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ATOMIC-Meso

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

Phase 2/3N = 249NCT02709512

Population
Chemotherapy-naive, histologically proven non-resectable non-epithelioid (biphasic or sarcomatoid) pleural mesothelioma, aged 18 years or older, ECOG performance status 0 or 1
Design
Double-blind randomised phase 2/3 trial at 43 centres in 5 countries, with patients enrolled from 1 August 2017 to 15 August 2021 and final follow-up on 15 August 2022. Patients were randomly assigned 1:1 to weekly intramuscular pegargiminase or placebo, with pemetrexed and platinum (cisplatin or carboplatin) every 3 weeks for up to 6 cycles; pegargiminase or placebo continued until progression, toxicity or 24 months. Randomisation was stratified by non-epithelioid subtype (biphasic versus sarcomatoid). The Data and Safety Monitoring Board recommended stopping after the second interim analysis, after consultation with the FDA, so the analysis included all 249 patients enrolled to August 2021 rather than the planned 386. The primary endpoint of the phase 2 portion was objective response rate by blinded independent central review and of the phase 3 portion overall survival. The registry record lists an enrolment of 249.
Primary endpoint
OS
Arms
  • Pegargiminase plus chemotherapy (experimental, n = 125): Weekly intramuscular pegargiminase with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 every 3 weeks for up to 6 cycles
  • Placebo plus chemotherapy (control, n = 124): Weekly intramuscular placebo with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 every 3 weeks for up to 6 cycles
People
Szlosarek PW
OSHR 0.71 (95% CI 0.55–0.93)Δ median OS+1.6 monthsPFSHR 0.65 (95% CI 0.46–0.90)Δ median PFS+0.6 monthsΔ ORR+0.3 points
Show the numbers
Results reported for ATOMIC-Meso
EndpointAnalysisPegargiminase plus chemotherapyPlacebo plus chemotherapyEffect
OSAll 249 randomised patients (the full text calls this the intention-to-treat population)primarySzlosarek 2024median 9.3 months (7.9–11.8)median 7.7 months (6.1–9.5)HR 0.71 (95% CI 0.55–0.93)P=0.02All patients had at least 12 months of follow-up; final follow-up 15 August 2022 (abstract).
PFSAll 249 randomised patientsprimarySzlosarek 2024median 6.2 months (5.8–7.4)median 5.6 months (4.1–5.9)HR 0.65 (95% CI 0.46–0.90)P=0.02Secondary endpoint, analysed at the same time as the primary analysis.
ORRPhase 2 portion only (number of patients not stated in the text read)Objective response rate by blinded independent central review, phase 2 portion onlyprimarySzlosarek 202413.8%13.5%P=0.95Cochran-Mantel-Haenszel test. The full text states that response rate was tested once at the end of the phase 2 portion, for the purposes of accelerated approval only.
Results reported for ATOMIC-Meso
EndpointAnalysisPegargiminase plus chemotherapyPlacebo plus chemotherapyEffect
OSAll 249 randomised patients (the full text calls this the intention-to-treat population)primarySzlosarek 2024median 9.3 months (7.9–11.8)median 7.7 months (6.1–9.5)HR 0.71 (95% CI 0.55–0.93)P=0.02All patients had at least 12 months of follow-up; final follow-up 15 August 2022 (abstract).
PFSAll 249 randomised patientsprimarySzlosarek 2024median 6.2 months (5.8–7.4)median 5.6 months (4.1–5.9)HR 0.65 (95% CI 0.46–0.90)P=0.02Secondary endpoint, analysed at the same time as the primary analysis.
ORRPhase 2 portion only (number of patients not stated in the text read)Objective response rate by blinded independent central review, phase 2 portion onlyprimarySzlosarek 202413.8%13.5%P=0.95Cochran-Mantel-Haenszel test. The full text states that response rate was tested once at the end of the phase 2 portion, for the purposes of accelerated approval only.
Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.
OSPFS0.512◀ experimentalcontrol ▶
Data table
EndpointHR95% CI
OS0.710.55–0.93
PFS0.650.46–0.9
Illustrative — modelled from reported values, not trial data. OS, primary.
0%25%50%75%100%05101520Months (modelled)
  • Pegargiminase plus chemotherapy (experimental)
  • Placebo plus chemotherapy (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsPegargiminase plus chemotherapyPlacebo plus chemotherapy
0100.0%100.0%
663.9%58.3%
1240.9%34.0%
1728.2%21.6%
2318.0%12.6%
Illustrative — modelled from reported values, not trial data. PFS, primary.
0%25%50%75%100%02468101214Months (modelled)
  • Pegargiminase plus chemotherapy (experimental)
  • Placebo plus chemotherapy (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsPegargiminase plus chemotherapyPlacebo plus chemotherapy
0100.0%100.0%
463.9%61.0%
840.9%37.1%
1226.1%22.6%
1616.7%13.8%
Primary publication: Szlosarek PW, Creelan BC, Sarkodie T, Nolan L, Taylor P, Olevsky O, et al. Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. JAMA Oncol. 2024;10(4):475-483. PubMedDOI

Appears in

Sources

  1. Szlosarek PW, Creelan BC, Sarkodie T, Nolan L, Taylor P, Olevsky O, et al. Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. JAMA Oncol. 2024;10(4):475-483.

    PubMedDOI