Arginine deprivation with pegylated Arginine Deiminase in patients with Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial

Szlosarek, Peter W.; Steele, Jeremy P.; Nolan, Luke; Gilligan, David; Taylor, Paul; Spicer, James; Lind, Michael; Mitra, Sankhasuvra; Shamash, Jonathan; Phillips, Melissa M.; Luong, Phuong; Payne, Sarah; Hillman, Paul; Ellis, Stephen; Szyszko, Teresa; Dancey, Gairin; Butcher, Lee; Beck, Stephan; Avril, Norbert E.; Thomson, Jim; Johnston, Amanda; Tomsa, Marianne; Lawrence, Cheryl; Schmid, Peter; Crook, Timothy; Wu, Bor-Wen; Bomalaski, John S.; Lemoine, Nicholas; Sheaff, Michael T.; Rudd, Robin M.; Fennell, Dean; Hackshaw, Allan

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.

Citation

Szlosarek, P. W., Steele, J. P., Nolan, L., Gilligan, D., Taylor, P., Spicer, J., Lind, M., Mitra, S., Shamash, J., Phillips, M. M., Luong, P., Payne, S., Hillman, P., Ellis, S., Szyszko, T., Dancey, G., Butcher, L., Beck, S., Avril, N. E., Thomson, J., …Hackshaw, A. (2017). Arginine deprivation with pegylated Arginine Deiminase in patients with Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial. JAMA Oncology, 3(1), 58-66. https://doi.org/10.1001/jamaoncol.2016.3049

• Journal Article Type: Article
• Acceptance Date: Jun 6, 2016
• Online Publication Date: Sep 1, 2016
• Publication Date: Jan 1, 2017
• Deposit Date: Aug 8, 2018
• Journal: JAMA oncology
• Electronic ISSN: 2374-2445
• Publisher: American Medical Association
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 1
• Pages: 58-66
• DOI: https://doi.org/10.1001/jamaoncol.2016.3049
• Public URL: https://hull-repository.worktribe.com/output/535938
• Publisher URL: https://jamanetwork.com/journals/jamaoncology/fullarticle/2546657
• Related Public URLs: http://discovery.ucl.ac.uk/1514930/