Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Apr 1;10(4):475-483.
doi: 10.1001/jamaoncol.2023.6789.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial

Peter W Szlosarek  1   2   3 , Benjamin C Creelan  4 , Thomas Sarkodie  2 , Luke Nolan  5 , Paul Taylor  6 , Olga Olevsky  7 , Federica Grosso  8 , Diego Cortinovis  9 , Meenali Chitnis  10 , Amy Roy  11 , David Gilligan  12 , Hedy Kindler  13 , Dionysis Papadatos-Pastos  14 , Giovanni L Ceresoli  15 , Aaron S Mansfield  16 , Anne Tsao  17 , Kenneth J O'Byrne  18 , Anna K Nowak  19 , Jeremy Steele  3 , Michael Sheaff  3 , Chiung-Fang Shiu  20 , Chih-Ling Kuo  20 , Amanda Johnston  20 , John Bomalaski  20 , Marjorie G Zauderer  21 , Dean A Fennell  22 ; ATOMIC-Meso Study Group
Collaborators, Affiliations
Clinical Trial

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial

Peter W Szlosarek et al. JAMA Oncol. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Prof Szlosarek reported grants from Barts Cancer Institute and Polaris Group and personal fees from Nestle Health Science (advisory board) during the conduct of the study. Dr Creelan reported grants from Iovance Biotherapeutics and SU2C/AACR; personal fees from Achilles Therapeutics, AstraZeneca, Regeneron, Hoffmann-La Roche, MJH Life Sciences, and ER Squibb LLC; and nonfinancial support from BMS and Clinigen outside the submitted work. Dr Taylor reported personal fees from AstraZeneca (speakers fees) outside the submitted work. Dr Grosso reported personal fees (advisory role) from MSD, BMS, Novartis, Novocure, and PharmaMar outside the submitted work. Dr Cortinovis reported personal fees (scientific adviser) from AstraZeneca, MSD, BMS, Roche, Sanofi Genzyme, Novartis, Amgen, and Seagen outside the submitted work. Dr Gilligan reported personal fees from AstraZeneca and Takeda outside the submitted work. Dr Kindler reported other from Polaris (payment to institution to support the clinical trial) during the conduct of the study; personal fees from AstraZeneca, Deciphera, Sanofi, Opna, Tempus, and Bluestar Genomics outside the submitted work. Dr Papadatos-Pastos reported personal fees from Takeda, MSD, Merck, AstraZeneca, Pfizer, and Amgen and travel support from Merck outside the submitted work. Dr Mansfield reported grants from Polaris Pharmaceuticals, Inc (payments to Mayo Clinic for conduct of clinical trial) during the conduct of the study; honoraria to Mayo Clinic from Sanofi Genzyme, Gilead, AbbVie, Immunocore, Roche, BeiGene, Janssen, and Bristol Myers Squibb Company, and serving on the board of directors (nonremunerated) for Mesothelioma Applied Research Foundation and Friends of Patan Hospital outside the submitted work. Dr Tsao reported personal fees from Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, Genentech, GSK, Merck, Novartis, Pfizer, Roche, Seattle Genetics, Gilead Sciences, Inc, and Summit Therapeutics outside the submitted work. Dr Nowak reported nonfinancial support from Douglas Pharmaceuticals and AstraZeneca outside the submitted work. Dr Bomalaski reported a patent for Polaris Pharmaceuticals licensed to Polaris. Dr Zauderer reported grants from Polaris to MSK during the conduct of the study; grants to MSK from MedImmune, GSK, Epizyme, Sellas Life Sciences, BMS, Takeda, Curis, and Atara and personal fees from Curis, Ikena, Takeda, GSK, Novocure; and personal fees and CME content from PER, Medscape, and Research to Practice outside the submitted work; and serving as Chair, Board of Directors, for Mesothelioma Applied Research Foundation (uncompensated). Dr Fennell reported grants from Astex Therapeutics, Bayer Oncology, Boehringer Ingelheim, BMS, Bergen Bio, Roche Oncology, and GSK; personal fees from AstraZeneca; and nonfinancial support from Clovis Oncology, Eli Lilly, and MSD outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
ITT indicates intention-to-treat; PP, per-protocol. aOther refers to stable disease, trial completion/stable disease, and patient continuing in the expanded phase. bOther refers to study completion for the majority of patients with a reason of other, 1 patient with study termination, 2 patients moving away, 1 patient with an unknown reason, and 1 patient who continued treatment in the blinded expanded phase. cOther refers to study completion.
Figure 2.
Figure 2.. Overall and Progression-Free Survival in Phase 3 Patients (Intention-to-Treat Population)
Analysis population was the intention-to-treat population, which included all randomized patients. A, Overall survival (OS) was calculated as the time from randomization until death. In the event that no death was documented prior to study termination or analysis cutoff, OS was censored at the last known date the patient was known to be alive (using last contact day or last dose day). Total number of patients from the analysis population was 249, including 25 censored (17 from pegargiminase-chemotherapy group, 8 from placebo-chemotherapy group) and 224 with OS events (108 from pegargiminase group, 116 from placebo group). The 48-month survival percentage was not computed in the pegargiminase group due to the large number of censored patients (eTable 3 in Supplement 3). The blue vertical dashed lines indicate the 12-, 24-, and 36-month follow-up. B, Progression-free survival (PFS) was calculated as the time from randomization until date of tumor progression or death. In the event that no tumor progression or death was documented prior to end of treatment, analysis cutoff, or the start of confounding anticancer therapy, PFS was censored at the date of the last tumor assessment demonstrating no tumor progression. Total number of patients from the analysis population was 249, including 104 censored (54 from pegargiminase group, 50 from placebo group) and 145 with PFS events (71 from pegargiminase group, 74 from placebo group). Tick marks indicate censoring.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Delage B, Fennell DA, Nicholson L, et al. . Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 2010;126(12):2762-2772. doi:10.1002/ijc.25202 - DOI - PubMed
    1. Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA. Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res. 2002;62(19):5443-5450. - PubMed
    1. Szlosarek PW, Klabatsa A, Pallaska A, et al. . In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin Cancer Res. 2006;12(23):7126-7131. doi:10.1158/1078-0432.CCR-06-1101 - DOI - PubMed
    1. Bowles TL, Kim R, Galante J, et al. . Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int J Cancer. 2008;123(8):1950-1955. doi:10.1002/ijc.23723 - DOI - PMC - PubMed
    1. Nicholson LJ, Smith PR, Hiller L, et al. . Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer. Int J Cancer. 2009;125(6):1454-1463. doi:10.1002/ijc.24546 - DOI - PubMed

Publication types

Associated data