Micrograph of Pleural Mesothelioma with tubule/papillary pattern.
Credit: OGphoto/Getty Images

Results of the pivotal ATOMIC-Meso trial show that adding the arginine-depleting agent pegargiminase (ADI-PEG20) to standard platinum and pemetrexed chemotherapy significantly improves survival in patients with nonepithelioid pleural mesothelioma.

The study, led by Professor Peter Szlosarek at Queen Mary University of London and sponsored by Polaris Pharmaceuticals, marks a significant a breakthrough in the treatment of this rare and often rapidly fatal cancer that currently has limited therapeutic options.

“The pegargiminase-pemetrexed-platinum triplet was safe and validates arginine deprivation as a novel therapeutic antimetabolite strategy for patients with nonepithelioid mesothelioma,” write Szlosarek and co-authors in JAMA Oncology.

The trial arose from more than 20 years of research by Szlosarek which began with him investigating argininosuccinate synthetase 1 (ASS1), a tumor suppressor and urea cycle enzyme that catalyzes the condensation of the amino acids citrulline and aspartate to form argininosuccinate, the immediate precursor of arginine.

He discovered that a high proportion of mesothelioma cell lines were deficient for ASS1 and could be readily killed by removing arginine from the culture medium. The cells were critically dependent on arginine for survival and therefore intrinsically sensitive to amino acid deprivation strategies as they were unable to manufacture it themselves.

Preclinical studies showed that ADI-PEG20 degrades arginine into citrulline and ammonia and triggers cytotoxicity in multiple ASS1-deficient cancers, while phase 1 and 2 studies have shown its efficacy as monotherapy and in combination with standard chemotherapy for mesothelioma, particularly in patients with the nonepithelioid subtype which has a 3-fold higher rate of tumoral ASS1 deficiency than the epithelioid subtype (60% vs 20%).

To investigate further, Szlosarek et al launched the phase 3 ATOMIC-meso study in 2018. They recruited 249 patients (mean age 69.5 years, 83% men) with chemotherapy-naïve, nonresectable, nonepithelioid pleural mesothelioma from 43 centers in five countries.

Participants were randomly assigned to receive weekly intramuscular ADI-PEG20 (36.8 mg/m2) or placebo for up to 2 years in addition to intravenous pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (AUC 5) chemotherapy every 3 weeks for up to six cycles.

The researchers report that patients given ADI-PEG20 had a significant 29% lower risk for death during follow-up than those given placebo. Median overall survival was 9.3 months with ADI-PEG20-chemotherapy versus 7.7 months with placebo-chemotherapy.

Malignant pleural mesothelioma has among the lowest 5-year survival rates of any solid cancer, estimated at 5% to 10%, and Szlosarek told Inside Precision Medicine that the near 30% reduction in the risk for death represents “a major extension of life,” for these patients.

He also notes that survival could potentially be improved further with the addition of immunotherapy.

The survival curves for the two arms diverged early, at around 3 months, and remained separate throughout the course of the study. By 36 months, when the number of deaths appeared to plateau, the survival rate was almost four-fold higher in the ADI-PEG20 group than in the placebo group (11.9 vs 3.3%).

The median progression-free survival time was also significantly longer with ADI-PEG20 than with placebo, at 6.2 months and 5.6 months, respectively, which corresponded to a 35% lower risk for disease progression or death in favor of ADI-PEG20.

The positive results meant that the trial was stopped early after the second interim analysis on the recommendation of the data and safety monitoring board, in consultation with the US Food and Drug Administration.

In addition, approximately 5% of patients receiving ADI-PEG20 completed 2 years of weekly therapy. This highlights “a subgroup of patients displaying exquisite sensitivity to arginine depletion that warrants further molecular characterization,” the researchers remark. By comparison, none of the patients in the placebo arm reached this milestone.

ADI-PEG20-based chemotherapy was well tolerated with no new safety signals. Szlosarek explained that arginine is a non-essential amino acid in normal human cells, which reduces the risk for systemic toxicity. “The only side effects are allergic in nature ie a rash and occasionally anaphylactoid reactions and also low bloods counts in around 10% of patients,” he said.

The authors conclude: “While not replacing frontline immunotherapy with the more modest survival improvement in the ATOMIC-Meso study, pegargiminase nonetheless provides an incremental chemotherapeutic advance for patients with essentially chemotherapy-refractory nonepithelioid disease.”

“Thus, deployment of pegargiminase would be envisaged second-line alongside platinum-pemetrexed.”

They also say that ADI-PEG20 “warrants additional studies in arginine-dependent cancers with poor survival outcomes.”

Indeed, there is currently a global phase 3 trial ongoing in sarcoma and a phase 1/2 trial in patients with glioblastoma multiforme, both of which are arginine-dependent tumors.

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