Arginine Starvation Boosts OS in Mesothelioma

First-line chemotherapy plus an investigational arginine-depleting agent improved survival in nonepithelioid pleural mesothelioma compared with chemotherapy alone, a randomized trial showed.

For the study’s primary endpoint, median overall survival (OS) reached 9.3 months with the addition of pegylated arginine deiminase (ADI-PEG20; pegargiminase) versus 7.7 months with placebo (HR 0.71, 95% CI 0.55-0.93, P=0.02), reported Peter Szlosarek, MD, PhD, of Queen Mary University of London, and coauthors.

Progression-free survival improved as well when the first-in-class agent was added to pemetrexed (Alimta) and cisplatin chemotherapy (6.2 vs 5.6 months with placebo; HR 0.65, 95% CI 0.46-0.90, P=0.02), according to findings in JAMA Oncology.

However, standard treatment for nonepithelioid pleural mesothelioma has changed since the current trial (ATOMIC-Meso) launched in 2017. As a result of CheckMate 743, combination therapy with ipilimumab (Yervoy) and nivolumab (Opdivo) is now established and approved for the initial treatment of malignant pleural mesothelioma, with the nonepithelioid subgroup helping drive the OS advantage with immunotherapy (18.1 vs 8.8 months with chemotherapy).

Given its more modest improvement in OS compared with that immunotherapy doublet, pegargiminase plus chemotherapy won’t replace that frontline approach for most patients, noted Szlosarek and colleagues.

But “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 wrote. “Pegargiminase-based chemotherapy remains a practical upfront consideration for patients with active autoimmune disease.”

Last November, developer Polaris Group announced it had initiated a rolling biologic license application with the FDA for the arginine-depleting agent pegargiminase in malignant pleural mesothelioma, though no timeline for a decision from the agency was indicated.

In their paper, Szlosarek and coauthors explained that “cancers with loss of argininosuccinate synthetase 1 (ASS1), a tumor suppressor and urea cycle enzyme, are critically dependent on arginine for survival and intrinsically sensitive to amino acid deprivation strategies.” They added that 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.”

Phase I data showed that pegargiminase in combination with chemotherapy was associated with a good safety profile and a high rate of disease control in ASS1-deficient thoracic cancers, and also that the rate of tumoral ASS1 deficiency was three times higher in nonepithelioid versus epithelioid mesothelioma (60% vs 20%).

“It’s truly wonderful to see the research into the arginine starvation of cancer cells come to fruition,” Szlosarek said in a press release. “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.”

From 2017 to 2021, the ATOMIC-Meso trial randomized 249 patients with nonepithelioid pleural mesothelioma 1:1 to pemetrexed and cisplatin plus either weekly pegargiminase or placebo at 43 centers across the globe. Pegargiminase was administered at a dose of 36.8 mg/m² intramuscularly until disease progression or unacceptable toxicity, for up to 24 months.

To be eligible for the trial, patients needed to have a documented history of unresectable and treatment-naive disease, a good performance status, adequate organ function, and an expected survival of at least 3 months.

Average participant age was 69 years, 83% were men, and 93% were white. Most patients were enrolled in Europe (70%), with 21% from North America. Overall, 17% had stage I disease, 11% had stage II disease, 29% had stage III disease, and 23% had stage IV disease, with the rest unknown. Prior surgery was recorded in 15% and radiation therapy in 5%.

Overall response rates between the study and placebo arms were similar (about 14% in each).

In terms of safety, the group receiving pegargiminase had a higher rate of grade 3/4 adverse events (28.8% vs 16.9% in the placebo group). Drug hypersensitivity and skin reactions were seen in 2.4% and 1.6% of patients in the pegargiminase group, respectively, but in none of the placebo patients.