Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers. (1st January 2021)

• Record Type: Journal Article
• Authors: Chang, Kwang-Yu; Chiang, Nai-Jung; Wu, Shang-Yin; Yen, Chia-Jui; Chen, Shang-Hung; Yeh, Yu-Min; Li, Chien-Feng; Feng, Xiaoxing; Wu, Katherine; Johnston, Amanda; Bomalaski, John S.; Wu, Bor-Wen; Gao, Jianjun; Subudhi, Sumit K.; Kaseb, Ahmed O.; Blando, Jorge M.; Yadav, Shalini S.; Szlosarek, Peter W.; Chen, Li-Tzong
• Is Part Of: Oncoimmunology. Volume 10:Number 1(2021)
• Publication Date: 2021-01-01
• Subjects: Arginine -- arginine deiminase -- ADI-PEG 20 -- argininosuccinate synthetase-1 -- cd-3 -- pembrolizumab -- pd-l1 -- cancer -- tumor immunity -- citrulline; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2021.1943253
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Background: Pegylated arginine deiminase (ADI-PEG 20) is a metabolism-based strategy that depletes arginine, resulting in tumoral stress and cytotoxicity. Preclinically, ADI-PEG 20 modulates T-cell activity and enhances the therapeutic efficacy of programmed death-1 (PD-1) inhibition. Methods: A phase 1b study, including a dose-escalation cohort and an expansion cohort, was undertaken to explore the effects of ADI-PEG 20 in combination with pembrolizumab, an anti-PD-1 antibody, for safety, pharmacodynamics, and response. CD3 levels and programmed death-ligand 1 (PD-L1) expression were assessed in paired biopsies collected prior to and after ADI-PEG 20 treatment but before pembrolizumab. Results: Twenty-five patients, nine in the dose-escalation cohort and sixteen in the expansion cohort, were recruited. Treatment was feasible with adverse events consistent with those known for each agent, except for Grade 3/4 neutropenia which was higher than expected, occurring in 10/25 (40%) patients. Mean arginine levels were suppressed for 1–3 weeks, but increased gradually. CD3 + T cells increased in 10/12 (83.3%) subjects following ADI-PEG 20 treatment, including in three partial responders ( p = .02). PD-L1 expression was low and increased in 3/10 (30%) of subjects. Partial responses occurred in 6/25 (24%) heavily pretreated patients, in both argininosuccinate synthetase 1 proficient and deficient subjects. Conclusions: The immunometabolic combination was safe with the caveat that the incidence of neutropenia might be increased compared with either agent alone. ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment. The recommended phase 2 doses are 36 mg/m 2 weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.