TY - JOUR
T1 - A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy
AU - Jang, H. Josh
AU - Hostetter, Galen
AU - Macfarlane, Alexander W.
AU - Madaj, Zachary
AU - Ross, Eric A.
AU - Hinoue, Toshinori
AU - Kulchycki, Justin R.
AU - Burgos, Ryan S.
AU - Tafseer, Mahvish
AU - Alpaugh, R. Katherine
AU - Schwebel, Candice L.
AU - Kokate, Rutika
AU - Geynisman, Daniel M.
AU - Zibelman, Matthew R.
AU - Ghatalia, Pooja
AU - Nichols, Peter W.
AU - Chung, Woonbok
AU - Madzo, Jozef
AU - Hahn, Noah M.
AU - Quinn, David I.
AU - Issa, Jean Pierre J.
AU - Topper, Michael J.
AU - Baylin, Stephen B.
AU - Shen, Hui
AU - Campbell, Kerry S.
AU - Jones, Peter A.
AU - Plimack, Elizabeth R.
N1 - Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160966591&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85160966591&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-22-3642
DO - 10.1158/1078-0432.CCR-22-3642
M3 - Article
C2 - 36928921
AN - SCOPUS:85160966591
SN - 1078-0432
VL - 29
SP - 2052
EP - 2065
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -