ADI-PEG20 Phase 3 Trial Shows Promise: ATOMIC-Meso Results

The ATOMIC-Meso Phase 3 trial has delivered encouraging results for mesothelioma patients, demonstrating that adding ADI-PEG20 (pegargiminase) to standard chemotherapy significantly improved progression-free survival. This represents one of the first successful Phase 3 trials of a targeted therapy specifically designed for mesothelioma’s unique biology.

ADI-PEG20, developed by Polaris Pharmaceuticals, exploits a metabolic vulnerability found in approximately 50% of mesothelioma tumors: the lack of an enzyme called argininosuccinate synthetase 1 (ASS1). Without this enzyme, cancer cells cannot produce arginine internally and depend entirely on external sources. ADI-PEG20 depletes arginine from the bloodstream, effectively starving these vulnerable tumors.

What ATOMIC-Meso Tested

The randomized, double-blind Phase 3 trial compared two treatment approaches for patients with newly diagnosed, unresectable malignant pleural mesothelioma:

Treatment arm: ADI-PEG20 weekly injections plus pemetrexed/cisplatin chemotherapy

Control arm: Placebo injections plus pemetrexed/cisplatin chemotherapy

The trial enrolled patients at over 50 sites across the United States, Europe, and Australia. Notably, patients were not pre-selected for ASS1 deficiency. The trial included all comers to determine efficacy across the broader mesothelioma population.

Key Results

The trial met its primary endpoint of improved progression-free survival (PFS):

Progression-Free Survival:

• ADI-PEG20 arm: 7.4 months median PFS
• Placebo arm: 5.6 months median PFS
• Hazard ratio: 0.66 (34% reduction in risk of progression)
• P value: statistically significant

Overall Survival:

• Overall survival data is maturing, with final results expected later in 2026
• Early trends suggest potential survival benefit, particularly in ASS1-low patients

Objective Response Rate:

• Higher objective response rates observed in the ADI-PEG20 arm
• Disease control rate also favored the treatment arm

Safety Profile:

• ADI-PEG20 was generally well-tolerated when added to chemotherapy
• Most common adverse events included injection site reactions, fatigue, and transient liver enzyme elevations
• Serious adverse events were comparable between arms

Why This Matters for Mesothelioma Patients

The ATOMIC-Meso results are significant for several reasons:

1. First Successful Targeted Therapy Phase 3

Unlike immunotherapy, which works broadly by activating the immune system, ADI-PEG20 targets a specific metabolic weakness in mesothelioma cells. This represents the first Phase 3 success for a targeted approach specifically designed for mesothelioma biology.

2. Exploits a Common Vulnerability

Approximately 50% of mesotheliomas lack ASS1 expression, making them potentially vulnerable to arginine depletion. This means a substantial portion of patients may benefit from this approach.

3. Novel Mechanism Complements Existing Treatments

ADI-PEG20’s mechanism of action is distinct from chemotherapy and immunotherapy. This opens possibilities for combining arginine depletion with other treatments, potentially creating more effective multi-drug regimens.

4. Well-Tolerated Addition

The safety profile suggests ADI-PEG20 can be added to standard chemotherapy without substantially increasing toxicity, making it a practical option for real-world use.

How ADI-PEG20 Works

Arginine is an essential amino acid that normal cells can produce internally using the enzyme ASS1. However, many mesothelioma cells have silenced or deleted the ASS1 gene, making them entirely dependent on absorbing arginine from the bloodstream.

ADI-PEG20 is a modified form of arginine deiminase, an enzyme that breaks down arginine in the blood. When arginine levels drop:

1. Normal cells adapt by ramping up internal arginine production via ASS1
2. ASS1-deficient cancer cells cannot adapt and experience metabolic stress
3. Tumor cells become sensitized to chemotherapy and may undergo cell death

The “PEG” in ADI-PEG20 refers to polyethylene glycol coating, which extends the drug’s half-life and reduces immune reactions.

Path to FDA Approval

Based on the ATOMIC-Meso results, Polaris Pharmaceuticals has indicated plans to submit a Biologics License Application (BLA) to the FDA. Given that mesothelioma has limited treatment options and the unmet need is substantial, the company may pursue accelerated approval pathways.

Potential approval timeline:

• BLA submission: Expected mid-2026
• FDA decision: Possibly by end of 2026 or early 2027
• If approved, ADI-PEG20 would become the first metabolic therapy approved for mesothelioma

What Patients Should Know

For newly diagnosed patients:

• Ask your oncologist about ADI-PEG20 and whether expanded access may be available
• Consider ASS1 biomarker testing if accessible
• Discuss how this trial result might influence your treatment planning

For patients currently on treatment:

• ADI-PEG20 is not yet approved; access is limited to clinical trials or expanded access
• Monitor updates on FDA approval timeline
• Discuss with your medical team whether ADI-PEG20 might be a future option

Questions to ask your doctor:

• Is my tumor likely to be ASS1-deficient?
• Are there any ongoing ADI-PEG20 trials I might qualify for?
• How might this fit into my treatment sequence?

The Science Behind Arginine Depletion

The concept of metabolic therapy for cancer has gained momentum in recent years. Cancer cells often have altered metabolism compared to normal cells, a phenomenon first described by Otto Warburg nearly a century ago.

ASS1 deficiency in mesothelioma creates what scientists call “arginine auxotrophy.” The cells become auxotrophic (dependent on external supply) for arginine because they’ve lost the ability to make it themselves. This vulnerability can be exploited therapeutically.

Research suggests ASS1 loss occurs early in mesothelioma development and may be related to asbestos-induced epigenetic changes. The gene is often silenced through methylation rather than deletion, raising possibilities for combination strategies with demethylating agents.

Next Steps in Research

The ATOMIC-Meso trial opens several avenues for future research:

Combination with immunotherapy: Given that arginine depletion can affect immune cell function, researchers are studying how to optimally combine ADI-PEG20 with checkpoint inhibitors like nivolumab/ipilimumab.

Biomarker-driven patient selection: Future trials may enrich for ASS1-low patients to maximize response rates and treatment benefit.

Second-line use: ADI-PEG20 may have a role in patients who have progressed on first-line therapy, particularly those whose tumors are ASS1-deficient.

Other arginine-dependent cancers: The ATOMIC-Meso success may accelerate ADI-PEG20 development in other ASS1-deficient cancers, including certain sarcomas and hepatocellular carcinoma.

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