ADI PEG20

Overview

ADI-PEG20 (pegargiminase; also known as Hepacid, Melanocid) is a pegylated arginine deiminase that systemically depletes extracellular arginine. Many tumors (often those lacking argininosuccinate synthetase 1, ASS1) are arginine-auxotrophic and may be vulnerable to pharmacologic arginine deprivation. The most mature clinical data are from the phase 2/3 ATOMIC-Meso trial in nonepithelioid malignant pleural mesothelioma, where adding pegargiminase to first-line pemetrexed/platinum chemotherapy improved overall and progression‑free survival versus placebo. In contrast, pegargiminase monotherapy did not improve survival in a large phase 3 second‑line hepatocellular carcinoma (HCC) study. (jamanetwork.com)

Mechanism of action

• Target/process: ADI-PEG20 enzymatically converts arginine to citrulline and ammonia, depleting circulating arginine. Normal cells can resynthesize arginine from citrulline via ASS1, but many cancers silence ASS1, creating selective vulnerability. Resistance can emerge through ASS1 re‑expression and microenvironmental protein scavenging pathways. (aacrjournals.org)
• Rationale for combinations: Arginine deprivation rewires pyrimidine metabolism and can sensitize ASS1‑deficient tumors to antifolates (e.g., pemetrexed); preclinical work also supports combinations with taxanes/gemcitabine and autophagy inhibitors. (jamanetwork.com)

Efficacy

• Malignant pleural mesothelioma (nonepithelioid subtypes; first line, with chemotherapy)
• ATOMIC‑Meso (phase 2/3, double‑blind, n=249): Pegargiminase + pemetrexed/platinum vs placebo + pemetrexed/platinum.
  • Overall survival: median 9.3 vs 7.7 months; HR 0.71 (95% CI 0.55–0.93; P=0.02).
  • Progression‑free survival: median 6.2 vs 5.6 months; HR 0.65 (95% CI 0.46–0.90; P=0.02).
  • Three‑year survival was increased (authors note a fourfold improvement). (jamanetwork.com)

• Prior phase 1/expansion (ASS1‑deficient thoracic cancers/mesothelioma): high disease control (93.5%) and partial response rate 35.5% with ADI‑PEG20 + pemetrexed + cisplatin; recommended weekly dose 36 mg/m². (pubmed.ncbi.nlm.nih.gov)

• Hepatocellular carcinoma (second line, monotherapy)

• Phase 3, randomized, n=635: ADI‑PEG20 vs placebo; no OS benefit (median 7.8 vs 7.4 months; HR 1.02; P=0.88). Post hoc analyses suggested longer survival with more prolonged arginine depletion, but primary endpoint was negative. Earlier small studies showed disease stabilization without objective responses. (pubmed.ncbi.nlm.nih.gov)

• Melanoma (phase 1/2, monotherapy)

• No objective responses; some patients achieved stable disease; toxicities mostly grade 1–2. (pubmed.ncbi.nlm.nih.gov)

• Other tumor types

• Early-phase clinical exploration includes ASS1‑deficient recurrent high‑grade glioma (stable disease in 80% in a small phase 1 cohort with ADI‑PEG20 + pemetrexed/cisplatin); additional trials in lung and sarcoma settings are ongoing or early‑stage. Preclinical data support activity in ASS1‑deficient ovarian cancers (including SCCOHT). (pubmed.ncbi.nlm.nih.gov)

Safety

• In ATOMIC‑Meso, adding pegargiminase to chemotherapy was generally well tolerated; grade 3–4 adverse events occurred in 28.8% vs 16.9% with placebo. Reported events included drug hypersensitivity (2.4%) and skin reactions (1.6%) in the experimental arm; no new safety signals were identified. Weekly intramuscular dosing (36.8 mg/m²) was continued until progression/toxicity or up to 24 months. (jamanetwork.com)
• In second‑line HCC monotherapy, common adverse events were fatigue and decreased appetite (<5% grade ≥3); rare grade ≥3 anaphylactic reactions occurred. Immunogenicity (anti‑ADI antibodies) and injection‑site reactions are known risks. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Pegargiminase plus first‑line chemotherapy in nonepithelioid pleural mesothelioma (ATOMIC‑Meso, JAMA Oncology, 2024). (jamanetwork.com)
• Phase 3 ADI‑PEG20 monotherapy in second‑line HCC (Annals of Oncology, 2018). (pubmed.ncbi.nlm.nih.gov)
• Phase 1/expansion ADI‑PEG20 + pemetrexed/cisplatin in ASS1‑deficient thoracic cancers/mesothelioma. (pubmed.ncbi.nlm.nih.gov)
• Mechanistic reviews and resistance biology in ASS1‑deficient cancers (AACR journals; MCT/CCR). (aacrjournals.org)
• Preclinical data in ASS1‑deficient ovarian cancer models. (pubmed.ncbi.nlm.nih.gov)

Notes: Pegargiminase remains investigational. Responses and benefit have been most evident when combined with cytotoxic chemotherapy in ASS1‑low tumors, particularly nonepithelioid mesothelioma; single‑agent activity has been limited in later‑line HCC and melanoma. Biomarker selection (ASS1 loss) and combination strategies appear central to ongoing development. (jamanetwork.com)

Last updated: Oct 2025