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dc.contributor.authorSzlosarek, Peter W
dc.contributor.authorPhillips, Melissa M
dc.contributor.authorPavlyk, Iuliia
dc.contributor.authorSteele, Jeremy
dc.contributor.authorShamash, Jonathan
dc.contributor.authorSpicer, James
dc.contributor.authorKumar, Sanjeev
dc.contributor.authorPacey, Simon
dc.contributor.authorFeng, Xiaoxing
dc.contributor.authorJohnston, Amanda
dc.contributor.authorBomalaski, John
dc.contributor.authorMoir, Graeme
dc.contributor.authorLau, Kelvin
dc.contributor.authorEllis, Stephen
dc.contributor.authorSheaff, Michael
dc.date.accessioned2020-09-03T23:30:53Z
dc.date.available2020-09-03T23:30:53Z
dc.date.issued2020-11
dc.identifier.issn2666-3643
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/309911
dc.description.abstractINTRODUCTION: 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.
dc.description.sponsorshipNIHR BRC
dc.format.mediumElectronic-eCollection
dc.languageeng
dc.publisherElsevier BV
dc.rightsAll rights reserved
dc.titleExpansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms.
dc.typeArticle
prism.issueIdentifier4
prism.publicationDate2020
prism.publicationNameJTO Clin Res Rep
prism.startingPage100093
prism.volume1
dc.identifier.doi10.17863/CAM.57011
dcterms.dateAccepted2020-08-27
rioxxterms.versionofrecord10.1016/j.jtocrr.2020.100093
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-11
dc.contributor.orcidKumar, Sanjeev [0000-0001-6017-1117]
dc.contributor.orcidPacey, Simon [0000-0002-3303-7577]
dc.identifier.eissn2666-3643
rioxxterms.typeJournal Article/Review
cam.issuedOnline2020-09-03
cam.orpheus.counter66
rioxxterms.freetoread.startdate2023-09-03


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