ADI-PEG 20 Depletes Arginine to Induce Antitumor Activity

Patients with advanced malignant pleural mesothelioma (MPM) or nonsquamous, non–small cell lung cancer (NSCLC) are often treated with cytotoxic chemotherapy (cisplatin plus pemetrexed), but new therapies are needed as the prognosis remains poor. Many patients with NSCLC and MPM exhibit reduced expression of the argininosuccinate synthetase 1 (ASS1) enzyme, which combines citrulline with aspartate to synthesize arginine. Thus, the tumors are dependent on exogenous arginine for growth. A pegylated arginine deiminase (ADI-PEG 20) has been developed for clinical use and converts arginine to citrulline to deplete arginine in ASS1-deficient tumors. Early preclinical and clinical studies have suggested that ADI-PEG 20 may have activity in multiple tumor types. Beddowes and colleagues performed an open-label phase I dose-escalation study evaluating ADI-PEG 20 in combination with pemetrexed and cisplatin (ADIPemCis) in 9 patients with chemotherapy-naïve ASS1-deficient NSCLC (four patients) or mesothelioma (five patients). The primary objectives were to determine the toxicity profile and recommended phase II dose of ADIPemCis, and secondary objectives included determination of the progression-free survival, overall survival, and pharmacodynamics of ADI-PEG 20 in combination with pemetrexed and cisplatin. ADI-PEG 20 resulted in a rapid and sustained depletion of circulating plasma arginine. Most adverse events were grade 1–2, and no dose-limiting toxicities occurred at the determined recommended phase II dose. In total, 7 of 9 patients (78%) achieved partial responses, and the remaining 2 patients achieved stable disease. The median overall survival was 55.7 weeks and the median progression-free survival was 30.1 weeks, which is notable given the aggressive subtypes of cancer treated in the study. Collectively, these findings indicate that ADIPemCis is well tolerated and has antitumor activity in patients with ASS1-deficient MPM and NSCLC, supporting further investigation in larger clinical trials which are currently under way.

Beddowes E, Spicer J, Chan PY, Khadeir R, Corbacho JG, Repana D, et al. Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers. J Clin Oncol 2017 Apr 7 [Epub ahead of print].

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