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Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers
Kwang-Yu Chang1,2, Nai-Jung Chiang1,2, Shang-Yin Wu1
1Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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.
Insights
Pegylated arginine deiminase (ADI-PEG 20) combined with PD-1 inhibition is safe and shows promise. This immunometabolic therapy increased T-cell infiltration and led to partial responses in heavily pretreated patients.
Area of Science:
- Immunotherapy
- Metabolic therapy
- Oncology
Background:
- Pegylated arginine deiminase (ADI-PEG 20) depletes arginine, inducing tumoral stress and cytotoxicity.
- Preclinical studies suggest ADI-PEG 20 enhances programmed death-1 (PD-1) inhibition efficacy by modulating T-cell activity.
Purpose of the Study:
- To evaluate the safety, pharmacodynamics, and response of ADI-PEG 20 in combination with pembrolizumab (anti-PD-1 antibody).
- To assess changes in CD3 levels and PD-L1 expression in response to neoadjuvant ADI-PEG 20 treatment.
Main Methods:
- A Phase 1b study with dose-escalation and expansion cohorts.
- Paired tumor biopsies were analyzed for CD3+ T cells and PD-L1 expression before and after ADI-PEG 20 treatment.
- Twenty-five heavily pretreated patients were enrolled.
Main Results:
- The combination was feasible, with adverse events consistent with known profiles, though Grade 3/4 neutropenia occurred in 40% of patients.
- Arginine levels were suppressed for 1-3 weeks post-treatment.
- T-cell infiltration increased in 83.3% of subjects, and partial responses were observed in 24% of patients, irrespective of argininosuccinate synthetase 1 (ASS1) status.
Conclusions:
- The immunometabolic combination of ADI-PEG 20 and pembrolizumab is safe, with a noted increase in neutropenia risk.
- ADI-PEG 20 enhances T-cell infiltration in PD-L1-low tumors.
- Recommended Phase 2 doses are 36 mg/m² weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.
