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

Peter W Szlosarek, Melissa M Phillips, Iuliia Pavlyk, Jeremy Steele, Jonathan Shamash, James Spicer, Sanjeev Kumar, Simon Pacey, Xiaoxing Feng, Amanda Johnston, John Bomalaski, Graeme Moir, Kelvin Lau, Stephen Ellis, Michael Sheaff, Peter W Szlosarek, Melissa M Phillips, Iuliia Pavlyk, Jeremy Steele, Jonathan Shamash, James Spicer, Sanjeev Kumar, Simon Pacey, Xiaoxing Feng, Amanda Johnston, John Bomalaski, Graeme Moir, Kelvin Lau, Stephen Ellis, Michael Sheaff

Abstract

Introduction: Pegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed (Pem) 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 of ADI-PEG 20 with Pem and cisplatin (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1-deficient MPM and explore the mechanisms of resistance.

Methods: A total of 32 patients with ASS1-deficient MPM (11 epithelioid; 10 biphasic;11 sarcomatoid) who were chemonaive received weekly intramuscular pegargiminase (36 mg/m2) with Pem (500 mg/m2) and cisplatin (75 mg/m2) intravenously, every 3 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 the mechanisms of resistance to pegargiminase.

Results: The treatment was well tolerated. Most adverse events were of grade 1/2, whereas four nonhematologic grade 3/4 adverse events related to pegargiminase were reversible. Plasma arginine decreased whereas citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in 31 assessed patients was 93.5% (n = 29 of 31; 95% confidence interval [CI]: 78.6%-99.2%), with a partial response rate of 35.5% (n = 11 of 31; 95% CI: 19.2%-54.6%). The median progression-free and overall survivals were 5.6 (95% CI: 4.0-6.0) and 10.1 (95% CI: 6.1-11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n = 6; p = 0.0255) and patchy tumoral ASS1 reexpression (n = 2 of 6). In addition, we observed increased tumoral programmed death-ligand 1-an ADI-PEG 20 inducible gene-and the formation of CD3-positive T lymphocyte aggregates on disease progression (n = 2 of 5).

Conclusions: The dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.govNCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and-along with the tumor immune microenvironment-warrants further study to optimize arginine deprivation for the treatment of mesothelioma.

Keywords: ADIPemCis; ASS1; Arginine; Macrophages; Mesothelioma.

© 2020 The Authors.

Figures

Figure 1
Figure 1
CONSORT diagram. AE, adverse event; ASS1, argininosuccinate synthetase 1; MPM, malignant pleural mesothelioma; SARC, sarcomatoid.
Figure 2
Figure 2
Pharmacodynamics and response. (A) Pharmacodynamics of arginine and citrulline in patients treated with ADIPemCis. Serum arginine and citrulline are revealed by week of treatment (mean ± SEM). (B) Serum levels of anti–ADI-PEG 20 antibodies in all patients by week of ADIPemCis (mean ± SEM). (C) Waterfall plot of response by modified RECIST to ADIPemCis. (D) Spider plots revealing response duration to ADIPemCis. Ab, antibody; ADI, arginine deiminase; ADIPemCis, ADI-PEG 20 with pemetrexed and cisplatin; B, biphasic; E, epithelioid; PEG, PEGylated; RECIST, Response Evaluation Criteria in Solid Tumors; S, sarcomatoid.
Figure 3
Figure 3
Survival outcomes. (A) PFS by MPM histologic subtype. (B) Kaplan-Meier survival estimates by MPM histologic subtype. CI, confidence interval; MPM, malignant pleural mesothelioma; OS, overall survival; PFS, progression-free survival.
Figure 4
Figure 4
Baseline and progression biopsies analyzed for ASS1 and CD68. (A) Tumoral ASS1 reexpression at progression noted in two patients (×200 magnification; epithelioid and sarcomatoid). (B) Increase in CD68pos macrophages at disease progression in ASS1–deficient tumoral regions (n = 6; p = 0.0255; paired t test); two epithelioid, one sarcomatoid, and three biphasic tumors (N.B. one epithelioid tumor was reclassified as biphasic on operative rebiopsy). (C) Representative serial sections of epithelioid, biphasic, and sarcomatoid MPM at baseline and progression stained for ASS1 and CD68, revealing the increase in ASS1posCD68pos macrophages at progression (×200 magnification). ASS1, argininosuccinate synthetase 1; MPM, malignant pleural mesothelioma; N.B., nota bene; pos, positive.
Figure 5
Figure 5
Baseline and progression biopsies analyzed for PD-L1 and CD3 modulation of PD-L1 expression and CD3pos lymphocytes in two patients at progression (×200 magnification; epithelioid and biphasic). PD-L1 increased from 10% to 30% (in epithelioid disease) and 0% to 5% (in biphasic disease) with clustering of CD3pos T cells in both patients at progression. PD-L1, programmed death-ligand 1; pos, positive.

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