Patients with malignant mesothelioma whose tumor cells are unable to synthesize the amino acid arginine show marked improvements in progression-free survival when treated with agents that deplete arginine supply, according to the results of a Phase 2 clinical trial published in JAMA Oncology.
The study, “Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1–Deficient Malignant Pleural Mesothelioma,” was led by researchers at the Barts Cancer Institute, and reveals that arginine-depleting agents may be a promising therapeutic approach in certain malignant mesothelioma patients.
Arginine is an amino acid essential for normal cell metabolism. It is not only required of proteins and nitric oxide, but also contributes to the production of other amino acids, such as proline and glutamate. Usually, cells can synthesize arginine through the protein argininosuccinate synthetase 1 (ASS1) and do not require an extracellular supply of arginine.
But in some cancers, it is more advantageous to shut down the expression of this protein and use the arginine precursor to synthesize nucleic acids (DNA molecules) instead. This phenomenon, which renders the tumor more aggressive but dependent on an extracellular source of arginine, has been observed in about 63 percent of mesotheliomas.
The researchers had already shown that arginine supply was required for the survival of mesothelioma cells displaying loss of ASS1. In this study, they sought to find out whether administering an arginine depleter, called mycoplamal-derived pegylated arginine deiminase (ADI-PEG20), could improve progression-free survival (PFS) in mesothelioma patients.
The ADAM Phase 2 study (NCT01279967) included 68 mesothelioma patients with a median age 66 who were randomly assigned to best supportive care with or without weekly intramuscular ADI-PEG20 36.8 mg/m2. Those assigned to ADI-PEG20 were treated for up to six months and remained in the study until their disease progressed; an unacceptable toxicity; or withdrawal.
The study’s primary endpoint was PFS, and secondary endpoints included overall survival (OS), tumor response rate, safety and quality of life.
After a median follow-up of 38 months, the median PFS for ADI-PEG20 was of 3.2 months, compared to the two months observed in the best supportive care group. No partial or completes responses occurred, with stable disease at four months serving as best response observed.
Results showed that 52 percent of patients in the ADI-PEG20 group showed stable disease at four months, compared to 22 percent in the best supportive care group.
The researchers used life expectancy measures to quantify overall survival, since the curves in the OS analysis crossed. Among patients in the ADI-PEG20 group, the mean life expectancy was of 15.7 months, 3.6 months higher than in the best supportive care group.
It is important to note that although a higher proportion of patients in the ADI-PEG20 group experienced adverse events of any grade, the most common being neutropenia, gastrointestinal issues, fatigue, and injection site reactions, they were not more likely to experience grade 3 or grade 4 events than those on the best supportive care group.
This is the first study that shows that arginine deprivation can improve the outcomes of patients with malignant mesothelioma who are deficient for ASS1. However, Surein Arulananda, MBBS, of Austin Health in Victoria, Australia, and Thomas John, MBBS, PhD, FRACP, of Austin Health and the Olivia Newton-John Cancer Research Institute, believe the study design may question the study findings.
“The lack of a blinded placebo control group is of concern, especially in a study in which PFS was the primary endpoint,” they wrote in an accompanying editorial. “Patients and their clinicians watching and waiting for disease progression are more likely to react to symptomatic change than those receiving an active treatment, especially in the chemo-naive [patients who have never received chemotherapy] cohort in which there is an accepted standard of care.
“Although the authors explain that it was considered unjustified to subject patients to weekly placebo intramuscular injections, this opens potential reporting and questioning bias of symptoms and quality-of-life measurements,” they wrote.
“Whether arginine depletion represents a novel therapeutic strategy in mesothelioma remains to be confirmed; however, there is an encouraging signal deserving of further study,” Arulananda and John wrote.