Pegargiminase plus first-line chemotherapy in patients with nonepithelioid pleural mesothelioma: The ATOMIC-Meso randomized clinical trial Journal Article


Authors: Szlosarek, P. W.; Creelan, B. C.; Sarkodie, T.; Nolan, L.; Taylor, P.; Olevsky, O.; Grosso, F.; Cortinovis, D.; Chitnis, M.; Roy, A.; Gilligan, D.; Kindler, H.; Papadatos-Pastos, D.; Ceresoli, G. L.; Mansfield, A. S.; Tsao, A.; O'Byrne, K. J.; Nowak, A. K.; Steele, J.; Sheaff, M.; Shiu, C. F.; Kuo, C. L.; Johnston, A.; Bomalaski, J.; Zauderer, M. G.; Fennell, D. A.; for the ATOMIC-Meso Study Group
Article Title: Pegargiminase plus first-line chemotherapy in patients with nonepithelioid pleural mesothelioma: The ATOMIC-Meso randomized clinical trial
Abstract: Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P =.02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P =.02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512. © 2024 American Medical Association. All rights reserved.
Keywords: cancer chemotherapy; cancer survival; controlled study; aged; major clinical study; overall survival; clinical trial; fatigue; neutropenia; cisplatin; placebo; cancer growth; drug efficacy; drug safety; cancer patient; cancer radiotherapy; cancer staging; follow up; antineoplastic agent; carboplatin; progression free survival; multiple cycle treatment; phase 2 clinical trial; anemia; protein depletion; nausea; randomized controlled trial; antineoplastic combined chemotherapy protocols; lung neoplasms; dexamethasone; cytotoxicity; lung tumor; hyponatremia; maculopapular rash; immunogenicity; malignant mesothelioma; pleura mesothelioma; mesothelioma; sepsis; platinum; pleura tumor; folic acid; phase 3 clinical trial; double blind procedure; anaphylaxis; pemetrexed; gastrointestinal disease; pleural neoplasms; macrogol; polyethylene glycols; arginine; hydroxocobalamin; hydrolases; hydrolase; first-line treatment; response evaluation criteria in solid tumors; humans; human; male; female; article; pegargiminase; ecog performance status; urea cycle disorder; mesothelioma, malignant; nonepithelioid pleural mesothelioma
Journal Title: JAMA Oncology
Volume: 10
Issue: 4
ISSN: 2374-2437
Publisher: American Medical Association  
Date Published: 2024-04-01
Start Page: 475
End Page: 483
Language: English
DOI: 10.1001/jamaoncol.2023.6789
PUBMED: 38358753
PROVIDER: scopus
PMCID: PMC10870227
DOI/URL:
Notes: Source: Scopus
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  1. Marjorie G Zauderer
    189 Zauderer