Combining an arginine-depleting agent with chemotherapy has improved survival in patients with mesothelioma and also holds promise as a strategy for other cancers, an Australian and international research team report.

In a phase 3 trial in 249 patients with nonepithelioid pleural mesothelioma, pegargiminase-chemotherapy increased significantly the median overall survival by 1.6 months and quadrupled the survival at 36 months compared to placebo-chemotherapy, according to results published in JAMA Oncology. (link here).

Patients taking pegargiminase had a 29% lower risk of death and a 35% lower risk of progression versus those given a placebo (HR of 0.71 and 0.65, respectively), according to researchers including Australian oncologists Professor Ken O’Byrne and Professor Anna Nowak.

The ATOMIC-meso trial, sponsored by Polaris Pharmaceuticals and involving Australian and international researchers, included patients (mean age 69.5 years; 83% male) with non-epithelioid pleural mesothelioma who were randomised to receive treatment with pegargiminase-chemotherapy or placebo-chemotherapy for up to two years.

Results showed median overall survival of 9.3 months with pegargiminase-chemotherapy as compared with 7.7 months with placebo-chemotherapy, giving a hazard ratio (HR) for death of 0.71 (95% CI 0.55-0.93; p=0.02).

Median PFS was 6.2 months in the pegargiminase arm versus 5.6 months in the control group (HR 0.65; 95% CI, 0.46-0.90; p =0.02).

Notably, investigators reported that a therapeutic plateau had been reached by 36 months, at which point up to four-time more patients were alive in the pegargiminase versus placebo group (11.9% vs 3.3%, respectively).

Disease control (objective response rate and stable disease) at 12-weeks was numerically greater in the pegargiminase group (85%) than in the placebo group (76%) but did not reach statistical significant (p= 0.15), according to the paper.

On tolerability, Grade 3 to 4 adverse events occurred in 29% of patients taking pegargiminase and in 17% taking placebo. There were two deaths potentially related to the drug (sudden death, sepsis) and one to placebo (sepsis), according to the paper.

Importantly, immune checkpoint blockade has recently become the first-line treatment of choice for mesothelioma over platinum-based chemotherapy. As such, the researchers envisage that pegargiminase would a second-line option in the treatment pathway, alongside chemotherapy.

“However, pegargiminase-based chemotherapy remains a practical up-front consideration for patients with active autoimmune disease,” they stressed.

Nevertheless, the emerging use of immunotherapy was cited as a key limitation of the findings, given that “almost twice as many patients in the pegargiminase-chemotherapy arm accessed ipilimumab and nivolumab immunotherapy (16.8% vs 8.9%) compared to the placebo-chemotherapy arm, potentially affecting long-term survival”.

The authors concluded that the trial “demonstrated significantly improved OS with pegargiminase-chemotherapy compared with chemotherapy alone”. Findings also showed the combination to be safe, and validated arginine deprivation as a new antimetabolite strategy nonepithelioid mesothelioma, they added.

“It’s truly wonderful to see the research into the arginine starvation of cancer cells come to fruition,” said lead author Professor Peter Szlosarek, Centre for Cancer Cell and Molecular Biology in Barts Cancer Institute. “This discovery is something I have been driving from its earliest stages in the lab, with a new treatment, ADI-PEG20, now improving patient lives affected by mesothelioma”.

Co-author Professor Anna Nowak, Deputy Vice-Chancellor (Research) of the University of Western Australia said results of the trial were promising.

She said the he premise of the new drug (ADI-PEG20) was simple; it starved the tumour by cutting off its food supply.

Cancers with loss of argininosuccinate synthetase 1 (ASS1), a tumour suppressor and urea cycle enzyme, are critically dependent on arginine for survival and intrinsically sensitive to amino acid deprivation strategies, the study investigators noted. Pegylated arginine deiminase (ADI-PEG20; pegargiminase) degrades arginine into citrulline and ammonia and triggers cytotoxicity in multiple ASS1-silenced cancers preclinically, with evidence of single-agent activity in the clinic.

“This innovative approach marks the first successful use of a metabolism-based treatment for mesothelioma,” Professor Nowak said.