Arginine Deprivation Therapy May Extend ASS1-Deficient Mesothelioma PFS

Select patients with malignant pleural mesothelioma may benefit from treatment with an arginine-lowering agent

medwireNews: ADAM trial results suggest that arginine deprivation may have potential for the treatment of patients with malignant pleural mesothelioma deficient in argininosuccinate synthetase 1 (ASS1).

The phase II study of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) included 68 advanced disease patients with at least 50% of cells showing low immunohistochemical expression of the tumour suppressor ASS1.

The primary endpoint of progression-free survival (PFS) was a median 3.2 months for the 44 patients randomly assigned to receive weekly intramuscular injections of ADI-PEG20 36.8 mg/m2 plus best supportive care compared with 2.0 months for the 24 patients given only best supportive care.

This gave a significant hazard ratio (HR) for PFS of 0.56, which the researchers describe as a “clinically important effect for patients with advanced cancers with a poor prognosis” and close to the expected HR of 0.60.

The absolute risk of progression at 6 months was 18% versus 0%, but the researchers acknowledge in JAMA Oncology that there were a small number of patients at this time point.

Median overall survival was 11.5 months for the ADI-PEG20 group versus 11.1 months for best supportive care only, with a nonsignificant HR of 0.68, and the researchers note they are unable to explain why the survival curves crossed, except as a possible “spurious feature” of a small trial.

Analysis of restricted mean survival time gave longer life expectancy of 15.7 months for the ADI-PEG20 group versus 12.1 months for the best supportive care only group, a nonsignificant difference of 3.6 months.

However, the researchers note that the benefit of ADI-PEG20, compared with best supportive care, appeared to be greater for patients with more than 75% ASS1 loss than for those with 50–75% deficiency, with HRs for PFS of 0.25 versus 0.72, and OS of 0.25 versus 0.64.

None of the patients achieved a partial or complete radiological response; the best modified RECIST response was stable disease at 4 months in 52% of the ADI-PEG20 group and 22% of the controls.

Safety analysis found no significant difference in the rate of grade 3 or 4 adverse events between the ADI-PEG20 and control groups, at 30% versus 17%, or in patient-reported and observer-reported quality of life.

“ADAM is the first biomarker-driven trial showing that arginine deprivation using ADI-PEG20 significantly improves PFS, and possibly OS, in patients with mesothelioma who are deficient in the enzyme ASS1”, write Peter Szlosarek, from Queen Mary University of London in the UK, and co-workers.

“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.”

Discussing the ADAM trial in an accompanying commentary, Surein Arulananda and Thomas John, both from Austin Health in Heidelberg, Victoria, Australia, say the lack of a blinded placebo control group is “of concern” as it “opens potential reporting and questioning bias of symptoms and quality-of-life measurements”.

They agree that the trial is small but believe the results are in line with the underlying hypothesis that arginine depletion in patients with low expression of the ASS1 biomarker may improve PFS. 

“In a disease with few studies with positive results, we are compelled to accept these data as encouraging while also exercising caution”, the commentators write, acknowledging earlier phase II study findings that have not held up in more rigorous settings.

The commentators conclude: “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.”

References

Szlosarek PW, Steele JP, Nolan L, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininiosuccinate synthetase 1-deficient malignant pleural mesothelioma. A randomized clinical trial. JAMA Oncol 2016; Advance online publication 1 September. doi:10.1001/jamaoncol.2016.3049

Arulananda S, John T. The ADAM trial. Visiting the road less traveled. JAMA Oncol 2016; Advance online publication 1 September. doi:10.1001/jamaoncol.2016.2854

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