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Original Investigation
January 2017

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1–Deficient Malignant Pleural MesotheliomaA Randomized Clinical Trial

Author Affiliations
  • 1Center for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England
  • 2Barts Health NHS Trust, St Bartholomew’s Hospital, London, England
  • 3Southampton University Hospital NHS Foundation Trust, Southampton, England
  • 4Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, England
  • 5University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, England
  • 6Division of Cancer Studies, King's College London, Guy’s Hospital, London, England
  • 7University of Hull, Castle Hill Hospital, Cottingham, England
  • 8Brighton and Sussex University Hospitals, Brighton, England
  • 9King’s College London, St Thomas’ Hospital, London, England
  • 10Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea, England
  • 11University College London Cancer Institute, University College London, London, England
  • 12Cleveland Clinic, Cleveland, Ohio
  • 13Polaris Pharmaceuticals Inc, San Diego, California
  • 14Center for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, England
  • 15University of Leicester, Leicester Royal Infirmary, Leicester, England
  • 16Cancer Research UK and UCL Cancer Trials Center, University College London, London, England
JAMA Oncol. 2017;3(1):58-66. doi:10.1001/jamaoncol.2016.3049
Key Points

Question  What is the effect of arginine deprivation in patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma?

Findings  In this phase 2 randomized clinical trial of 68 patients with ASS1-deficient mesotheliomas, arginine deprivation with pegylated arginine deiminase led to improved progression-free survival compared with patients receiving best supportive care.

Meaning  Arginine deprivation with pegylated arginine deiminase warrants further clinical investigation in patients with ASS1-deficient malignant mesothelioma.

Abstract

Importance  Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer.

Objective  To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma.

Design, Setting, and Participants  A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma.

Interventions  Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone.

Main Outcomes and Measures  The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography.

Results  Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS.

Conclusions and Relevance  In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers.

Trial Registration  clinicaltrials.gov Identifier: NCT01279967

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