A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy
Mené sur 21 patients atteints d'un carcinome urothélial de stade métastatique ou récidivant, cet essai de phase II détermine la dose maximale tolérée de la guadécitabine en combinaison avec l'atézolizumab et évalue l'efficacité, du point de vue du taux de réponse et de la survie sans progression, de cette combinaison après l'échec d'anti-PD-1/PD-L1
Purpose: Based on preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab (anti-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 urothelial carcinoma who had previously progressed on ICI therapy with PD-1 or PD-L1 targeting agents were eligible. Pre-planned 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, 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 stable disease. Furthermore, high IL-6 and IL-8 levels in the patients’ plasma associates 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.
Clinical Cancer Research , résumé, 2022