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Arginine deprivation shows promise for malignant pleural mesothelioma

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September 1, 2016

Arginine deprivation with pegylated arginine deiminase may improve PFS and prolong life expectancy in patients with argininosuccinate synthetase 1–deficient malignant pleural mesothelioma, according to the results of a randomized phase 2 trial.

The incidence of malignant pleural mesothelioma has risen in the United States and in Europe. The disease has a median survival from diagnosis of less than 1 year, and few validated treatment options exist.

“To our knowledge, we were the first to show that an exogenous supply of the amino acid arginine is critical for the survival of mesothelioma cell lines displaying loss of the urea cycle and arginine biosynthetic enzyme argininosuccinate synthetase 1 (ASS1),” Peter W. Szlosarek, MD, PhD, clinical senior lecturer at Barts Cancer Institute and Barts and The London School of Medicine and Dentistry, in London, and colleagues wrote. “Various ASS1–negative tumors have been shown to be sensitive to arginine depleters, mycoplasmal-derived pegylated arginine deiminase (ADI-PEG20, Polaris Group) and recombination human arginases, in preclinical studies.”

Szlosarek and colleagues sought to observe the clinical impact of arginine deprivation with ADI-PEG2O in patients with ASS1–deficient malignant pleural mesothelioma.

The Arginine Deiminase and Mesothelioma (ADAM) study included data from 68 patients (median age, 66 years; range, 48-83; 19% women), whom the researchers randomly assigned to best supportive care alone (n = 24) or with weekly ADI-PEG2O (36.8 mg/m2, administered intramuscularly; n = 44).

Treatment with ADI-PEG2O continued for up to 6 months, with patients remaining on study until disease progression, unacceptable toxicity or withdrawal of consent.

Chemotherapy-naive patients were offered chemotherapy after progression; however, the researchers did not allow patients from the best supportive care arm to cross over and receive ADI-PEG2O.

PFS served as the study’s primary endpoint. Secondary endpoints included OS, tumor response rate, safety and quality of life.

Median follow-up was 38 months (range, 2.5-39).

Nineteen patients in the ADI-PEG2O arm (44%) completed two 4-week cycles, and 10 patients (23%) completed at least six cycles.

Twenty-two patients in this arm (50%) had at least nine injections. Eight patients stopped treatment early due to toxicity (n = 4), clinical decision (n = 3) or patient decision (n = 1).

No partial or complete responses occurred; stable disease at 4 months served as the best response observed (ADI-PEG2O, n = 23; best supportive care, n = 2). Twenty-one patients in the ADI-PEG2O arm experienced disease progression by the first 8-week scan.

Median PFS was 3.2 months (interquartile range [IQR], 1.8-5.5) in the ADI-PEG2O arm and 2 months (IQR, 1.8-3.6) among patients assigned best supportive care (HR = 0.56; 95% CI, 0.33-0.96; P = .03).

Ninety-four percent (n = 64) of patients on study died by the end of follow-up. Three patients assigned to best supportive care alone and 10 patients assigned to ADI-PEG2O lived beyond 24 months; four patients in the ADI-PEG2O arm remained alive at the last follow-up.

The researchers used life expectancy measures to quantify OS, due to a crossing of curves in the OS analysis. Mean life expectancy as 15.7 months among patients in the ADI-PEG2O arm and 12.1 months among patients in the best supportive care arm, representing a 3.6-month increase for ADI-PEG2O (95% CI, –1 to 8.1).

A higher proportion of patients in the ADI-PEG2O arm experienced adverse events of any grade (91% vs. 58%; P = .001); however, the researchers did not observe a significant difference in grade 3 or grade 4 events (30% vs. 17%).

Common adverse events in the ADI-PEG2O arm included neutropenia, gastrointestinal issues, fatigue or lethargy, and injection site reactions. Four patients experienced grade 3 anaphylaxis and three patients experienced serum sickness.

Both groups reported similar quality-of-life outcomes; patients in the ADI-PEG2O arm did not report noticeably poorer quality of life in any domain.

A pharmacodynamics analysis showed that ASS1 gene-body methylation corresponded with ASS1 immunohistochemistry. Longer arginine deprivation correlated with better PFS outcomes.

“ADAM is the first biomarker-driven trial showing that arginine deprivation using ADI-PEG2O significantly improves PFS, and possibly OS, in patients with mesothelioma who are deficient in the enzyme ASS1,” Szlosarek and colleagues wrote. “Further cancer studies using tissue, fluid and imaging biomarkers are warranted in tumors auxotrophic for arginine to optimize arginine deprivation as a novel antimetabolic strategy.”

Some aspects of the study design may put the findings into question, Surein Arulananda, MBBS, of Austin Health in Heidelberg, Victoria, Australia, and Thomas John, MBBS, PhD, FRACP, of Austin Health and Olivia Newton-John Cancer Research Institute, wrote in an accompanying editorial.

“The lack of a blinded placebo control group is of concern, especially in a study in which PFS was the primary endpoint,” Arulananda and John wrote. “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 chemonaive 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.”

Molecular studies will likely play an important role in future research into treatment options for malignant pleural mesothelioma.

“In a disease with few therapeutic changes since 2004, suddenly we are faced with the prospect of several novel agents,” Arulananda and John wrote. “In lung and breast cancer, molecular subclassification has enabled personalization of treatment. Given that most mesotheliomas are driven by tumor suppressor gene mutations rather than single oncogenic drivers, this study represents an important milestone in which a biomarker-based study improved survival and may bring the prospect of personalized care to some patients with mesothelioma.” – by Cameron Kelsall

Disclosure: Polaris Group supplied the study drug and provided funding for this research. Szlosarek reports a grant from Polaris Pharma. Other study researchers report employment with Polaris Group. Arulananda and John report no relevant financial disclosures.

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PERSPECTIVE

Marjorie Zauderer

Pegylated arginine deiminase (ADI-PEG2O, Polaris Group) is an interesting new biomarker-driven therapy for mesothelioma. Exploiting the underlying biologic dependencies of mesothelioma, as does ADI-PEG2O, is a vital research approach in trying to break through the current therapeutic plateau in mesothelioma. In the ADAM trial, Szlosarek and colleagues have shown that treatment with ADI-PEG2O was associated with a statistically significant improvement in PFS compared with best supportive care. However, the clinical significance of the modest 1.2-month difference in median PFS remains unclear. Certainly, ADI-PEG2O is an intriguing novel therapy with a clear biomarker (ASS1 deficiency) to enrich response, and I look forward to future studies exploring its role in combination with other therapeutic agents.


Marjorie Zauderer, MD

Memorial Sloan Kettering Cancer Center

Disclosures: Zauderer reports no relevant financial disclosures.