Arginine Deprivation Therapy (Pegargiminase) for Mesothelioma
Arginine deprivation therapy is an experimental metabolic treatment strategy for mesothelioma that starves tumor cells of the amino acid arginine. In nonepithelioid pleural mesothelioma, the drug pegargiminase (also called ADI-PEG 20) was tested in the ATOMIC-Meso randomized clinical trial, where adding it to standard chemotherapy modestly extended survival.[1] Pegargiminase is investigational and not approved by the U.S. Food and Drug Administration for any indication.[2]
Executive Summary
Arginine deprivation therapy targets a metabolic vulnerability found in many mesothelioma tumors: the loss of an enzyme called argininosuccinate synthetase 1 (ASS1). Cells that lose ASS1 cannot manufacture their own arginine and must import it from the bloodstream — a state called arginine auxotrophy. Pegargiminase (ADI-PEG 20) is a pegylated form of the enzyme arginine deiminase that breaks down circulating arginine, effectively cutting off the tumor's supply.[1]
The strategy was tested in ATOMIC-Meso, a phase 2-3, double-blind randomized clinical trial of 249 patients with chemotherapy-naive nonepithelioid pleural mesothelioma across 43 centers in 5 countries. Patients who received pegargiminase plus chemotherapy had a median overall survival of 9.3 months, compared with 7.7 months for those who received placebo plus chemotherapy (hazard ratio for death, 0.71; P = .02).[1] The trial met its overall-survival endpoint with a statistically significant result in a mesothelioma subtype that has historically carried a poor prognosis and few treatment options.
Pegargiminase is not a treatment patients can currently receive outside a clinical trial. It has no U.S. Food and Drug Administration marketing approval; the sponsor, Polaris Group, submitted a Biologics License Application that entered FDA substantive review in August 2025, but no approval decision has been publicly announced.[2][3] Families evaluating emerging mesothelioma options should understand the difference between a promising trial result and an available, approved therapy — and should confirm current trial availability with a treating oncologist.
At-a-Glance
Arginine deprivation therapy for mesothelioma at a glance:
- Metabolic mechanism — Pegargiminase (ADI-PEG 20) depletes blood arginine, starving ASS1-deficient tumor cells that cannot make their own arginine.[1]
- Nonepithelioid focus — The ATOMIC-Meso trial enrolled only biphasic and sarcomatoid (nonepithelioid) pleural mesothelioma, subtypes with historically poor prognosis.[1]
- 249 patients, 5 countries — The pivotal trial randomized 249 chemotherapy-naive patients across 43 centers in five countries.[1]
- 9.3 vs 7.7 months — Median overall survival was 9.3 months with pegargiminase-chemotherapy versus 7.7 months with placebo-chemotherapy (hazard ratio 0.71; 95% CI 0.55-0.93; P = .02).[1]
- Progression-free survival — Median progression-free survival was 6.2 months versus 5.6 months (hazard ratio 0.65; 95% CI 0.46-0.90; P = .02).[1]
- Added to standard chemotherapy — Pegargiminase was given weekly by intramuscular injection alongside pemetrexed plus platinum chemotherapy, not as a replacement for it.[1]
- Manageable safety profile — Grade 3 to 4 adverse events occurred in 28.8% of the pegargiminase group versus 16.9% of the placebo group.[1]
- Not FDA-approved — Pegargiminase is investigational; a Biologics License Application is under FDA review with no approval decision announced.[2]
Key Facts
| Measure | Finding (Source) |
|---|---|
| Drug | Pegargiminase (ADI-PEG 20), a pegylated arginine deiminase enzyme — ATOMIC-Meso, 2024[1] |
| Pivotal trial | ATOMIC-Meso (NCT02709512), phase 2/3, double-blind, n=249 — status Completed[1][4] |
| Population | Nonepithelioid (biphasic/sarcomatoid) pleural mesothelioma, chemotherapy-naive — ATOMIC-Meso, 2024[1] |
| Median overall survival (OS) | 9.3 months vs 7.7 months placebo; hazard ratio (HR) 0.71 (95% confidence interval [CI] 0.55-0.93; P = .02)[1] |
| Median progression-free survival (PFS) | 6.2 months vs 5.6 months placebo; HR 0.65 (95% CI 0.46-0.90; P = .02)[1] |
| Grade 3-4 adverse events (AEs) | 28.8% pegargiminase vs 16.9% placebo — ATOMIC-Meso, 2024[1] |
| Regimen | Weekly intramuscular pegargiminase + pemetrexed/platinum chemotherapy every 3 weeks, up to 6 cycles[1] |
| U.S. FDA status | Investigational — not approved; Biologics License Application in FDA review (2025)[2][3] |
| Sponsor | Polaris Group — ATOMIC-Meso (NCT02709512)[4] |
What Is Arginine Deprivation Therapy?
Arginine deprivation therapy is a metabolic approach to cancer treatment that exploits a weakness in how some tumor cells handle the amino acid arginine. Most healthy cells can synthesize their own arginine when needed, using an enzyme called argininosuccinate synthetase 1 (ASS1). Many mesothelioma tumors — along with several other cancers — silence or lose the ASS1 gene. Without ASS1, the tumor cannot make arginine internally and becomes dependent on arginine circulating in the blood. This dependence is called arginine auxotrophy.[1]
Pegargiminase, also known as ADI-PEG 20, is a pegylated form of the bacterial enzyme arginine deiminase. When injected, it circulates through the bloodstream and breaks down arginine into citrulline, sharply lowering the amount of arginine available to tissues. Healthy cells with functioning ASS1 can adapt by making their own arginine from citrulline, but ASS1-deficient tumor cells cannot — so they are selectively starved. The "peg" (polyethylene glycol) coating extends how long the enzyme remains active in the body, allowing weekly dosing.[1]
This strategy is a form of antimetabolite therapy — a class of treatments that interfere with the building blocks cancer cells need to grow. It is mechanistically distinct from chemotherapy, which damages DNA, and from immunotherapy, which recruits the immune system. Because arginine auxotrophy is common in nonepithelioid mesothelioma, that subtype was the focus of the pivotal trial.
How Did the ATOMIC-Meso Trial Test Pegargiminase?
ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity — Mesothelioma) was a phase 2-3, double-blind, randomized clinical trial registered as NCT02709512 and sponsored by Polaris Group. It enrolled patients from August 2017 through August 2021 at 43 centers across five countries, with final follow-up in August 2022.[1][4]
The trial enrolled 249 patients with histologically confirmed, unresectable nonepithelioid pleural mesothelioma — specifically biphasic or sarcomatoid histology — who had not received prior chemotherapy or immunotherapy and had good performance status (Eastern Cooperative Oncology Group [ECOG] score 0-1). Patients were randomly assigned in a 1:1 ratio to one of two arms:[1][4]
- Pegargiminase arm: weekly intramuscular pegargiminase (36.8 mg/m²) plus standard chemotherapy
- Placebo arm: weekly intramuscular placebo plus standard chemotherapy
Both arms received the same backbone chemotherapy: intravenous pemetrexed (500 mg/m²) with platinum (cisplatin 75 mg/m² or carboplatin) every three weeks for up to six cycles. Pegargiminase or placebo was then continued until disease progression, unacceptable toxicity, or a maximum of 24 months. The primary endpoint was overall survival, with progression-free survival and safety as secondary endpoints.[1]
What Survival and Safety Results Did ATOMIC-Meso Show?
Among the 249 randomized patients (mean age 69.5 years; 82.7% male), the pegargiminase arm achieved a median overall survival of 9.3 months (95% confidence interval, 7.9-11.8 months), compared with 7.7 months (95% CI, 6.1-9.5 months) in the placebo arm. The hazard ratio for death was 0.71 (95% CI, 0.55-0.93; P = .02) — a statistically significant reduction in the risk of death.[1]
Progression-free survival also favored pegargiminase: a median of 6.2 months versus 5.6 months with placebo (hazard ratio 0.65; 95% CI, 0.46-0.90; P = .02).[1]
The objective tumor response rate, by contrast, did not differ between the two arms — roughly 14% of patients had a measurable tumor response in each group (relative risk 1.02; P = .95). In other words, the survival and progression-free gains reflected better disease control over time rather than greater tumor shrinkage.[1][4]
On safety, grade 3 to 4 adverse events occurred in 28.8% of pegargiminase-treated patients versus 16.9% of placebo-treated patients. Drug hypersensitivity and skin reactions were seen in a small number of patients in the pegargiminase arm (about 2% each) and none in the placebo arm. Rates of later-line treatments after the study were comparable between the two groups. The trial investigators concluded that pegargiminase plus chemotherapy extended survival beyond standard chemotherapy with a favorable safety profile, and that the antimetabolite strategy warrants wider testing in oncology.[1]
It is important to read these numbers in context. The survival gain was measured in months, not years, and both arms had short median survival — a reminder that nonepithelioid pleural mesothelioma remains among the most difficult cancers to treat. The result is meaningful because it shows, in a randomized trial, that a metabolic-targeting drug can extend survival in this subtype — not because it represents a cure.
Is Pegargiminase FDA-Approved for Mesothelioma?
No. Pegargiminase is investigational and is not approved by the U.S. Food and Drug Administration for mesothelioma or any other indication. As of mid-2026 it has no Drugs@FDA marketing authorization, and it is available only through clinical trials or expanded-access arrangements, not as a prescribed standard-of-care treatment.[2]
The drug's sponsor, Polaris Group, has been pursuing approval. The company began a rolling submission of a Biologics License Application (BLA) to the FDA in November 2023 for pegargiminase in combination with pemetrexed and a platinum agent for nonepithelioid pleural mesothelioma.[3] Polaris completed the final portion of that application in June 2025, and the BLA entered the FDA's substantive review stage in August 2025.[2] No approval decision, target action date, or special FDA designation for pegargiminase has been publicly confirmed as of this writing. Patients and families should treat any claim that pegargiminase is an "available" or "approved" mesothelioma treatment with caution and verify the drug's current status with a treating oncologist.
Who Might Be Eligible for Arginine Deprivation Therapy?
In the ATOMIC-Meso trial, eligibility was limited to adults with unresectable nonepithelioid pleural mesothelioma — biphasic or sarcomatoid histology — who had not yet received chemotherapy or immunotherapy and who had good functional status. Patients with the more common epithelioid subtype were not enrolled, because the arginine-auxotrophy rationale was strongest in nonepithelioid disease.[1][4]
Because the drug is not approved, the only current route to arginine deprivation therapy is enrollment in an open clinical trial or an expanded-access program where available. Trial availability changes over time, so patients interested in this or other emerging approaches should ask their oncologist or a specialized mesothelioma center to check current openings and eligibility. Individuals diagnosed with mesothelioma should not delay standard, approved treatment while investigating experimental options.
Determining eligibility for any experimental therapy also intersects with legal and financial planning. Patients pursuing mesothelioma treatment — approved or experimental — may be entitled to compensation through asbestos trust funds or litigation, which can help cover the cost of care and travel to trial sites.[5]
Frequently Asked Questions
What is pegargiminase (ADI-PEG 20)?
Pegargiminase, also called ADI-PEG 20, is an investigational drug that lowers the level of the amino acid arginine in the blood. It is designed to starve mesothelioma tumor cells that have lost the ability to make their own arginine. It was studied in the ATOMIC-Meso clinical trial for nonepithelioid pleural mesothelioma.[1]
Is pegargiminase FDA-approved for mesothelioma?
No. Pegargiminase is not approved by the U.S. Food and Drug Administration. Its sponsor, Polaris Group, has a Biologics License Application under FDA review, but no approval decision has been announced. The drug is available only through clinical trials.[2][3]
How much did pegargiminase improve survival in the trial?
In ATOMIC-Meso, patients who received pegargiminase plus chemotherapy lived a median of 9.3 months, compared with 7.7 months for those who received placebo plus chemotherapy — a statistically significant difference (hazard ratio 0.71; P = .02).[1]
Who was eligible for the pegargiminase trial?
The trial enrolled adults with unresectable nonepithelioid (biphasic or sarcomatoid) pleural mesothelioma who had not received prior chemotherapy or immunotherapy and had good performance status. It did not enroll patients with epithelioid mesothelioma.[1][4]
How is arginine deprivation therapy different from chemotherapy?
Chemotherapy works mainly by damaging the DNA of rapidly dividing cells. Arginine deprivation therapy is a metabolic strategy — it deprives tumor cells of a nutrient (arginine) they need to survive. In the trial, pegargiminase was added to chemotherapy rather than replacing it.[1]
Can I get pegargiminase right now?
Only through a clinical trial or expanded-access program, where available. Because the drug is not FDA-approved, it cannot be prescribed as a standard treatment. Ask your oncologist or a mesothelioma specialty center whether any trials are currently open.[2]
Quick Statistics
- 249 patients randomized in the ATOMIC-Meso pivotal trial.[1]
- 43 centers across 5 countries participated.[1]
- 9.3 months median overall survival with pegargiminase-chemotherapy.[1]
- 7.7 months median overall survival with placebo-chemotherapy.[1]
- 0.71 hazard ratio for death (95% CI 0.55-0.93; P = .02).[1]
- 6.2 months median progression-free survival with pegargiminase, versus 5.6 months.[1]
- 28.8% grade 3-4 adverse-event rate with pegargiminase, versus 16.9% with placebo.[1]
- 2023 — year Polaris Group began its rolling FDA Biologics License Application submission.[3]
External Links
- Danziger & De Llano — Mesothelioma Treatment Overview — overview of standard and emerging mesothelioma treatment options
- Danziger & De Llano — Asbestos Trust Funds — how trust-fund compensation can help cover the cost of care
- Mesothelioma Lawyer Center — treatment, diagnosis, and clinical-trial background information
- Mesothelioma.net — patient resources and information on emerging therapies
Related Pages
- Mesothelioma Treatment
- Chemotherapy for Mesothelioma
- Immunotherapy for Mesothelioma
- Mesothelioma Clinical Trials
- Pleural Mesothelioma
- Mesothelin CAR-T Therapy
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 Szlosarek PW, Creelan BC, Sarkodie T, 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. PubMed doi:10.1001/jamaoncol.2023.6789
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Polaris Group. Biologics License Application (BLA) for Pegargiminase (ADI-PEG 20) Has Entered the FDA Substantive Review Stage. Company announcement, August 2025. polarispharma.com
- ↑ 3.0 3.1 3.2 3.3 3.4 Polaris Group. Polaris Group Initiates Rolling Submission of Biologics License Application (BLA) for ADI-PEG 20 With U.S. FDA to Treat Malignant Pleural Mesothelioma. Press release, November 17, 2023. GlobeNewswire
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Randomized, Double-Blind, Phase 2/3 Study in Subjects With Malignant Pleural Mesothelioma to Assess ADI-PEG 20 With Pemetrexed and Cisplatin (ATOMIC-Meso). ClinicalTrials.gov identifier NCT02709512, sponsor Polaris Group; status Completed. ClinicalTrials.gov
- ↑ Asbestos Trust Funds, Danziger & De Llano — mesothelioma compensation and trust-fund claims.