Abstract CT121: A Phase II trial of guadecitabine (G) plus atezolizumab (A) in patients with metastatic urothelial carcinoma (UC) progressing after initial checkpoint inhibitor therapy
Authors: Plimack Elizabeth R. , Campbell Kerry , Issa Jean-Pierre J. , Hahn Noah M. , Quinn David I. , Jang Hyo Sik , Hostetter Galen , Nichols Peter W. , Chung Woonbok , Madzo Jozef , Ohtani Hitoshi , Shen Hui , Hinoue Toshinori , Baylin Stephen B. , Jones Peter A. 
Published: July 2021

Abstract
Introduction: We report the results of a phase II trial testing the hypothesis that adding the hypomethylating agent G to the PDL1 inhibitor A in patients with mUC who developed primary or acquired resistance to checkpoint blockade (CB) will overcome this resistance by (1) eliciting viral mimicry in the tumor tissue to potentiate and reinvigorate anti-tumor immunity, (2) epigenetic reprogramming of T lymphocytes to overcome exhaustion.
Methods: Pts with mUC resistant to CB accrued at 3 centers were treated with G 45mg/m2 daily days 1-5 every 6 wks and A 1200mg every 3 wks. After initial safety lead in with 6 patients, trial was designed to add 37 additional patients. The primary endpoint was ORR. Correlative analyses included analysis of peripheral blood T cells and tumor tissue collected at baseline and once during treatment.
Results: 21 pts were enrolled. 20 pts were evaluable for response. Best response was PD (16), SD (4). 10 patients progressed clinically prompting earlier than scheduled (12 wk) imaging. Four pts exhibited a “hyperprogression” phenotype exhibiting rapid acceleration of tumor growth rate starting with initiation of therapy. At presepcified interim analysis it was determined that the trial would not meet its primary endpoint and it closed early. Median PFS 2.6 mo, median OS 8 mo. The 4 patients with SD maintained that status for median 13 months (range 9-15 mo). Global DNA methylome and transcriptome profiles from pre- and post-treatment tumor samples revealed a lack of transposable element-induced viral mimicry activation, which correlated with minimal DNA demethylation being induced in the tumors. Of note, flow cytometry-based immune profiling of peripheral blood from patients suggests a correlation between increased progression-free survival (PFS) with 1) lower expression of DNAM-1 on mature NK cells and 2) lower expression of CD39 on CD8+ effector T cells at time of inclusion on the trial.
Conclusions: While no responses were seen, both prolonged SD and hyperprogression were seen. Further tissue and peripheral blood based analyses are ongoing to elucidate the biological determinates of this dichotomy.
Citation Format: Elizabeth R. Plimack, Kerry Campbell, Jean-Pierre J. Issa, Noah M. Hahn, David I. Quinn, Hyo Sik Jang, Galen Hostetter, Peter W. Nichols, Woonbok Chung, Jozef Madzo, Hitoshi Ohtani, Hui Shen, Toshinori Hinoue, Stephen B. Baylin, Peter A. Jones. A Phase II trial of guadecitabine (G) plus atezolizumab (A) in patients with metastatic urothelial carcinoma (UC) progressing after initial checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT121.