :
-
Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Apr 11; Vol. 12 (4). Date of Electronic Publication: 2024 Apr 11. - Publication Year :
- 2024
-
Abstract
- Background: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities.<br />Methods: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing.<br />Results: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines.<br />Conclusions: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade.<br />Trial Registration Number: NCT04049617.<br />Competing Interests: Competing interests: JMO, AAO, K-WL, AYW, JN, OKY, JL, LL, and DT are employees and stockholders of Gilead Sciences. PRD, EA, NW, and SD received research funding from Gilead Sciences for the purposes of this study.<br /> (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Details
- Language :
- English
- ISSN :
- 2051-1426
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal for immunotherapy of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 38604815
- Full Text :
- https://doi.org/10.1136/jitc-2023-008547