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Figure S2 from A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

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posted on 2023-06-01, 08:23 authored by H. Josh Jang, Galen Hostetter, Alexander W. Macfarlane, Zachary Madaj, Eric A. Ross, Toshinori Hinoue, Justin R. Kulchycki, Ryan S. Burgos, Mahvish Tafseer, R. Katherine Alpaugh, Candice L. Schwebel, Rutika Kokate, Daniel M. Geynisman, Matthew R. Zibelman, Pooja Ghatalia, Peter W. Nichols, Woonbok Chung, Jozef Madzo, Noah M. Hahn, David I. Quinn, Jean-Pierre J. Issa, Michael J. Topper, Stephen B. Baylin, Hui Shen, Kerry S. Campbell, Peter A. Jones, Elizabeth R. Plimack

Supplementary Figure 2: Modest treatment-induced DNA methylation changes in UC tumors.

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Stand Up To Cancer (SU2C)

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ARTICLE ABSTRACT

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. 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. 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. 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.

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