학술논문
Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.
Document Type
Academic Journal
Author
Szlosarek PW; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.; The Mid and South Essex University Hospitals Group, Chelmsford, United Kingdom.; Barts Cancer Centre, St Bartholomew's Hospital, London, United Kingdom.; Creelan BC; H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.; Sarkodie T; The Mid and South Essex University Hospitals Group, Chelmsford, United Kingdom.; Nolan L; Southampton University Hospital NHS Foundation Trust, Southampton, United Kingdom.; Taylor P; Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, United Kingdom.; Olevsky O; David Geffen School of Medicine at UCLA, Los Angeles, California.; Grosso F; Mesothelioma Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.; Cortinovis D; Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.; Chitnis M; Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.; Roy A; University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom.; Gilligan D; Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom.; Kindler H; University of Chicago Medicine, Chicago, Illinois.; Papadatos-Pastos D; University College London Hospitals, London, United Kingdom.; Ceresoli GL; Cliniche Humanitas Gavazzeni, Bergamo, Italy.; Mansfield AS; Mayo Clinic, Rochester, Minnesota.; Tsao A; The University of Texas MD Anderson Cancer Center, Houston.; O'Byrne KJ; Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia.; Nowak AK; Medical School, The University of Western Australia and Sir Charles Gairdner Hospital, Perth, Western Australia.; Steele J; Barts Cancer Centre, St Bartholomew's Hospital, London, United Kingdom.; Sheaff M; Barts Cancer Centre, St Bartholomew's Hospital, London, United Kingdom.; Shiu CF; Polaris Pharmaceuticals, Inc, San Diego, California.; Kuo CL; Polaris Pharmaceuticals, Inc, San Diego, California.; Johnston A; Polaris Pharmaceuticals, Inc, San Diego, California.; Bomalaski J; Polaris Pharmaceuticals, Inc, San Diego, California.; Zauderer MG; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.; Fennell DA; University of Leicester & University Hospitals of Leicester NHS, United Kingdom.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 101652861 Publication Model: Print Cited Medium: Internet ISSN: 2374-2445 (Electronic) Linking ISSN: 23742437 NLM ISO Abbreviation: JAMA Oncol Subsets: MEDLINE
Subject
Language
English
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/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 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.
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/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 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.