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

• Main Authors: Kwang-Yu Chang, Nai-Jung Chiang, Shang-Yin Wu, Chia-Jui Yen, Shang-Hung Chen, Yu-Min Yeh, Chien-Feng Li, Xiaoxing Feng, Katherine Wu, Amanda Johnston, John S. Bomalaski, Bor-Wen Wu, Jianjun Gao, Sumit K. Subudhi, Ahmed O. Kaseb, Jorge M. Blando, Shalini S. Yadav, Peter W. Szlosarek, Li-Tzong Chen
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2021-01-01
• Series: OncoImmunology
• Subjects: arginine; arginine deiminase; adi-peg 20; argininosuccinate synthetase-1; cd-3; pembrolizumab; pd-l1; cancer; tumor immunity; citrulline
• Online Access: http://dx.doi.org/10.1080/2162402X.2021.1943253

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/m2 weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.