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

Our plain-English summary of Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms, by P.W. Szlosarek, M.M. Phillips, I. Pavlyk, et al (JTO Clinical and Research Reports, 2020).

The study

• Authors: P.W. Szlosarek, M.M. Phillips, I. Pavlyk, J. Steele, J. Shamash, J. Spicer, S. Kumar, S. Pacey, X. Feng, A. Johnston, J. Bomalaski, G. Moir, K. Lau, S. Ellis, M. Sheaff
• Journal: JTO Clinical and Research Reports
• Published: 2020;1(4):100093
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2020 The Authors.

In plain English

This phase 1 study tested pegargiminase (ADI-PEG 20), which breaks down arginine, plus pemetrexed and cisplatin. From February 2015 to May 2016 it enrolled 32 patients, none previously given chemotherapy, with malignant pleural mesothelioma lacking the enzyme ASS1 (11 epithelioid, 10 biphasic, 11 sarcomatoid). Side effects occurred in 24 of 32 patients; 116 of 137 events were grade 1 or 2. Four reversible grade 3 or 4 non-blood side effects were linked to pegargiminase. Of these, posterior reversible encephalopathy syndrome was the only serious grade 3 toxicity attributed to pegargiminase maintenance therapy; the patient recovered completely. Of 31 patients assessed, disease was controlled in 29 (93.5%; 95% confidence interval 78.6% to 99.2%) and tumors partly shrank in 11 (35.5%; 19.2% to 54.6%). Median progression-free survival was 5.6 months and median overall survival 10.1 months (95% confidence intervals 4.0 to 6.0 and 6.1 to 11.1). Repeat biopsies from 6 progressing patients showed a statistically significant increase in immune cells called macrophages. Two showed ASS1 reappearing in some tumor cells. The authors concluded the combination was safe and active; a phase 3 trial was underway.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicenter phase 1 dose-expansion clinical trial of a drug combination, with exploratory tumor biopsies at disease progression
• Who was studied: 32 adults with ASS1-deficient advanced malignant pleural mesothelioma (11 epithelioid, 10 biphasic, 11 sarcomatoid) who had not previously received chemotherapy. They were selected from 93 patients screened, with enrollment from February 2015 to May 2016 at UK centers. 31 patients were included in the efficacy analysis.
• Exposure: Drug treatment, not asbestos exposure. Patients received pegargiminase (ADI-PEG 20) 36 mg/m2 weekly by intramuscular injection, plus cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks, for up to six cycles (18 weeks). Maintenance pegargiminase was allowed until disease progression or withdrawal.
• Main results:
  • Adverse events were reported in 24 of 32 patients (75%).
  • Of 137 adverse events, 116 (84.7%) were grade 1 or 2.
  • There were four non-blood grade 3 or 4 adverse events related to pegargiminase: increased alkaline phosphatase, hyperuricemia, skin rash, and posterior reversible encephalopathy syndrome.
  • The authors described the grade 3 or 4 events as manageable and reversible.
  • The authors identified only one serious grade 3 toxicity attributed to pegargiminase maintenance therapy, posterior reversible encephalopathy syndrome. It occurred in a patient with sarcomatoid mesothelioma, who recovered completely.
  • In treated patients, plasma arginine fell and plasma citrulline rose.
  • Among 31 assessed patients, the disease control rate was 93.5% (29 of 31; 95% CI 78.6% to 99.2%).
  • Among 31 assessed patients, the partial response rate was 35.5% (11 of 31; 95% CI 19.2% to 54.6%).
  • For the whole cohort, median progression-free survival was 5.6 months (95% CI 4.0 to 6.0) and median overall survival was 10.1 months (95% CI 6.1 to 11.1).
  • Later, 11 of 31 patients (35.5%) received pembrolizumab, and one of them (9.1%) achieved stable disease.
  • In repeat biopsies at progression, ASS1 levels rose in some tumor cells in two of six patients (epithelioid and sarcomatoid disease).
  • In the 6 patients with repeat biopsies, CD68-positive, ASS1-positive macrophages increased significantly at progression in ASS1-negative tumor areas (p = 0.0255).
  • In two of five patients with available tissue, tumor PD-L1 expression increased and CD3-positive T lymphocytes clustered within tumor cell islands.
• The authors' conclusion: The authors concluded that the pegargiminase, pemetrexed and cisplatin combination was safe and active in this expansion cohort of patients with aggressive ASS1-deficient mesothelioma, and that a phase 3 trial was underway.
• Limitations the authors state:
  • No formal sample size calculation was made.
  • Limited baseline tissue restricted the biopsy analyses.
  • The PD-L1 and CD3 analysis in five biopsies was too limited to draw firm conclusions.
  • Resistance caused by neutralizing antibodies against the drug could not be fully excluded.

Topics

Medical terms in this study, explained in our Lexicon: Pegargiminase (ADI-PEG20), Pemetrexed (Alimta), Cisplatin, Mesothelioma, Pleural Mesothelioma, Epithelioid, Biphasic Mesothelioma, Sarcomatoid.

Related studies

• Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers — E. Beddowes, J. Spicer, et al. (2017)
• Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase — T.A. Szyszko, J.T. Dunn, et al. (2022)
• A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma — M.M. Phillips, I. Pavlyk, et al. (2023)
• Loss of Argininosuccinate Synthetase-1 (ASS1) Occurs in Esophageal Adenocarcinoma and Represents a Promising Biomarker for Therapy with Pegargiminase — K. Knipper, S.I. Lyu, et al. (2025)
• Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma — O. Arrieta, W. Muñoz-Montaño, et al. (2021)
• Bevacizumab plus cisplatin/pemetrexed then bevacizumab alone for unresectable malignant pleural mesothelioma: A Japanese safety study — T. Nakano, K. Kuribayashi, et al. (2021)

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