TY - JOUR
T1 - Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma The ATOMIC-Meso Randomized Clinical Trial
AU - the ATOMIC-Meso Study Group
AU - Szlosarek, Peter W.
AU - Creelan, Benjamin C.
AU - Sarkodie, Thomas
AU - Nolan, Luke
AU - Taylor, Paul
AU - Olevsky, Olga
AU - Grosso, Federica
AU - Cortinovis, Diego
AU - Chitnis, Meenali
AU - Roy, Amy
AU - Gilligan, David
AU - Kindler, Hedy
AU - Papadatos-Pastos, Dionysis
AU - Ceresoli, Giovanni L.
AU - Mansfield, Aaron S.
AU - Tsao, Anne
AU - O'Byrne, Kenneth J.
AU - Nowak, Anna K.
AU - Steele, Jeremy
AU - Sheaff, Michael
AU - Shiu, Chiung Fang
AU - Kuo, Chih Ling
AU - Johnston, Amanda
AU - Bomalaski, John
AU - Zauderer, Marjorie G.
AU - Fennell, Dean A.
AU - Rybkin, Igor I.
AU - Rolfo, Christian D.
AU - MacKean, Melanie
AU - Steele, Nicola
AU - Franks, Kevin
AU - Shaw, Paul
AU - Lind, Michael J.
AU - Upadhyay, Sunil
AU - John, Thomas
AU - Karapetis, Christos
AU - Srivastav, Ratnesh
AU - Mencoboni, Manlio
AU - Chella, Antonio
AU - Zilembo, Nicoletta
AU - de Marinis, Filippo
AU - Stella, Maria Giulia
AU - Chong, Inn Wen
AU - Wang, Chin Chou
N1 - Publisher Copyright:
© 2024 Szlosarek PW et al. JAMA Oncology.
PY - 2024
Y1 - 2024
N2 - 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 Thiswas 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 (36.8mg/m2) or placebo. All patients received intravenous pemetrexed (500mg/m2) and platinum (75-mg/m2 cisplatin 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 pointwas 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.
AB - 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 Thiswas 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 (36.8mg/m2) or placebo. All patients received intravenous pemetrexed (500mg/m2) and platinum (75-mg/m2 cisplatin 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 pointwas 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.
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U2 - 10.1001/jamaoncol.2023.6789
DO - 10.1001/jamaoncol.2023.6789
M3 - Article
C2 - 38358753
AN - SCOPUS:85185969473
SN - 2374-2437
JO - JAMA Oncology
JF - JAMA Oncology
ER -