Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1–Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms

Abstract

INTRODUCTION: Pegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed cytotoxicity in argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). We conducted a phase 1 dose-expansion study at the recommended phase 2 dose (RP2D) of ADI-PEG 20 with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1-deficient MPM and explore mechanisms of resistance.

METHODS: Thirty-two chemonaïve patients with ASS1-deficient MPM (11 epithelioid;10 biphasic;11 sarcomatoid) received weekly intramuscular pegargiminase (36 mg/m2) with Pem (500 mg/m2) and Cis (75 mg/m2) intravenously, every three weeks (six cycles maximum). Maintenance pegargiminase was permitted until disease progression or withdrawal. Safety, pharmacodynamics, immunogenicity, and efficacy were determined. Biopsies were performed in progressing patients to explore mechanisms of resistance to pegargiminase.

RESULTS: Treatment was well-tolerated. Most adverse events (AEs) were Grade 1/2, while four non-hematologic Grade 3/4 AEs related to pegargiminase, were reversible. Plasma arginine decreased while citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in thirty-one evaluable patients was 93.5% (n=29/31; 95% CI 78.6% - 99.2%), with a partial response rate of 35.5 % (n=11/31; 95% CI 19.2% - 54.6%). The median progression-free and overall survivals were 5.6 (95% CI, 4.0 to 6.0) and 10.1 (95% CI, 6.1 to 11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n=6; p=0.0255) and patchy tumoral ASS1 re-expression (n=2/6). Additionally, we observed increased tumoral PD-L1 – an ADI-PEG20 inducible gene – and the formation of CD3-positive T lymphocyte aggregates on disease progression (n=2/5).

CONCLUSIONS: The dose-expansion of ADIPemCis confirmed high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (clinicaltrials.gov NCT02709512). Notably, resistance to pegargiminase correlated significantly with macrophage recruitment and – along with the tumor immune microenvironment – warrants further study to optimize arginine deprivation for the treatment of mesothelioma.