A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy.

Autor:	Jang HJ; Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan., Hostetter G; Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, Michigan., Macfarlane AW; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Madaj Z; Bioinformatics & Biostatistics Core, Van Andel Institute, Grand Rapids, Michigan., Ross EA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Hinoue T; Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan., Kulchycki JR; Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan., Burgos RS; Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan., Tafseer M; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Alpaugh RK; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Schwebel CL; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Kokate R; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Geynisman DM; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Zibelman MR; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Ghatalia P; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Nichols PW; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California., Chung W; The Coriell Institute for Medical Research, Camden, New Jersey., Madzo J; The Coriell Institute for Medical Research, Camden, New Jersey., Hahn NM; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland., Quinn DI; University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, California., Issa JJ; The Coriell Institute for Medical Research, Camden, New Jersey., Topper MJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland., Baylin SB; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland., Shen H; Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan., Campbell KS; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Jones PA; Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan., Plimack ER; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Jun 01; Vol. 29 (11), pp. 2052-2065.
DOI:	10.1158/1078-0432.CCR-22-3642
Abstrakt:	Purpose: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti-programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. Patients and Methods: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Results: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients' plasma was associated with short survival. Conclusions: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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