ATOMIC Meso Trial

ATOMIC-Meso Trial
Pegargiminase Phase 2-3 in Nonepithelioid Mesothelioma
Registry ID	NCT02709512
Trial Type	Phase 2-3, double-blind, randomized, placebo-controlled
Sites / Countries	43 centers across 5 countries
Population	Nonepithelioid pleural mesothelioma (sarcomatoid + biphasic), chemotherapy-naive
Patients Enrolled	249
Primary Endpoint	Overall survival (OS)
Median OS (Primary)	9.3 vs 7.7 months (HR 0.71, P=.02)
Median PFS (Secondary)	6.2 vs 5.6 months (HR 0.65, P=.02)
Lead Investigator	Peter W. Szlosarek, MD
Sponsor	Polaris Pharmaceuticals
Primary Publication	JAMA Oncology, April 2024

Executive Summary

The ATOMIC-Meso Trial is a Phase 2-3 double-blind, randomized, placebo-controlled study that tested whether adding pegargiminase — a pegylated bacterial enzyme that depletes circulating arginine — to first-line chemotherapy improves survival in patients with nonepithelioid (sarcomatoid and biphasic) malignant pleural mesothelioma (MPM). The trial enrolled 249 chemotherapy-naive patients at 43 centers across 5 countries from August 2017 through August 2021, randomized them 1:1 to pegargiminase + pemetrexed/platinum or placebo + pemetrexed/platinum, and reported results in JAMA Oncology in April 2024.

The trial met its primary endpoint of overall survival (OS). Median overall survival was 9.3 months in the pegargiminase arm versus 7.7 months in the placebo arm — a hazard ratio for death of 0.71 (95% confidence interval [CI] 0.55–0.93; P = .02). Median progression-free survival, a secondary endpoint, was also significantly extended: 6.2 versus 5.6 months, hazard ratio 0.65 (95% CI 0.46–0.90; P = .02), representing a 35% reduction in the risk of disease progression or death.

ATOMIC-Meso is the first positive Phase 3 result of an arginine-deprivation strategy in any solid tumor and the most significant treatment advance specifically for nonepithelioid mesothelioma in approximately two decades. Nonepithelioid disease — particularly the sarcomatoid subtype — has historically been excluded from or underrepresented in immunotherapy trials and has consistently shown worse outcomes than epithelioid mesothelioma across every standard of care.

The trial exploits a metabolic vulnerability: many mesothelioma tumors silence the enzyme argininosuccinate synthetase 1 (ASS1) through epigenetic methylation, leaving the cancer cell unable to synthesize its own arginine. Pegargiminase systemically degrades extracellular arginine, starving ASS1-deficient tumor cells of a building block they cannot replace. The mechanism is most active in nonepithelioid subtypes, where ASS1 deficiency rates approach 90%.

As of May 2026, pegargiminase has not yet received U.S. Food and Drug Administration (FDA) approval specifically for mesothelioma. Regulatory discussions with the sponsor, Polaris Pharmaceuticals, are ongoing. Access is currently limited to expanded-access programs and select academic centers.

At a Glance

Item	Detail
Trial Name	ATOMIC-Meso (NCT02709512)
Disease	Chemotherapy-naive nonepithelioid (sarcomatoid + biphasic) malignant pleural mesothelioma (MPM)
Trial Design	Phase 2-3, double-blind, randomized 1:1, placebo-controlled
Treatment Tested	Pegargiminase (ADI-PEG20) 36.8 mg/m² intramuscular (IM) weekly + pemetrexed/platinum vs placebo + pemetrexed/platinum
Sites	43 centers across 5 countries
Patients Enrolled	249, randomized 1:1
Primary Endpoint	Overall survival (OS)
Median Overall Survival (Primary)	9.3 months (pegargiminase) vs 7.7 months (placebo); hazard ratio (HR) 0.71 (95% confidence interval [CI] 0.55–0.93; P=.02)
Median Progression-Free Survival (Secondary)	6.2 months vs 5.6 months; HR 0.65 (95% CI 0.46–0.90; P=.02)
Mechanism	Systemic arginine depletion exploits ASS1 (argininosuccinate synthetase 1) deficiency in nonepithelioid tumors
Lead Investigator	Peter W. Szlosarek, MD (Barts Cancer Institute, Queen Mary University of London)
Sponsor	Polaris Pharmaceuticals (now Polaris Group)
Primary Publication	JAMA Oncology, April 2024
Regulatory Status	No FDA-approved indication as of May 2026; expanded access at select centers

Key Facts

Fact	Source
ATOMIC-Meso enrolled 249 chemotherapy-naive patients with nonepithelioid pleural mesothelioma at 43 centers across 5 countries between August 2017 and August 2021; randomization was 1:1 to pegargiminase + chemotherapy or placebo + chemotherapy.	Szlosarek et al., JAMA Oncology 2024
The primary endpoint was overall survival. Median overall survival was 9.3 months for pegargiminase + chemotherapy versus 7.7 months for placebo + chemotherapy; hazard ratio for death 0.71 (95% confidence interval 0.55–0.93; P=.02).	Szlosarek et al., JAMA Oncology 2024
Secondary endpoint median progression-free survival was 6.2 months versus 5.6 months; hazard ratio 0.65 (95% CI 0.46–0.90; P=.02), representing a 35% reduction in the risk of progression or death.	Szlosarek et al., JAMA Oncology 2024
The trial mechanism depends on tumor-cell ASS1 deficiency, which is present in roughly 90% of nonepithelioid pleural mesothelioma and approximately half of epithelioid tumors.	Szlosarek et al., JAMA Oncology 2017 (ADAM trial)
Pegargiminase development began with a Phase 1 dose-escalation study published in Journal of Clinical Oncology in 2017 and an expansion Phase 1 study published in JTO Clinical and Research Reports in 2020.	Beddowes et al., JCO 2017; Szlosarek et al., JTO Clin Res Rep 2020
The most common Grade 3 or higher adverse events were anemia and neutropenia, in line with platinum/pemetrexed toxicity; immunogenicity (anti-drug antibodies) developed in roughly two-thirds of patients but did not abolish clinical benefit.	Szlosarek et al., JAMA Oncology 2024
The companion biomarker hypothesis — that BAP1 loss alters ASS1 expression in epithelioid mesothelioma and therefore changes which patients benefit from arginine deprivation — was published in Molecular Cancer Research in 2023.	Barnett et al., Mol Cancer Res 2023

Why Was ATOMIC-Meso Needed?

Malignant pleural mesothelioma is divided into three histologic subtypes based on tumor cell morphology: epithelioid (~60% of cases), biphasic (~20%), and sarcomatoid (~15%). The remainder are unclassified or rare variants. Across every line of therapy and every era of treatment, nonepithelioid disease — sarcomatoid more so than biphasic — has been associated with substantially worse outcomes than epithelioid mesothelioma.

The two most consequential therapeutic advances of the last decade — first-line dual immunotherapy with nivolumab plus ipilimumab approved in 2020 based on the CheckMate 743 trial, and second-line bevacizumab + atezolizumab combinations — extended overall survival across mesothelioma broadly. But they did so primarily through gains in the epithelioid subgroup. The non-epithelioid subgroup of CheckMate 743 showed a substantial benefit from immunotherapy compared with chemotherapy alone, but the absolute survival numbers remained low: median survival in the 12-month range, with single-digit 5-year survival rates.

For patients with sarcomatoid or biphasic mesothelioma, the standard-of-care toolkit before ATOMIC-Meso reported was effectively (1) pemetrexed plus a platinum agent — a chemotherapy regimen unchanged in its basic shape since 2003 — or (2) dual immunotherapy, with response rates and median survival measured in months rather than years. A new mechanism specifically suited to nonepithelioid biology had been missing from the field for two decades.

ATOMIC-Meso was designed to fill that gap by exploiting the metabolic vulnerability that nonepithelioid mesotheliomas tend to share: ASS1 deficiency.

The Biology: Arginine Deprivation and ASS1

Arginine is a conditionally essential amino acid required for cancer cell growth, protein synthesis, polyamine production, and survival. Normal human cells can synthesize arginine intracellularly through the urea cycle, in which argininosuccinate synthetase 1 (ASS1) catalyzes a key step. Most healthy tissues maintain functional ASS1 expression and can compensate when extracellular arginine is depleted.

Many cancers, however — including a large fraction of mesotheliomas — epigenetically silence ASS1 expression through promoter hypermethylation. The result is a tumor cell that cannot synthesize arginine internally and depends on circulating, extracellular arginine for survival. This dependency is sometimes called "arginine auxotrophy."

ASS1 deficiency rates in malignant pleural mesothelioma vary by subtype:

• Nonepithelioid (sarcomatoid and biphasic): approximately 90% ASS1-deficient
• Epithelioid: approximately 50–60% ASS1-deficient

This subtype-level difference is the rationale for restricting the ATOMIC-Meso Phase 3 enrollment to nonepithelioid disease. The same biology that makes sarcomatoid tumors so difficult to treat with conventional chemotherapy and immunotherapy — their stromal-rich, mesenchymal phenotype — is the biology that makes them most vulnerable to arginine deprivation.

How Pegargiminase Works

Pegargiminase (also known as ADI-PEG20, sometimes spelled ADI-PEG 20) is a pegylated form of arginine deiminase, a bacterial enzyme originally derived from Mycoplasma. Arginine deiminase converts circulating L-arginine to citrulline plus ammonia. The pegylation — covalent attachment of polyethylene glycol (PEG) chains — extends the enzyme's half-life in human circulation from minutes to days, making weekly dosing feasible. Pegylation also reduces immunogenicity, though it does not eliminate it.

Once injected intramuscularly, pegargiminase depletes plasma arginine to undetectable levels within 24 to 48 hours, and arginine remains suppressed throughout the dosing interval. Normal cells survive because they can upregulate ASS1 and produce their own arginine from citrulline. ASS1-deficient tumor cells, however, cannot make this metabolic switch and are progressively starved of a building block essential to protein synthesis and survival.

The kinetics matter clinically: arginine depletion is rapid, but tumor regression and progression-free benefit take weeks to months to manifest because the mechanism is cytostatic and metabolic rather than directly cytotoxic. Trials therefore measured outcomes over 6- to 36-month windows.

Predecessor Trials That Set Up ATOMIC-Meso

Pegargiminase did not arrive at Phase 3 by surprise. A multi-year clinical-translational program built the case:

• ADAM trial (Szlosarek et al., JAMA Oncology 2017) — A randomized Phase 2 study of pegargiminase versus best supportive care in 68 patients with ASS1-deficient malignant pleural mesothelioma. Pegargiminase monotherapy doubled progression-free survival (3.2 vs 2.0 months; HR 0.56) and confirmed the biomarker-targeted strategy in vivo.
• Phase 1 dose-escalation (Beddowes et al., JCO 2017) — Established the pegargiminase + pemetrexed + cisplatin combination at 36 mg/m² weekly with acceptable safety and signals of activity in ASS1-deficient thoracic cancers.
• Expansion Phase 1 (Szlosarek et al., JTO Clinical and Research Reports 2020) — Expanded the combination study in ASS1-deficient mesothelioma and reported disease control in 94% of evaluable patients, with a median PFS in the 5- to 6-month range — directly motivating the Phase 3 design.

By the time ATOMIC-Meso opened to enrollment, the mechanism, the dose, the schedule, the combination partner (pemetrexed/platinum), and the biomarker (ASS1 deficiency, enriched in nonepithelioid disease) were all pre-specified on the basis of earlier-phase evidence.

Trial Design

ATOMIC-Meso (NCT02709512) was an international, multicenter, double-blind, randomized, placebo-controlled Phase 2-3 study. The trial was conducted at 43 centers across 5 countries, with enrollment running from August 1, 2017 through August 15, 2021 and final follow-up on August 15, 2022.

Eligibility

• Histologically confirmed malignant pleural mesothelioma
• Nonepithelioid subtype: sarcomatoid or biphasic (epithelioid disease was excluded)
• Chemotherapy-naive — no prior systemic therapy for mesothelioma
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1
• Adequate organ function for platinum-doublet chemotherapy

Patients with prior pegargiminase exposure, active second malignancy, or contraindications to pemetrexed or platinum agents were excluded.

Randomization

249 patients were randomized 1:1 to one of two arms. Both patients and investigators were blinded to assignment. Mean age at randomization was 69.5 years (standard deviation 7.9), and 82.7% of enrolled patients were male.

Treatment Arms

Arm	Regimen
Experimental	Pegargiminase (Peg-arginine deiminase, ADI-PEG20) 36.8 mg/m² intramuscular (IM) weekly + pemetrexed 500 mg/m² intravenous (IV) on Day 1 of each 21-day cycle + cisplatin 75 mg/m² IV Day 1 (or carboplatin area-under-the-curve [AUC] 5 IV Day 1) for up to 6 cycles. Pegargiminase was continued until disease progression, unacceptable toxicity, or 24 months.
Control	Placebo IM weekly + pemetrexed 500 mg/m² IV Day 1 + cisplatin 75 mg/m² IV Day 1 (or carboplatin AUC 5 IV Day 1) for up to 6 cycles. Placebo was continued until disease progression, unacceptable toxicity, or 24 months.

Endpoints

• Primary endpoint: Overall survival (OS)
• Secondary endpoints: Progression-free survival (PFS), safety
• Response rate by blinded independent central review (BICR) was assessed in the Phase 2 portion only.

Results

Overall Survival (Primary Endpoint)

ATOMIC-Meso met its primary endpoint of overall survival. Median OS was 9.3 months in the pegargiminase arm (95% CI 7.9–11.8) versus 7.7 months in the placebo arm (95% CI 6.1–9.5). The hazard ratio for death was 0.71 (95% CI 0.55–0.93; P = .02), corresponding to a 29% reduction in the risk of death.

Progression-Free Survival (Secondary)

Median PFS was 6.2 months in the pegargiminase arm (95% CI 5.8–7.4) versus 5.6 months in the placebo arm (95% CI 4.1–5.9). The hazard ratio was 0.65 (95% CI 0.46–0.90; P = .02), representing a 35% reduction in the risk of progression or death.

Safety and Tolerability

Grade 3 or 4 adverse events occurred in 28.8% of patients in the pegargiminase arm (36 of 125) versus 16.9% in the placebo arm (21 of 124). Drug hypersensitivity reactions were reported in 3 patients (2.4%) in the pegargiminase arm and 0 patients in the placebo arm; skin reactions were reported in 2 patients (1.6%) in the pegargiminase arm and 0 in the placebo arm. Rates of poststudy treatments were comparable between arms — 45.6% with pegargiminase and 46.8% with placebo.

Pegargiminase-specific safety considerations described in the published trial and supporting Phase 1 work include:

• Anti-drug antibodies (ADAs): Anti-pegargiminase antibodies are a known feature of bacterial-enzyme-derived therapeutics and have been reported across the pegargiminase development program.
• Injection site reactions: Local reactions at the intramuscular injection site occurred in a minority of patients in earlier-phase studies and are typically Grade 1–2 and self-limited.
• Hypersensitivity: Pre-treatment with antihistamines and corticosteroids has been used in pegargiminase studies to mitigate infusion-related reactions.

Who Should Be Considered for Pegargiminase

ATOMIC-Meso enrolled and demonstrated benefit in a specific population:

• Histology: Sarcomatoid or biphasic (i.e., nonepithelioid) malignant pleural mesothelioma confirmed on biopsy
• Treatment status: Treatment-naive (first-line systemic therapy)
• Performance status: ECOG PS 0–1
• Organ function: Adequate for platinum-doublet chemotherapy

The trial did not enroll patients with epithelioid mesothelioma, peritoneal mesothelioma, or pretreated disease, and benefit in those populations cannot be assumed from the ATOMIC-Meso data. Phase 1/2 studies in epithelioid disease and in pretreated disease have shown some activity, but the Phase 3 evidence base is restricted to first-line nonepithelioid pleural mesothelioma.

ASS1 IHC testing is feasible and clinically informative. In the predecessor ADAM trial, ASS1-deficient status was the eligibility criterion, and biomarker-positive patients showed the largest benefit. ATOMIC-Meso enrolled by histology rather than by IHC because nonepithelioid disease enriches for ASS1 deficiency (~90%) at the population level. In clinical practice in 2026, decisions about whether to test ASS1 status — particularly for an epithelioid patient considering off-label access — are made case by case.

Regulatory and Access Status (May 2026)

As of May 2026, pegargiminase + chemotherapy is not yet an FDA-approved indication for malignant pleural mesothelioma. The ATOMIC-Meso Phase 3 results were published in JAMA Oncology in April 2024, and the sponsor, Polaris Pharmaceuticals (Polaris Group), has been in regulatory discussions about an appropriate path to U.S. approval and parallel regulatory review in other jurisdictions.

Access is currently available through:

• Expanded access / compassionate use programs — typically requested by treating oncologists for individual patients on a case-by-case basis
• Investigator-initiated clinical trials — ongoing studies testing pegargiminase in combination with immunotherapy and in pretreated populations
• Off-label use at select academic centers — institutions where principal investigators have experience prescribing based on the published Phase 3 data

Patients and clinicians seeking access should contact a center actively running pegargiminase studies or consult Polaris Pharmaceuticals' medical-information channel.

ATOMIC-Meso in the 2025–2026 Treatment Landscape

ATOMIC-Meso is one of several Phase 3 results reshaping mesothelioma therapy across the 2024–2026 reporting cycle:

• CheckMate 743 — first-line nivolumab + ipilimumab versus chemotherapy. Approved by the FDA in October 2020 for unresectable pleural mesothelioma. The 5-year update published in Journal of Clinical Oncology in 2026 confirmed sustained survival benefit (~14% versus ~6% at 5 years, hazard ratio 0.74).
• ATOMIC-Meso — first-line pegargiminase + chemotherapy versus placebo + chemotherapy in nonepithelioid disease. Reported in JAMA Oncology April 2024.
• NIPU Trial / UV1 vaccine — second-line UV1 telomerase peptide vaccine added to immunotherapy in pretreated mesothelioma.
• eVOLVE-Meso — Phase 3 volrustomig (PD-1 × LAG-3 bispecific) in mesothelioma.
• MARS2 — extended pleurectomy/decortication (P/D) versus chemotherapy alone; reframed the role of cytoreductive surgery.

The collective picture for 2025–2026 is that nonepithelioid disease — historically the most poorly served subtype — now has both an immunotherapy option (CheckMate 743) and a metabolic-targeted option (ATOMIC-Meso). The next clinical-research question is how these mechanisms combine, sequence, or substitute for each other.

Related Topics

• CheckMate 743 Trial — first-line nivolumab + ipilimumab immunotherapy
• NIPU Trial / UV1 Vaccine — telomerase peptide vaccine in pretreated mesothelioma
• eVOLVE-Meso Trial — volrustomig PD-1 × LAG-3 bispecific
• MARS2 Trial — extended pleurectomy/decortication
• BAP1 Gene Mutation — germline and somatic loss in mesothelioma
• Argininosuccinate Synthetase 1 (ASS1) — metabolic biomarker
• Pleural Mesothelioma — overview of disease subtypes
• Sarcomatoid Mesothelioma — nonepithelioid subtype
• Biphasic Mesothelioma — mixed-histology subtype
• Pemetrexed Chemotherapy — backbone combination partner

Glossary

• ADI-PEG20 — Pegylated arginine deiminase 20,000 daltons; the development name for pegargiminase.
• ASS1 — Argininosuccinate synthetase 1; a urea-cycle enzyme that catalyzes a key step in intracellular arginine synthesis.
• ECOG PS — Eastern Cooperative Oncology Group performance status; a 0–5 scale of functional status (0 = fully active; 4 = bedridden).
• IHC — Immunohistochemistry; a tissue-staining technique used here to assess ASS1 protein expression in tumor biopsies.
• IM — Intramuscular; the route of administration for pegargiminase (deep IM injection).
• Modified RECIST — Modified Response Evaluation Criteria in Solid Tumors; the standard radiologic response framework adapted specifically for the rind-pattern growth of pleural mesothelioma.
• Nonepithelioid mesothelioma — Sarcomatoid or biphasic subtypes; collectively ~35% of pleural mesothelioma cases; historically associated with worse outcomes than epithelioid disease.
• ORR — Objective response rate; the proportion of patients achieving a complete or partial response by RECIST.
• OS — Overall survival; time from randomization to death from any cause.
• PFS — Progression-free survival; time from randomization to first documented disease progression or death.
• Pegargiminase — Pegylated arginine deiminase; the active drug studied in ATOMIC-Meso.
• Pemetrexed — A folate antimetabolite chemotherapy agent used as the platinum-doublet partner in mesothelioma first-line therapy.

External Links

• ATOMIC-Meso (NCT02709512) — ClinicalTrials.gov registry record
• Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial — Szlosarek et al., JAMA Oncology 2024
• Arginine Deprivation With Pegylated Arginine Deiminase in ASS1-Deficient Mesothelioma — Szlosarek et al., JAMA Oncology 2017 (ADAM trial)