Pegylated arginine deiminase acts against ASS1-deficient thoracic tumors
medwireNews: Phase I trial data show that pegylated arginine deiminase (ADI-PEG 20) is well tolerated, with a high response rate, when used in combination with cisplatin and pemetrexed to treat patients with argininosuccinate synthetase 1 (ASS1)-deficient thoracic cancers.
Overall, nine chemotherapy-naïve patients with ASS1-deficient advanced pleural mesothelioma (MPM) or stage IIIB or IV nonsquamous non-small-cell lung cancer (NSCLC) were treated with ADI-PEG 20, which depletes essential amino acid levels in ASS1–negative tumors by converting arginine to citrulline and ammonia.
They received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2 until disease progression or withdrawal, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2, which were given every 3 weeks for a maximum of six cycles.
During a median treatment period of 31.0 weeks for the five patients with MPM and 23.5 weeks for the four patients with NSCLC, there were 38 adverse events, most commonly fatigue, nausea, vomiting, oropharyngeal toxicity (stomatitis, mucositis, and oral candidiasis), and rash.
Of these, the vast majority (87%) were grade 1 or 2, none were dose-limiting, and just nine (all grade 1 or 2) were deemed possibly or probably related to ADI-PEG 20.
In addition, circulating plasma arginine concentrations declined rapidly during the first 2 weeks of treatment in all patients and remained suppressed at approximately 30% of baseline levels throughout the 18 weeks of triplet therapy.
Correspondingly, plasma citrulline levels increased rapidly and remained elevated during the same dosing period.
The team also measured antidrug antibody levels, and observed a gradual increase that levelled off at about 10-3 by week 10, and remained below 10-4 by week 18.
According to the Response Evaluation Criteria in Solid Tumors, all patients had stable disease, with seven (78%) achieving a partial response that was not dose-dependent. Median overall survival was 55.7 weeks, while median progression-free survival was 30.1 weeks.
Peter Szlosarek (Queen Mary University of London, UK) and study co-authors note that these outcomes “are within the range expected for platinum and pemetrexed doublets but with less aggressive cancers.”
They conclude in the Journal of Clinical Oncologythat their findings “are consistent with preclinical data that support a synergistic interaction of platinum-based and antifolate chemotherapy with concomitant arginine depletion in patients selected for tumors deficient in ASS1.”
The researchers add that further studies are warranted and recommend a phase II dose of weekly, intramuscular ADI-PEG 20 36 mg/m2 plus 3-weekly intravenous cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 be used.
In an accompanying editorial, James Chung-Man Ho and Sze-Kwan Lam, both from The University of Hong Kong in the People’s Republic of China, agree that the “encouraging results” should be confirmed in large-scale randomized controlled trials.
“Future development of ADI-PEG 20 as an arginine depletor with or without systemic chemotherapy will add to the growing armamentarium in the fight against advanced lung cancer and MPM,” they write.
By Laura Cowen
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